Genetic Developmental and Epileptic Encephalopathy

Genetic MONDO:0100062 Pathograph 79 Show in embeddings browser Epilepsy Neurodevelopmental Disorder

Genetic developmental and epileptic encephalopathy (DEE) is a broad, genetically heterogeneous umbrella group of severe early-onset epilepsy syndromes in which pathogenic variants in any of more than nine hundred genes cause both refractory seizures and developmental impairment that exceeds what would be expected from the epileptic activity alone. Under the 2017 ILAE classification, "developmental and epileptic encephalopathy" recognizes two overlapping but separable contributors to the encephalopathy: a developmental component intrinsic to the underlying genetic etiology, and an epileptic component in which frequent seizures and epileptiform activity themselves worsen cognitive and behavioral outcome. Individual monogenic forms (numbered DEE1-DEE121+ in OMIM/MONDO, e.g. SCN1A-related Dravet syndrome, STXBP1 encephalopathy, KCNQ2-DEE, SCN2A-DEE, SCN8A-DEE, CDKL5 deficiency disorder, SYNGAP1-related DEE) are curated as their own dismech entries; this entry captures the mechanisms, phenotypic core, and clinical approach shared across the umbrella group. Modelling note: this is deliberately curated as an umbrella Disease rather than a Grouping over the gene-specific entries. A Grouping cannot carry pathophysiology, and the shared two-component DEE mechanism - the very thing that makes DEE a coherent concept - is the primary content here. The existing Epilepsy and Diabetes_Mellitus entries set the same precedent. Gene-specific detail (variant spectra, gene-specific EEG signatures, per-gene natural history and treatment response) belongs on the child entries, not here. Numbered forms that do not yet have a dismech entry of their own are enumerated in has_subtypes instead, each anchored to its MONDO term and to its causal gene, so that the concept and the gene are both recorded until a full entry exists. A subtype row is therefore a placeholder for a child entry, not a substitute for one.

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Inheritance

Autosomal dominant inheritance HP:0000006

Genetic DEE is most commonly regarded as a de novo dominant disease class, and the highest-prevalence individual entities (SCN1A, SCN2A, STXBP1, KCNQ2, SCN8A) are indeed de novo autosomal dominant, so affected children typically have unaffected parents. Parental germline mosaicism gives a small but non-zero sibling recurrence risk. Note that this reflects the distribution of *cases*: counted by *gene*, more DEE genes follow autosomal recessive than dominant inheritance.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:39237642 SUPPORT Human Clinical

"Genetic DEEs are most commonly regarded as de novo dominant disorders ; however, more DEE genes follow autosomal recessive than dominant inheritance, with a small number following X-linked or mitochondrial inheritance patterns"

Establishes de novo dominant inheritance as the prevailing mode while making explicit the gene-count versus case-count distinction that this description records.

PMID:39613335 SUPPORT Human Clinical

"Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance."

Quantifies the case-level distribution of inheritance modes across 1568 molecularly diagnosed genetic DEE patients, confirming autosomal dominant as the predominant mode by case count.

PMID:39237642 SUPPORT Human Clinical

"Parental mosaicism places parents at an increased risk of having a second child with a DEE, as a small population of their sperm or ova carry the pathogenic variant."

Supports the non-zero sibling recurrence risk stated in this description, which would otherwise be an uncited claim.

Autosomal recessive inheritance HP:0000007

Counted by gene rather than by case, more DEE genes follow autosomal recessive than dominant inheritance. Biallelic forms are individually rarer but collectively numerous, and are enriched in consanguineous families and among metabolic and glycosylation-pathway DEE genes.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:39237642 SUPPORT Human Clinical

"more DEE genes follow autosomal recessive than dominant inheritance"

Directly supports autosomal recessive inheritance as the most common mode when DEE genes are counted individually.

PMID:39613335 SUPPORT Human Clinical

"6% (n=90) in genes with autosomal recessive inheritance."

Quantifies the autosomal recessive share of molecularly diagnosed genetic DEE cases, contrasting with its larger share of the gene count.

X-linked inheritance HP:0001417

A small number of genetic DEE genes are X-linked, including CDKL5, PCDH19, and ARX, together accounting for 17% of molecularly diagnosed cases. X-linked disease and mosaicism complicate cellular targeting for emerging gene therapies. PCDH19 departs from the usual X-linked pattern in that heterozygous females are affected while hemizygous males are typically unaffected transmitting carriers; that observation is recorded in the PCDH19 genetic entry, while its mechanistic explanation (cellular interference) is left to the PCDH19 Clustering Epilepsy child entry, since no source cached here states it.

X-linked inheritance

Show evidence (3 references)

PMID:39237642 SUPPORT Human Clinical

"with a small number following X-linked or mitochondrial inheritance patterns"

Establishes X-linked inheritance as a recognized but numerically minor mode among DEE genes.

PMID:39613335 SUPPORT Human Clinical

"17% (n=271) in X-linked genes"

Quantifies the X-linked share of molecularly diagnosed genetic DEE cases.

PMID:39237642 SUPPORT Human Clinical

"Mosaicism and X-linked disorders further complicate cellular targeting."

Supports the therapeutic-targeting caveat noted for X-linked genetic DEE.

◆

Subtypes

Developmental and epileptic encephalopathy 6B, non-Dravet (SCN1A) MONDO:0030268

SCN1A hgnc:10585

The non-Dravet pole of SCN1A developmental and epileptic encephalopathy. MONDO treats this as a class distinct from both Dravet syndrome and SCN1A DEE6A, and the founding cohort argues the same clinically: seizure onset at 6 to 12 weeks, profound developmental impairment with no speech and no ambulation, and a hyperkinetic movement disorder with prominent oral dyskinesia, a combination the authors describe as readily distinguishable from Dravet syndrome. Eight of the nine children carried the recurrent missense variant p.Thr226Met. Dravet syndrome itself is curated as the separate Dravet_syndrome entry, and SCN1A is carried in this entry's genetic section and wired to the ion-channel and synaptic lesion node, so this row records only the non-Dravet concept.

Show evidence (2 references)

PMID:28794249 SUPPORT Human Clinical

"We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus."

Establishes the non-Dravet SCN1A encephalopathy that this subtype term names, and its separation from Dravet syndrome.

PMID:28794249 SUPPORT Human Clinical

"Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy."

Quantifies the onset window and the severity that distinguish this subtype from Dravet syndrome.

Developmental and epileptic encephalopathy 23 (DOCK7) MONDO:0014371

DOCK7 hgnc:19190

Biallelic truncating DOCK7 variants. The founding report described three girls from two nonconsanguineous families with dysmorphic features, early-onset intractable epilepsy, intellectual disability and cortical blindness, all compound heterozygous for truncating DOCK7 alleles. DOCK7 encodes a Rac guanine nucleotide exchange factor implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of cortical GABAergic interneurons, so the lesion is developmental rather than primarily one of channel conduction.

Show evidence (2 references)

PMID:24814191 SUPPORT Human Clinical

"We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness."

Establishes the DEE23 clinical entity, including the cortical blindness that distinguishes it.

PMID:24814191 SUPPORT Human Clinical

"Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7."

Establishes biallelic truncating DOCK7 variants as the lesion defining this subtype.

Developmental and epileptic encephalopathy 35 (ITPA) MONDO:0014719

ITPA hgnc:6176

Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency, a purine pathway defect. Reported as an infantile-onset epileptic encephalopathy with a lethal course: infantile-onset neurodegeneration, progressive microcephaly and epilepsy, with cardiomyopathy in 42% of those in whom it was explicitly evaluated. This subtype sits in the metabolic rather than the channelopathy arm of the DEE umbrella, and MONDO also files it under inborn disorder of purine metabolism.

Show evidence (3 references)

PMID:35098521 SUPPORT Human Clinical

"Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency associated with mutations in the ITPA gene is a recently characterized purine pathway defect that presents with early infantile epileptic encephalopathy and lethal course."

Establishes ITPA as the causal gene and the early infantile epileptic encephalopathy phenotype.

PMID:35098521 SUPPORT Human Clinical

"ITPA-related encephalopathy presents with infantile-onset neurodegeneration, progressive microcephaly, and epilepsy."

Supports the microcephaly and neurodegenerative course recorded for this subtype.

PMID:35098521 SUPPORT Human Clinical

"Cardiomyopathy was noted in 42% of patients where it was explicitly evaluated (n = 5/12)."

Source for the cardiomyopathy figure recorded in this subtype's description.

Developmental and epileptic encephalopathy 36 (ALG13) MONDO:0010472

ALG13 hgnc:30881

X-linked ALG13-related DEE, in almost all reported cases caused by the recurrent de novo missense variant p.(Asn107Ser). In a 38-individual series 37 were girls and one was a boy. It usually manifests as West syndrome with severe to profound developmental delay. Transferrin electrophoresis is normal in most cases, and the cited series leaves open whether this is genuinely a congenital disorder of glycosylation, which is how MONDO classifies it.

Show evidence (3 references)

PMID:33410528 SUPPORT Human Clinical

"X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser)."

Establishes the recurrent de novo ALG13 variant and the West syndrome presentation of this subtype.

PMID:33410528 SUPPORT Human Clinical

"Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation."

Records that the glycosylation-disorder classification MONDO applies to this term is unsettled in the clinical literature.

PMID:33410528 SUPPORT Human Clinical

"We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants."

Source for the cohort size and the sex distribution recorded here.

Developmental and epileptic encephalopathy 37 (FRRS1L) MONDO:0014859

FRRS1L hgnc:1362

Biallelic loss-of-function FRRS1L variants. FRRS1L encodes an AMPA receptor outer-core protein, and its loss attenuates AMPA-mediated currents, so this is a postsynaptic glutamatergic lesion. The reported phenotype couples epilepsy with prominent choreoathetosis, which is why the founding report called it an epileptic-dyskinetic encephalopathy.

Show evidence (2 references)

PMID:27236917 SUPPORT Human Clinical

"We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein."

Establishes biallelic FRRS1L variants and the epileptic-dyskinetic phenotype of this subtype.

PMID:27236917 SUPPORT Human Clinical

"Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood."

Supports placing the FRRS1L lesion in the synaptic arm of the DEE mechanism.

Developmental and epileptic encephalopathy 48 (AP3B2) MONDO:0015000

AP3B2 hgnc:567

Biallelic AP3B2 variants. AP3B2 encodes the neuron-specific beta subunit of the AP-3 vesicle coat adaptor complex; the ubiquitous isoform AP3B1 causes Hermansky-Pudlak syndrome type 2 instead, so the neuronal restriction of this subunit is what makes the AP3B2 phenotype purely neurological. Reverse phenotyping of twelve affected individuals from eight families gave a homogeneous early-onset epileptic encephalopathy with severe developmental delay, optic atrophy and postnatal microcephaly, and no albinism or haematological involvement.

Show evidence (2 references)

PMID:27889060 SUPPORT Human Clinical

"Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly."

Establishes the DEE48 clinical entity and the optic atrophy that characterises it.

PMID:27889060 SUPPORT Human Clinical

"Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing."

Establishes autosomal-recessive AP3B2 variants as the lesion defining this subtype.

Developmental and epileptic encephalopathy 51 (MDH2) MONDO:0015025

MDH2 hgnc:6971

Biallelic MDH2 variants, a Krebs cycle defect. MDH2 encodes mitochondrial malate dehydrogenase, which converts malate to oxaloacetate. The three unrelated subjects of the founding report had early-onset generalised hypotonia, psychomotor delay and refractory epilepsy with raised lactate in blood and cerebrospinal fluid; their fibroblasts showed loss of MDH2 protein with enzymatic activity close to null, and accumulation of malate and fumarate. The lesion is therefore metabolic rather than one of channel conduction, which is why this subtype gene is wired to the non-channelopathy lesion node.

Show evidence (2 references)

PMID:27989324 SUPPORT Human Clinical

"We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid."

Establishes the DEE51 clinical entity and biallelic MDH2 variants as its lesion.

PMID:27989324 SUPPORT In Vitro

"Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null."

Shows the lesion abolishes malate dehydrogenase activity, which is the mechanism this subtype contributes.

Developmental and epileptic encephalopathy 53 (SYNJ1) MONDO:0033362

SYNJ1 hgnc:11503

Biallelic SYNJ1 variants. SYNJ1 encodes synaptojanin 1, a polyphosphoinositide phosphatase with two consecutive phosphatase domains that acts in synaptic vesicle dynamics. The allelic series separates two diseases: variants that selectively abolish only the Sac1 domain cause early-onset parkinsonism, whereas a critical reduction of the dual phosphatase activity causes this neonatal refractory epilepsy with progressive neurological decline. A screen of 543 further patients with epilepsy and intellectual disability found no additional pathogenic variants, so SYNJ1 deficiency is rare and tied to a specific phenotype.

Show evidence (2 references)

PMID:27435091 SUPPORT Human Clinical

"We performed whole exome or genome sequencing in three independent sib pairs with early onset refractory seizures and progressive neurological decline, and identified novel segregating recessive SYNJ1 defects."

Establishes the DEE53 clinical entity and recessive SYNJ1 variants as its lesion.

PMID:27435091 SUPPORT Human Clinical

"A genetic follow-up screening in a large cohort of 543 patients with a wide phenotypical range of epilepsies and intellectual disability revealed no additional pathogenic variants, showing that SYNJ1 deficiency is rare and probably linked to a specific phenotype."

Sources the rarity and phenotypic specificity stated in this row description.

Developmental and epileptic encephalopathy 57 (KCNT2) MONDO:0033366

KCNT2 hgnc:18866

De novo KCNT2 variants. KCNT2 encodes a sodium-activated potassium channel subunit of the same subfamily as KCNT1. The two girls of the founding report had West syndrome evolving to Lennox-Gastaut syndrome in one and epilepsy of infancy with migrating focal seizures in the other. In vitro analysis indicated quinidine-responsive gain of function, and quinidine add-on therapy produced marked clinical improvement in one of them, so this subtype shares the pharmacological profile as well as the phenotype of KCNT1-related disease.

Show evidence (2 references)

PMID:29740868 SUPPORT Human Clinical

"We report on 2 females with de novo variants in KCNT2 with West syndrome followed by Lennox-Gastaut syndrome or with DEE with migrating focal seizures."

Establishes the DEE57 clinical entity and de novo KCNT2 variants as its lesion.

PMID:29740868 SUPPORT Human Clinical

"After in vitro analysis suggested quinidine-responsive gain-of-function effects, we treated 1 of the girls with quinidine add-on therapy and achieved marked clinical improvements."

Sources both the gain-of-function mechanism and the quinidine response stated in this row description.

Developmental and epileptic encephalopathy 58 (NTRK2) MONDO:0033367

NTRK2 hgnc:8032

NTRK2-related DEE, reported with a recurrent variant in four of the five cases in the cited series. The phenotype is early-onset seizures beginning as infantile spasms and later evolving to multifocal seizures, with global developmental delay, variable movement disorders, microcephaly and optic nerve hypoplasia. HGNC names NTRK2 neurotrophic receptor tyrosine kinase 2, with TRKB as an alias symbol, so the lesion is in receptor signalling rather than in channel conduction.

Show evidence (2 references)

PMID:34425480 SUPPORT Human Clinical

"Five cases of NTRK2-related DEE were identified. Four had a previously described recurrent variant in NTRK2 and one had a novel variant."

Establishes NTRK2 as the causal gene of this subtype and the recurrence of one variant.

PMID:34425480 SUPPORT Human Clinical

"The phenotype was characterized by early-onset seizures (infantile spasms, later evolving to multifocal seizures), global developmental delay, variable movement disorders, microcephaly and optic nerve hypoplasia."

Source for the seizure evolution, microcephaly and optic nerve hypoplasia recorded here.

Developmental and epileptic encephalopathy 59 (GABBR2) MONDO:0033368

GABBR2 hgnc:4507

De novo GABBR2 variants. GABBR2 encodes the type 2 subunit of the metabotropic GABA-B receptor, so this subtype sits with the GABA-A receptor subunit subtypes as a lesion of GABAergic inhibition rather than of a voltage-gated channel. De novo GABBR2 mutations were reported in two individuals in the combined EuroEPINOMICS and Epi4K/EPGP trio cohort, which treated them as suggestive rather than statistically established; a later whole-genome study of unexplained DEE provided the causal link.

Show evidence (3 references)

PMID:25262651 SUPPORT Human Clinical

"In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each."

The first observation of de novo GABBR2 mutations in a DEE trio cohort, which is the report OMIM cites for DEE59.

PMID:25262651 SUPPORT Human Clinical

"de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. ... We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes"

Sources the statement that the first report treated GABBR2 as suggestive rather than established. The three additional genes with suggestive evidence are the three named earlier in the same abstract with two de novo carriers each, GABBR2 among them; the statistical evidence in that paper is for DNM1, not for GABBR2.

PMID:29100083 SUPPORT Human Clinical

"By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25."

Establishes GABBR2 as causal for DEE. The sentence names eight genes, so it supports gene-disease causality for each named gene and no gene-specific phenotype claim.

Developmental and epileptic encephalopathy 60 (CNPY3) MONDO:0033369

CNPY3 hgnc:11968

Biallelic CNPY3 variants. CNPY3 encodes an endoplasmic reticulum co-chaperone that regulates the subcellular distribution and responses of multiple Toll-like receptors, a function outside the channel and synaptic classes. The three individuals of the founding report presented as West syndrome and all three had hippocampal malrotation; CNPY3 protein was severely reduced in lymphoblastoid cells from two of them. Cnpy3-knockout mice showed spastic or dystonic features at rest and enhanced resting EEG activity in the fast beta band, which the authors suggest could mimic the fast waves seen in those two individuals.

Show evidence (2 references)

PMID:29394991 SUPPORT Human Clinical

"We have now identified biallelic CNPY3 variants in three individuals with WS; these include compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals 1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3)."

Establishes the DEE60 clinical entity, presenting as West syndrome, and biallelic CNPY3 variants as its lesion.

PMID:29394991 SUPPORT Model Organism

"Cnpy3-knockout mice exhibited spastic or dystonic features under resting conditions and hyperactivity and anxiolytic behavior during the open field test."

Model-organism support for CNPY3 loss producing a neurological phenotype.

Developmental and epileptic encephalopathy 61 (ADAM22) MONDO:0033370

ADAM22 hgnc:201

Biallelic inactivating ADAM22 variants. ADAM22 is the postsynaptic receptor for the secreted protein LGI1, and this subtype is the recessive counterpart of the dominant LGI1 epilepsy with auditory features. All affected individuals in the cited series had infantile-onset treatment-resistant epilepsy. Transfected-cell studies indicated three distinct pathological mechanisms: defective cell-membrane expression, impaired LGI1 binding, and impaired interaction with the postsynaptic density protein PSD-95.

Show evidence (3 references)

PMID:35373813 SUPPORT Human Clinical

"We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available."

Establishes biallelic inactivating ADAM22 variants in a cohort, defining this subtype.

PMID:35373813 SUPPORT Human Clinical

"All affected individuals exhibited infantile-onset, treatment-resistant epilepsy."

Source for the uniform infantile-onset drug-resistant epilepsy recorded here.

PMID:35373813 SUPPORT In Vitro

"Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density..."

Source for the three molecular consequences of ADAM22 loss recorded here.

Developmental and epileptic encephalopathy 62 (SCN3A) MONDO:0033371

SCN3A hgnc:10590

De novo SCN3A variants. SCN3A encodes the Nav1.3 sodium channel alpha subunit, highly expressed in brain and, before this report, not linked to early infantile epileptic encephalopathy. The four patients carried heterozygous de novo missense variants, and recordings showed gain of channel function with a markedly increased slowly inactivating current; phenytoin and lacosamide blocked that slowly inactivating component selectively, which is the pharmacological lead the authors draw from the mechanism. Variants known or presumed to be inherited did not show gain of function.

Show evidence (2 references)

PMID:29466837 SUPPORT Human Clinical

"Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala)."

Establishes the DEE62 clinical entity and de novo SCN3A missense variants as its lesion.

PMID:29466837 SUPPORT In Vitro

"Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component"

Sources the gain-of-function mechanism stated in this row description.

Developmental and epileptic encephalopathy 67 (CUX2) MONDO:0029138

CUX2 hgnc:19347

The recurrent de novo CUX2 p.Glu590Lys variant. CUX2 is a cut homeodomain transcription factor with a role in dendrite branching, spine development and synapse formation in layer II to III cortical neurons, so the lesion is transcriptional rather than a channel or synaptic protein defect and the gene is wired to the non-channelopathy lesion node. The nine-patient cohort spans a phenotypic range with infantile-onset myoclonic DEE at the severe end and generalised epilepsy with severe static developmental encephalopathy at the milder end; the variant affects a highly conserved residue in the CUT domain predicted to interfere with DNA binding.

Show evidence (2 references)

PMID:29630738 SUPPORT Human Clinical

"We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE)."

Establishes the DEE67 clinical entity and the recurrent CUX2 variant as its lesion.

PMID:29630738 SUPPORT Human Clinical

"Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum."

Sources the severity range stated in this row description.

Developmental and epileptic encephalopathy 68 (TRAK1) MONDO:0032598

TRAK1 hgnc:29947

Biallelic truncating TRAK1 variants. The founding report identified a homozygous splice variant in six lethal encephalopathic patients from three unrelated families; patient-derived fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced membrane potential and diminished respiration. Note that the founding report frames the phenotype as a fatal encephalopathy rather than using the DEE label that OMIM 618201 and MONDO later attached to this locus.

Show evidence (2 references)

PMID:28364549 SUPPORT Human Clinical

"Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families."

Establishes the biallelic TRAK1 lesion and the lethal encephalopathic phenotype of this subtype.

PMID:28364549 SUPPORT In Vitro

"In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration."

Source for the mitochondrial trafficking and respiration defect; the measurements are in patient-derived fibroblasts.

Developmental and epileptic encephalopathy 70 (PHACTR1) MONDO:0032663

PHACTR1 hgnc:20990

De novo PHACTR1 variants, whose founding report is titled for their identification in West syndrome. Immunoprecipitation showed that the disease variants impair either PHACTR1's actin-binding activity or its binding to protein phosphatase 1. In a later nine-patient series eight individuals carried missense variants and one a copy-number variant; infantile epileptic spasms syndrome was the unifying phenotype of the eight with missense variants, while the copy-number patient had a developmental encephalopathy phenotype instead.

Show evidence (3 references)

PMID:38272663 SUPPORT Human Clinical

"Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients with missense variants of PHACTR1."

Establishes epileptic spasms as the core phenotype of PHACTR1 missense variants, in the largest reported series.

PMID:38272663 SUPPORT Human Clinical

"Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to IESS."

Source for the developmental encephalopathy phenotype recorded alongside epileptic spasms in this subtype.

PMID:30256902 SUPPORT In Vitro

"Immunoprecipitation analyses revealed that actin-binding activity of PHACTR1 was impaired by the p.Leu500Pro, p.Asn479Ile and p.Ile518Asn mutations while the p.Arg521Cys mutation exhibited impaired binding to PP1."

Establishes the two molecular consequences of the disease variants, in transfected-cell immunoprecipitation assays.

Developmental and epileptic encephalopathy 73 (RNF13) MONDO:0034106

RNF13 hgnc:10057

De novo heterozygous gain-of-function RNF13 variants. Three unrelated individuals presented with congenital microcephaly, infantile epileptic encephalopathy and profound developmental delay. RNF13 interacts with the unfolded-protein-response sensor IRE1-alpha, and the variants act by increasing signalling through the ER stress response rather than by haploinsufficiency.

Show evidence (2 references)

PMID:30595371 SUPPORT Human Clinical

"Three unrelated affected individuals with congenital microcephaly, infantile epileptic encephalopathy, and profound developmental delay were found to carry heterozygous variants"

Establishes the three-patient founding cohort and the congenital microcephaly plus infantile epileptic encephalopathy phenotype.

PMID:30595371 SUPPORT Human Clinical

"These results indicate that the RNF13 variants confer gain of function to the encoded protein and thereby lead to altered signaling of the ER stress response associated with severe neurodegeneration in infancy."

Establishes the gain-of-function mechanism acting through the ER stress response.

Developmental and epileptic encephalopathy 75 (PARS2) MONDO:0032752

PARS2 hgnc:30563

Biallelic PARS2 variants. PARS2 encodes mitochondrial prolyl-tRNA synthetase, one of the mitochondrial aminoacyl-tRNA synthetases, and had first been linked to Alpers syndrome and infantile-onset neurodegeneration. Reported patients have epileptic spasms with an early treatment response, early developmental delay or regression, generalised hypotonia, postnatal microcephaly, elevated lactate and progressive cerebral atrophy. A nomenclature hazard is recorded on the NEUROD2-Related_Developmental_and_Epileptic_Encephalopathy entry: a publication cited there misapplies the DEE75 number to NEUROD2, which is DEE72.

Show evidence (2 references)

PMID:29915213 SUPPORT Human Clinical

"As a member of the mt-aaRS family, PARS2 encoding prolyl-tRNA synthetase 2 was recently shown to be associated with Alpers syndrome and certain infantile-onset neurodegenerative disorders in four patients."

Establishes PARS2 as a mitochondrial aminoacyl-tRNA synthetase gene causing infantile-onset encephalopathy.

PMID:29915213 SUPPORT Human Clinical

"Nearly all patients had epileptic spasms with early response to treatment, early developmental delay and/or regression followed by generalized hypotonia, postnatal microcephaly, elevated lactate levels, and progressive cerebral atrophy."

Source for the epileptic spasms, microcephaly, lactate elevation and cerebral atrophy recorded here.

Developmental and epileptic encephalopathy 76 (ACTL6B) MONDO:0032768

ACTL6B hgnc:160

Biallelic ACTL6B variants. ACTL6B encodes a subunit of the neuron-specific chromatin remodelling complex nBAF, which is the chromatin-regulator arm of the ion-channel and synaptic lesion node this subtype is wired to rather than a channel or synaptic protein in its own right. The two siblings in whom the gene was identified had severe DEE with microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature and kyphoscoliosis; the founding report describes three cases in total.

Show evidence (2 references)

PMID:30656450 SUPPORT Human Clinical

"In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis."

Source for the DEE76 phenotype recorded here, including the hypomyelination and cerebellar atrophy.

PMID:30656450 SUPPORT Human Clinical

"Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene"

Establishes the biallelic ACTL6B lesion defining this subtype.

Developmental and epileptic encephalopathy 78 (GABRA2) MONDO:0032812

GABRA2 hgnc:4076

A de novo GABRA2 variant. GABRA2 encodes the alpha2 subunit of the GABA-A receptor, a ligand-gated anion channel that regulates neuronal inhibition. The p.Thr292Lys variant was found by targeted resequencing of 279 epilepsy patients, in a patient with severe epilepsy and developmental delay. Patch-clamp recordings showed it reduced channel expression and produced channels that were tonically open even without GABA, so the receptor lesion is not a simple loss of GABA response. DEE78 and DEE79 were established together in this one study.

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PMID:29961870 SUPPORT Human Clinical

"Targeted resequencing of 279 additional epilepsy patients identified 19 rare variants from nine GABAA receptor genes, including a novel de novo missense variant in GABRA2 (c.875C > A, p.T292K) and a recurrent missense variant in GABRB3 (c.902C > T, p.P301L)."

Establishes the de novo GABRA2 variant that defines this subtype and how it was ascertained.

PMID:29961870 SUPPORT In Vitro

"The GABRA2 p.T292K variant reduced channel expression and produced mutant channels that were tonically open, even in the absence of GABA."

Gene-specific functional characterisation of the GABRA2 lesion, measured in transfected HEK293T cells.

Developmental and epileptic encephalopathy 79 (GABRA5) MONDO:0032813

GABRA5 hgnc:4079

A de novo GABRA5 variant. GABRA5 encodes the alpha5 subunit of the GABA-A receptor. The index patient was found by whole-genome sequencing and had severe early-onset epilepsy with developmental delay. The p.Val294Leu variant produced receptors ten times more sensitive to GABA but with a reduced maximal GABA-evoked current because of increased desensitisation, so the net effect is a loss of sustained inhibition despite the increased apparent affinity. DEE78 and DEE79 were established together in this one study.

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PMID:29961870 SUPPORT Human Clinical

"Using whole-genome sequencing, we identified a novel de novo missense variant in GABRA5 (c.880G > C, p.V294L) in a patient with severe early-onset epilepsy and developmental delay."

Establishes the DEE79 clinical entity and the de novo GABRA5 variant as its lesion.

PMID:29961870 SUPPORT In Vitro

"The GABRA5 p.V294L variant produced receptors that were 10-times more sensitive to GABA but had reduced maximal GABA-evoked current due to increased receptor desensitization."

Gene-specific functional characterisation of the GABRA5 lesion, measured in transfected HEK293T cells.

Developmental and epileptic encephalopathy 85, with or without midline brain defects (SMC1A) MONDO:0026771

SMC1A hgnc:11111

Heterozygous de novo truncating SMC1A variants, X-linked. SMC1A encodes a core structural subunit of the cohesin complex, so this is a cohesinopathy and the gene is wired to the non-channelopathy lesion node. The allelic split matters clinically: missense and small in-frame SMC1A changes cause about 5 per cent of Cornelia de Lange syndrome, which dismech curates separately, whereas protein-truncating changes cause this epilepsy phenotype. All ten cases of the defining series were female, none had a clinical diagnosis of Cornelia de Lange syndrome, and the striking feature was seizures occurring in clusters associated with developmental regression.

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PMID:28166369 SUPPORT Human Clinical

"Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein."

Establishes truncating SMC1A variants as the lesion defining this subtype.

PMID:28166369 SUPPORT Human Clinical

"All cases are female, and none had a clinical diagnosis of CdLS."

Sources the separation of this subtype from Cornelia de Lange syndrome, which is curated as its own dismech entry.

PMID:28166369 SUPPORT Human Clinical

"In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression."

Sources the cluster-seizure pattern and its link to regression stated in this row description.

Developmental and epileptic encephalopathy 86 (DALRD3) MONDO:0030054

DALRD3 hgnc:25536

A homozygous nonsense DALRD3 variant. DALRD3 forms a complex with the METTL2 methyltransferase that recognises particular arginine tRNA isoacceptors for 3-methylcytosine modification of the anticodon loop, and DALRD3-deficient human cells lose that modification almost completely. The lesion is therefore in tRNA modification, placing this subtype with the non-channelopathy mechanisms.

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PMID:32427860 SUPPORT Human Clinical

"Notably, we identify a homozygous nonsense mutation in the DALRD3 gene that impairs m3C formation in human patients exhibiting developmental delay and early-onset epileptic encephalopathy."

Establishes the DEE86 clinical entity and the homozygous DALRD3 lesion, together with the tRNA-modification defect it causes.

PMID:32427860 SUPPORT In Vitro

"DALRD3-deficient human cells exhibit nearly complete loss of the m3C modification in tRNA-Arg species."

Sources the molecular consequence of DALRD3 loss stated in this row description.

Developmental and epileptic encephalopathy 90 (FGF13) MONDO:0025353

FGF13 hgnc:3670

X-linked DEE caused by missense variants in the N-terminal domain of the A isoform of FHF2, the protein encoded by FGF13. Fibroblast growth factor homologous factors are intracellular regulators of voltage-gated sodium channels. Mutant FHF2A co-expressed with wild-type Nav1.6 lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties, a gain-of-function effect on excitability. Affected individuals - two sibling pairs and three unrelated males - had intractable focal seizures and severe developmental delay from infancy.

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PMID:33245860 SUPPORT Human Clinical

"Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A)."

Establishes the founding cohort and the FHF2A N-terminal variants defining this subtype.

PMID:33245860 SUPPORT Human Clinical

"Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Nav channel function."

States the gene-disease relationship and the sodium-channel regulatory mechanism that places this lesion in the channel arm.

PMID:33245860 SUPPORT In Vitro

"Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties."

Source for the gain-of-function effect on sodium-channel inactivation recorded here.

Developmental and epileptic encephalopathy 92 (GABRB2) MONDO:0020631

GABRB2 hgnc:4082

De novo GABRB2 variants. GABRB2 encodes the beta2 subunit of the GABA-A receptor. GABRB2 was one of eight genes given a causal link to DEE by a whole-genome sequencing study of 197 trios with unexplained DEE and pharmaco-resistant seizures, combined with targeted sequencing and de-novo-mutation enrichment meta-analysis. That study reports gene-disease causality for the set of eight; it does not characterise a GABRB2-specific phenotype, so none is asserted here.

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PMID:29100083 SUPPORT Human Clinical

"By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25."

Establishes GABRB2 as causal for DEE. The sentence names eight genes, so it supports gene-disease causality for each named gene and no gene-specific phenotype claim.

PMID:29100083 SUPPORT Human Clinical

"We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents."

Sources the cohort and design behind that causal link.

Developmental and epileptic encephalopathy 93 (ATP6V1A) MONDO:0020632

ATP6V1A hgnc:851

De novo heterozygous ATP6V1A variants. ATP6V1A encodes the A subunit of the vacuolar proton ATPase, the multi-subunit pump that sets organellar pH in all eukaryotic cells and has additional roles at the synapse in neurons. Severity in the four founding patients was strikingly variable and tracked the variant: two progressed to profound delay with hypotonic or dyskinetic quadriparesis and intractable seizures, while two had moderate delay with milder epilepsy. Modelling on v-ATPase structures predicted four different mechanisms for the four variants, from perturbed subunit interaction to impaired rotation.

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PMID:29668857 SUPPORT Human Clinical

"Through whole exome sequencing, we identified de novo heterozygous mutations (p.Pro27Arg, p.Asp100Tyr, p.Asp349Asn, p.Asp371Gly) in ATP6V1A, encoding the A subunit of v-ATPase, in four patients with developmental encephalopathy with epilepsy."

Establishes the DEE93 clinical entity and de novo ATP6V1A variants as its lesion.

PMID:29668857 SUPPORT Human Clinical

"Early manifestations, observed in all patients, were developmental delay and febrile seizures, evolving to encephalopathy with profound delay, hypotonic/dyskinetic quadriparesis and intractable multiple seizure types in two patients (p.Pro27Arg, p.Asp100Tyr), and to moderate delay with milder..."

Sources the variant-dependent severity range stated in this row description.

Developmental and epileptic encephalopathy 96 (NSF) MONDO:0023659

NSF hgnc:8016

De novo heterozygous NSF variants. NSF is the homo-hexameric AAA ATPase that acts in membrane fusion and in assembly and disassembly of the SNARE complex, so the lesion is in the presynaptic vesicle cycle and the gene is wired to the ion-channel and synaptic lesion node alongside NAPB, its own beta attachment protein. Expressing the mutant allele in the developing Drosophila eye severely disrupted eye development where the wild-type allele did not, which the authors read as a dominant negative effect.

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PMID:31675180 SUPPORT Human Clinical

"Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset."

Establishes the DEE96 clinical entity and de novo NSF variants as its lesion.

PMID:31675180 SUPPORT Model Organism

"When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild-type allele had no detectable effect under the same conditions."

Sources the dominant-negative reading of the NSF lesion stated in this row description.

Developmental and epileptic encephalopathy 97 (CELF2) MONDO:0030453

CELF2 hgnc:2550

Heterozygous CELF2 variants that disrupt nuclear localisation. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein with several roles in RNA processing and in development of the central nervous system and heart, so the lesion is post-transcriptional rather than one of channel conduction. Four of five individuals had DEE and one had intellectual disability with autistic features. All variants except a canonical splice site change clustered within twenty residues of the C-terminus, and mutant CELF2 protein was mislocalised outside the nucleus in transfected cells.

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PMID:33131106 SUPPORT Human Clinical

"We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features."

Establishes the DEE97 clinical entity and heterozygous CELF2 variants as its lesion.

PMID:33131106 SUPPORT In Vitro

"We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids."

Sources the mislocalisation mechanism stated in this row description.

Developmental and epileptic encephalopathy 98 (ATP1A2) MONDO:0030472

ATP1A2 hgnc:800

Heterozygous ATP1A2 variants at the severe end of the Na+/K+-ATPase alpha-subunit spectrum. The same gene is associated with familial hemiplegic migraine and alternating hemiplegia of childhood, which dismech curates in the Familial_Hemiplegic_Migraine entry; this subtype is instead the profound phenotype, featuring polymicrogyria or progressive brain atrophy with epilepsy, which caused early lethality in seven of 22 patients in the cited cohort. ATP1A2 accounted for six of those 22 patients, the remainder carrying ATP1A3 variants. Transfected-cell assays showed severely impaired pump activity.

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PMID:33880529 SUPPORT Human Clinical

"We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations."

Establishes heterozygous ATP1A2 variants as a cause of DEE with cortical malformation.

PMID:33880529 SUPPORT Human Clinical

"Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual)."

Source for the ATP1A2 share of the cited cohort recorded here.

PMID:33880529 SUPPORT BACKGROUND Human Clinical

"Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar..."

Source for the other ATP1A2 phenotypes this subtype is distinguished from, and for the Na+/K+-ATPase alpha-subunit identity. Recorded as BACKGROUND because the citing study established the DEE phenotype rather than these earlier associations.

+ 1 more reference

Developmental and epileptic encephalopathy 100 (FBXO28) MONDO:0030695

FBXO28 hgnc:29046

Heterozygous FBXO28 variants - missense, nonsense and frameshift - in one of the two genes in the 1q41-q42 microdeletion interval already implicated in monogenic disease. Across the ten cases assembled in the cited report all had epilepsy and nine of ten had DEE, including infantile spasms and a progressive myoclonic epilepsy. The report distinguishes FBXO28 encephalopathy from both 1q41-q42 deletion syndrome and WDR26 encephalopathy by more severe intellectual impairment, drug-resistant epilepsy and hyperkinetic movement disorders.

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PMID:33280099 SUPPORT Human Clinical

"We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a..."

Establishes FBXO28 as causal and quantifies the DEE fraction of the reported cohort.

PMID:33280099 SUPPORT Human Clinical

"We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders."

Supports separating this subtype from the overlapping 1q41-q42 deletion and WDR26 phenotypes.

PMID:33280099 SUPPORT BACKGROUND Human Clinical

"Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease."

Source for FBXO28 lying in the 1q41-q42 microdeletion interval. Recorded as BACKGROUND because the citing study set out to test the FBXO28-DEE hypothesis rather than to establish the interval.

Developmental and epileptic encephalopathy 102 (SLC38A3) MONDO:0030881

SLC38A3 hgnc:18044

Biallelic SLC38A3 variants. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter carrying asparagine, histidine and glutamine, the last being the precursor of both GABA and glutamate. Ten individuals from seven unrelated families in six countries were reported: global developmental delay, intellectual disability, hypotonia and absent speech were common, with microcephaly, epilepsy and visual impairment in the majority, and epilepsy drug-resistant in half.

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PMID:34605855 SUPPORT Human Clinical

"Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3."

Establishes the founding biallelic SLC38A3 observation in DEE.

PMID:34605855 SUPPORT Human Clinical

"Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis."

States the gene-disease relationship and the glutamine-homeostasis mechanism.

PMID:34605855 SUPPORT BACKGROUND Human Clinical

"The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate."

Source for the SNAT3 transport function and for glutamine being the precursor of both GABA and glutamate. Recorded as BACKGROUND because the gene's transport function was established before this study.

+ 1 more reference

Developmental and epileptic encephalopathy 103 (KCNC2) MONDO:0030957

KCNC2 hgnc:6234

De novo KCNC2 variants. KCNC2 encodes Kv3.2, a Shaw-related voltage-gated potassium channel subunit that supports sustained high-frequency firing. The defining series of eighteen patients spans genetic generalised epilepsy, focal epilepsy, myoclonic-atonic epilepsy and DEE, and the functional direction tracks severity: gain of function in three severely affected DEE cases and loss of function in one milder generalised-epilepsy case. Eight drug-responsive patients became seizure free on valproic acid alone or in combination, including severe DEE cases.

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PMID:35314505 SUPPORT Human Clinical

"We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy."

Establishes the KCNC2 phenotypic spectrum, of which DEE103 is the severe pole.

PMID:35314505 SUPPORT In Vitro

"Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms."

Sources the direction-of-effect correlation with severity stated in this row description.

PMID:35314505 SUPPORT Human Clinical

"Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases."

Sources the valproate response stated in this row description.

Developmental and epileptic encephalopathy 104 (ATP6V0A1) MONDO:0031021

ATP6V0A1 hgnc:865

ATP6V0A1 encodes the brain-enriched a1 isoform of the V0 domain of the vacuolar H+-ATPase. The cited cohort splits by inheritance: five individuals with biallelic variants had early-onset progressive myoclonus epilepsy with ataxia, while twelve with de novo missense variants had severe developmental and epileptic encephalopathy. The recurrent R740Q change accounts for almost half the mutations identified there and impairs acidification of the endolysosomal compartment, causing autophagic dysfunction.

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PMID:34909687 SUPPORT Human Clinical

"Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy."

Establishes the de novo missense DEE phenotype and its separation from the biallelic progressive myoclonus epilepsy phenotype.

PMID:34909687 SUPPORT Human Clinical

"Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals."

Records the prior reports that established the gene-disease relationship.

PMID:34909687 SUPPORT In Vitro

"The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction"

Source for the recurrent R740Q change, its share of the reported mutations, and the endolysosomal acidification defect.

Developmental and epileptic encephalopathy 105 with hypopituitarism (HID1) MONDO:0031028

HID1 hgnc:15736

Biallelic HID1 variants. HID1 acts in the trans-Golgi network, where precursors of peptide hormones are processed, which is why this subtype pairs an epileptic encephalopathy with central pituitary insufficiency. Seven individuals from six unrelated families shared hypopituitarism with brain atrophy, thin corpus callosum, severe developmental delay and visual impairment. Postmortem examination of one patient confirmed cerebral atrophy with enlarged lateral ventricles and markedly reduced pituitary hormone expression.

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PMID:33999436 SUPPORT Human Clinical

"Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients."

Establishes biallelic HID1 variants as the lesion defining this subtype.

PMID:33999436 SUPPORT Human Clinical

"We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy."

Sources the combined endocrine and neurological phenotype that distinguishes DEE105.

PMID:33999436 SUPPORT Human Clinical

"Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue."

Sources the neuropathological and pituitary findings stated in this row description.

Developmental and epileptic encephalopathy 106 (UFSP2) MONDO:0031052

UFSP2 hgnc:25640

Homozygosity for the UFSP2 p.V115E variant in eight children from four South Asian families with neurodevelopmental delay and epilepsy. UFSP2 encodes UFM1-specific peptidase 2, which acts in the UFMylation pathway of protein modification; patient fibroblasts showed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating impaired de-UFMylation. The variant residue lies in an N-terminal domain, whereas the variants causing the previously known autosomal dominant UFSP2 skeletal dysplasias lie in the catalytic domain.

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PMID:33473208 SUPPORT Human Clinical

"Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy."

Establishes the biallelic UFSP2 lesion and the neurodevelopmental-delay-with-epilepsy phenotype of this subtype.

PMID:33473208 SUPPORT Human Clinical

"Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy."

Supports separating this recessive neurodevelopmental subtype from the dominant UFSP2 skeletal dysplasias.

PMID:33473208 SUPPORT In Vitro

"Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation."

Source for the impaired de-UFMylation mechanism recorded here, measured in patient fibroblasts.

+ 1 more reference

Developmental and epileptic encephalopathy 107 (NAPB) MONDO:0031055

NAPB hgnc:15751

A homozygous nonsense NAPB variant. NAPB encodes the beta attachment protein of N-ethylmaleimide-sensitive factor and acts in SNARE complex dissociation and recycling during synaptic vesicle docking, so this subtype and DEE96 are lesions at two successive steps of the same machinery. The index patient was a girl of Irish Traveller descent with consanguineous parents, with multifocal seizures and profound global developmental delay. Napb knockout mice were already known to develop recurrent postnatal seizures without structural brain change.

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PMID:26235277 SUPPORT Human Clinical

"Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein."

Establishes the homozygous NAPB lesion defining this subtype and the extent of protein loss.

PMID:26235277 SUPPORT Human Clinical

"Here, we report a 6-year-old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay."

Sources the clinical presentation of the index case.

PMID:26235277 SUPPORT BACKGROUND Model Organism

"Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post-natal epileptic seizures in the absence of structural brain changes."

Model-organism support for NAPB loss causing seizures, restated by the citing paper from earlier work.

Developmental and epileptic encephalopathy 108 (MAST3) MONDO:0859314

MAST3 hgnc:19036

De novo MAST3 missense variants in the serine-threonine kinase domain. MAST3 is one of the microtubule-associated serine-threonine kinases, expressed in excitatory cortical neurons late in prenatal development and postnatally. All eleven individuals of the defining series had DEE, eight with normal development before seizure onset under two years of age, and fever-triggered and drug-resistant seizures in nine each. Transfected cells showed generally lower MAST3 expression with increased phosphorylation of its target ARPP-16, which the authors suggest may confer gain of function.

Show evidence (3 references)

PMID:34185323 SUPPORT Human Clinical

"We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3)."

Establishes the de novo MAST3 kinase-domain variants that define this subtype.

PMID:34185323 SUPPORT Human Clinical

"All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age."

Sources the DEE phenotype and the normal pre-seizure development stated in this row description.

PMID:34185323 SUPPORT Human Clinical

"All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures."

Sources the fever trigger and drug resistance counts stated in this row description.

Developmental and epileptic encephalopathy 109 (FZR1) MONDO:0859325

FZR1 hgnc:24824

De novo loss-of-function FZR1 variants. FZR1 encodes the Cdh1 subunit of the anaphase-promoting complex, with roles both in the cell cycle and in post-mitotic neurons, so the lesion is in cell-cycle regulation rather than in a channel or synaptic protein. The three individuals found among 250 unrelated DEE patients all had childhood-onset generalised epilepsy, intellectual disability, mild ataxia and normal head circumference, and two were diagnosed with the myoclonic atonic epilepsy subtype of DEE. Drosophila assays using three mutant alleles of the homologue fzr supported the variants being loss of function.

Show evidence (3 references)

PMID:34788397 SUPPORT Human Clinical

"In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1."

Establishes the de novo FZR1 variants that define this subtype and how they were ascertained.

PMID:34788397 SUPPORT Human Clinical

"All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference."

Sources the phenotype stated in this row description.

PMID:34788397 SUPPORT Model Organism

"Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays."

Sources the loss-of-function reading of the FZR1 variants.

Developmental and epileptic encephalopathy 110 (CACNA2D1) MONDO:0859327

CACNA2D1 hgnc:1399

Biallelic loss-of-function CACNA2D1 variants in two unrelated individuals. CACNA2D1 encodes the α2δ-1 auxiliary subunit of CaV1 and CaV2 voltage-gated calcium channels. Functional studies of the missense allele carried by one of the two showed that the amino-acid change severely impairs α2δ-1's function as a calcium channel subunit.

Show evidence (3 references)

PMID:35293990 SUPPORT Human Clinical

"Here we report biallelic variants in CACNA2D1, encoding the α2δ-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy."

Establishes biallelic CACNA2D1 variants as the lesion defining this subtype.

PMID:35293990 SUPPORT Human Clinical

"Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients."

States the loss-of-function mechanism and the severity of the resulting neurodevelopmental disorder.

PMID:35293990 SUPPORT In Vitro

"Our functional studies show that this amino-acid change severely impairs the function of α2δ-1 as a calcium channel subunit"

Source for the functional impairment of the auxiliary subunit recorded here.

Developmental and epileptic encephalopathy 111 (DEPDC5, biallelic) MONDO:0957780

DEPDC5 hgnc:18423

Germline biallelic missense DEPDC5 variants. DEPDC5 encodes an inhibitory component of the mTOR pathway, and the usual germline lesion is a single inactivating heterozygous variant, which dismech curates as the separate DEPDC5-Related_Epilepsy entry. This subtype is the biallelic germline phenotype, which is a different entity: extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, rather than a focal lesion produced by a brain-somatic second hit. Six of the children were of Irish Traveller origin sharing p.Thr337Arg, and two Tunisian plus one Lebanese child shared p.Arg806Cys; five of nine died in infancy or childhood.

Show evidence (3 references)

PMID:36067010 SUPPORT Human Clinical

"We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5."

Establishes the biallelic germline DEPDC5 entity that this subtype term names, as distinct from heterozygous DEPDC5-related focal epilepsy.

PMID:36067010 SUPPORT Human Clinical

"Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies."

Sources the phenotype stated in this row description, and its bilateral rather than focal distribution.

PMID:36067010 SUPPORT Human Clinical

"Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway."

Sources the mTOR hyperactivation mechanism in affected individuals.

Developmental and epileptic encephalopathy 112 (KCNH5) MONDO:0957812

KCNH5 hgnc:6254

De novo KCNH5 missense variants in or near the voltage-sensing and pore domains. KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. The defining cohort of seventeen patients shows that the severity tracks the variant rather than the gene: the recurrent p.Arg333His gave a self-limited drug-responsive epilepsy with normal intellect, while the recurrent p.Arg327His gave infantile-onset DEE, and two pore-domain variants gave a neonatal movement disorder with early-infantile DEE, profound disability and childhood death.

Show evidence (2 references)

PMID:36307226 SUPPORT Human Clinical

"We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants."

Establishes the KCNH5 variant series behind this subtype.

PMID:36307226 SUPPORT Human Clinical

"Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE."

Sources the variant-dependent split between self-limited epilepsy and DEE stated in this row description.

Developmental and epileptic encephalopathy 113 (SV2A) MONDO:0958330

SV2A hgnc:20566

SV2A encodes synaptic vesicle glycoprotein 2A, the binding site of levetiracetam. The reported lesion is a homozygous R383Q missense change in a multiply consanguineous family: the proband had intractable epilepsy, involuntary movements, microcephaly and developmental and growth retardation, and an earlier-born brother had a similar course and died at 7 months of age. Levetiracetam was not effective in the proband. The evidence base for this subtype is thin - a single family, with no independent replication found in a PubMed search on 2026-09-25 using the queries 'SV2A biallelic variants developmental and epileptic encephalopathy' (no hits), 'SV2A gene variants patients epilepsy developmental delay cohort' (no hits) and 'synaptic vesicle glycoprotein 2A SV2A homozygous variant patients' (this report only).

Show evidence (4 references)

PMID:26002053 SUPPORT Human Clinical

"Exome sequencing identified a homozygous arginine to glutamine mutation in amino acid position 383 (R383Q) in exon 5 of the SV2A gene."

Establishes the single reported biallelic SV2A lesion defining this subtype.

PMID:26002053 SUPPORT Human Clinical

"Our report provides the elusive evidence that an SV2A mutation can be a cause of epilepsy in humans."

States the gene-disease claim, and its wording marks how new and singular the observation was.

PMID:26002053 SUPPORT Human Clinical

"Both parents were multiply consanguineous and an earlier-born brother of the proband had a similar course and died at 7 months of age."

Source for the consanguinity and the affected sibling, the whole of the reported family evidence for this subtype.

+ 1 more reference

Developmental and epileptic encephalopathy 114 (SLC32A1) MONDO:0958331

SLC32A1 hgnc:11018

De novo missense SLC32A1 variants. SLC32A1 encodes the vesicular GABA transporter, which loads GABA into synaptic vesicles, so the lesion is presynaptic and inhibitory. Inherited missense variants in the same gene had already been linked to genetic epilepsy with febrile seizures plus, and this report establishes that de novo missense variants instead cause a DEE. Two mechanisms were demonstrated in a murine neuronal culture model: three variants lining the putative GABA transport pathway reduced quantal size, consistent with impaired vesicle filling, while an N-terminal variant left quantal size intact but raised presynaptic release probability.

Show evidence (3 references)

PMID:36073542 SUPPORT Human Clinical

"Using exome sequencing, we identified four individuals with a developmental and epileptic encephalopathy and de novo missense variants in SLC32A1."

Establishes the DEE114 clinical entity and de novo SLC32A1 variants as its lesion.

PMID:36073542 SUPPORT Human Clinical

"The main phenotype comprises moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder."

Sources the phenotype stated in this row description, including the movement disorder.

PMID:36073542 SUPPORT In Vitro

"In silico modeling and functional analyses reveal that three of these variants, which are located in helices that line the putative GABA transport pathway, result in reduced quantal size, consistent with impaired filling of synaptic vesicles with GABA."

Sources the vesicle-filling mechanism, measured in a murine neuronal cell culture model.

Developmental and epileptic encephalopathy 115 (SNF8) MONDO:0968946

SNF8 hgnc:17028

Biallelic SNF8 variants, the severe pole of the SNF8 disease spectrum. SNF8 encodes a subunit of ESCRT-II, one of the three complexes of the endosomal sorting machinery required for membrane remodelling and autophagy. The milder pole of the same spectrum, with intellectual disability and childhood-onset optic atrophy or ataxia, is curated as the separate SNF8-Related_Neurodevelopmental_Disorder entry, which lists this concept as an allelic differential diagnosis; all mildly affected individuals shared the hypomorphic variant p.Val102Ile. The DEE concept itself is curated here as a subtype row rather than as its own entry.

Show evidence (3 references)

PMID:38423010 SUPPORT Human Clinical

"The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death."

Establishes the DEE115 clinical entity as the severe pole of the SNF8 spectrum.

PMID:38423010 SUPPORT Human Clinical

"We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8."

Establishes biallelic SNF8 variants as the lesion and SNF8 as an ESCRT-II subunit.

PMID:38423010 SUPPORT Human Clinical

"All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile)."

Sources the allele that separates the mild pole, curated elsewhere, from this severe pole.

Developmental and epileptic encephalopathy 118 (TMEM63B) MONDO:0979238 MONDO:0800503

TMEM63B hgnc:17735 MONDO MONDO:0800503

Heterozygous, almost always de novo, missense or in-frame TMEM63B variants affecting conserved transmembrane residues. TMEM63B encodes a stretch-activated ion channel, and the mutated channels carried an inward leak cation current even under isotonic conditions while responding poorly to a hypo-osmotic challenge. Two features set this subtype apart from the other channel subtypes here: the brain changes are progressive and neurodegenerative rather than static, and haematological abnormalities such as macrocytosis and haemolysis occurred in twelve of seventeen individuals, some needing transfusion. The recurrent p.Val44Met accounted for seven of the seventeen.

Show evidence (3 references)

PMID:37421948 SUPPORT Human Clinical

"Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of..."

Establishes the clinical entity, the heterozygous TMEM63B lesion, and the progressive neurodegenerative course.

PMID:37421948 SUPPORT Human Clinical

"In 12 individuals, hematological abnormalities co-occurred, such as macrocytosis and hemolysis, requiring blood transfusions in some."

Sources the haematological involvement, which is the feature the duplicate MONDO class named in this row mappings block is named after.

PMID:37421948 SUPPORT In Vitro

"we modeled six variants (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr, and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, in transfected Neuro2a cells and demonstrated inward leak cation currents across the mutated channel even in isotonic conditions"

Sources the leak-current mechanism stated in this row description.

Developmental and epileptic encephalopathy 119 (RNU2-2) MONDO:1060177

RNU2-2 hgnc:10152

Recurrent de novo single-nucleotide mutations at positions 4 and 35 of RNU2-2, a 191-bp gene encoding the U2-2 small nuclear RNA of the major spliceosome. Twenty-five cases were assembled in the founding report, which estimates the disorder's prevalence at about 20% that of the related RNU4-2 syndrome. The phenotype is intellectual disability, autistic behaviour, microcephaly, hypotonia, epilepsy and hyperventilation, with a severe and complex seizure phenotype in all cases. Notably, mutant U2-2 was expressed in patient blood without detectable missplicing, so the mechanism downstream of the snRNA lesion is not yet established. This is the only non-protein-coding causal gene among the subtypes recorded here.

Show evidence (4 references)

PMID:40210679 SUPPORT Human Clinical

"By genetic association, we identified recurrent de novo single-nucleotide mutations at nucleotide positions 4 and 35 of RNU2-2 in nine cases."

Establishes the recurrent de novo RNU2-2 lesion defining this subtype.

PMID:40210679 SUPPORT Human Clinical

"The disorder is characterized by intellectual disability, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype."

Source for the phenotype and the uniformly severe seizure picture recorded here.

PMID:40210679 SUPPORT Human Clinical

"We replicated this finding in 16 additional cases, bringing the total to 25. We estimate that RNU2-2 syndrome has a prevalence of ~20% that of RNU4-2 syndrome."

Source for the total case count and the prevalence estimate relative to RNU4-2 syndrome.

+ 1 more reference

Developmental and epileptic encephalopathy 120 (BAIAP2) MONDO:0980948

BAIAP2 hgnc:947

De novo missense BAIAP2 variants in six patients. BAIAP2 acts in dendritic spine morphogenesis and excitatory synapse formation, and the reported variants cluster in the multiple phosphorylation site region that maintains the protein's autoinhibited conformation through 14-3-3 binding. All six patients had severe infantile or early childhood onset epilepsy, refractory in four, with language and motor delay and varying degrees of intellectual disability. Neurons expressing the variants were more excitable through enhanced excitatory synaptogenesis, which the authors read as gain of function.

Show evidence (5 references)

PMID:41133935 SUPPORT Human Clinical

"Using whole exome/genome sequencing, we identified de novo missense variants in BAIAP2 in six patients with DEEs."

Establishes de novo BAIAP2 missense variants as the lesion defining this subtype.

PMID:41133935 SUPPORT Human Clinical

"Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) plays a crucial role in dendritic spine morphogenesis and excitatory synapse formation."

States the synaptic function that places this lesion in the synaptic arm of the mechanism.

PMID:41133935 SUPPORT Human Clinical

"All six patients exhibited severe infantile or early childhood onset epilepsy, with refractory seizures in four individuals."

Source for the seizure onset and refractoriness recorded here.

+ 2 more references

Developmental and epileptic encephalopathy 121 (LGI1) MONDO:0980966

LGI1 hgnc:6572

Biallelic LGI1 variants - the recessive counterpart of the dominant LGI1 disease, autosomal dominant epilepsy with auditory features, which dismech curates as the separate Autosomal_Dominant_Epilepsy_with_Auditory_Features entry. Six individuals from four consanguineous families had DEE with neonatal or infantile-onset epilepsy and global developmental delay or intellectual disability; five of the six died in infancy or prematurely. All variants reduced LGI1 secretion and ADAM22 binding, and residual LGI1 function correlated with clinical severity. LGI1 is the ligand for ADAM22, so DEE121 and the ADAM22 subtype DEE61 are two ends of one pathway.

Show evidence (4 references)

PMID:40455867 SUPPORT Human Clinical

"Through international genetic data sharing, we identified the first ultra-rare biallelic LGI1 variants in six individuals from four consanguineous families. Affected individuals presented DEE with neonatal/infantile-onset epilepsy (n = 6/6), global developmental delay/intellectual disability (n..."

Establishes biallelic LGI1 variants as a cause of DEE and records the cohort and its mortality.

PMID:40455867 SUPPORT Human Clinical

"LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates excitatory synaptic transmission and neuronal excitability in the brain."

States the synaptic function shared with the ADAM22 subtype DEE61.

PMID:40455867 SUPPORT In Vitro

"Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding. Residual LGI1 function levels correlated with clinical severity, ranging from infantile lethality to intermediate phenotypes."

Source for the reduced secretion and ADAM22 binding, and for the correlation between residual function and severity.

+ 1 more reference

Microcephaly, seizures, and developmental delay (PNKP) MONDO:0013254

PNKP hgnc:9154

Biallelic PNKP variants. This is the one subtype recorded here that MONDO does not number in the DEE series: it is filed under both microcephaly and genetic developmental and epileptic encephalopathy, and carries EIEE10 only as a related synonym. The founding report mapped the locus to 19q13.33 and described an autosomal recessive disease of microcephaly, early-onset intractable seizures and developmental delay, with a splicing allele giving a milder course. PNKP encodes polynucleotide kinase 3'-phosphatase; unlike other human DNA repair defects, PNKP variants universally cause severe seizures. Allelic PNKP disorders are curated elsewhere in dismech, notably Charcot-Marie-Tooth_Disease_Type_2B2.

Show evidence (2 references)

PMID:20118933 SUPPORT Human Clinical

"We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ)."

Establishes the MCSZ entity and its autosomal recessive inheritance.

PMID:20118933 SUPPORT Human Clinical

"Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures."

Supports treating this DNA-repair disorder as a member of the DEE umbrella rather than only a microcephaly syndrome.

Neonatal-onset encephalopathy with rigidity and seizures (BRAT1) MONDO:0013784

BRAT1 hgnc:21701

Biallelic BRAT1 variants, also called lethal neonatal rigidity and multifocal seizure syndrome. BRAT1 is the BRCA1-associated ATM activator. The sibling pair in the first report cited here carried compound heterozygous variants, one of them affecting a conserved residue in the CIDE-N domain that regulates the DNA fragmentation pathway of apoptosis. BRAT1 produces two distinct phenotypes, and which one a genotype gives is largely predictable: in a 97-patient cohort every one of 46 genotypes made up of biallelic nonsense, frameshift or in-frame indel variants gave this lethal rigidity and multifocal-seizure phenotype, whereas genotypes including at least one missense variant gave the non-lethal cerebellar-atrophy phenotype in 28 of 34. Fifty-nine of the 97 had the phenotype this row names, and 93 per cent of those died prematurely.

Show evidence (4 references)

PMID:25319849 SUPPORT Human Clinical

"They had intractable seizures from neonatal period, dysmorphic features and hypertonia. Progressive microcephaly was also observed."

Clinical presentation of the sibling pair reported in this paper, who carried compound heterozygous BRAT1 variants.

PMID:25319849 SUPPORT BACKGROUND Human Clinical

"Homozygous frameshift BRAT1 mutations were found in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498)."

Identifies BRAT1 as the gene of the OMIM entity this subtype term names. The citing paper restates this from the earlier reports rather than establishing it.

PMID:37344571 SUPPORT Human Clinical

"Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%)."

Sources the genotype-phenotype split between this lethal phenotype and the non-lethal BRAT1 phenotype.

+ 1 more reference

⚙

Pathophysiology

Genetic Lesion in an Ion Channel or Synaptic Gene

A de novo or inherited pathogenic variant in one of a large and growing set of genes encoding voltage-gated ion channels (e.g. SCN1A, SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1E, HCN1), presynaptic vesicle-cycle and neurotransmitter-release machinery (STXBP1, DNM1, SNAP25, CPLX1, UNC13A), postsynaptic glutamate or GABA receptors (GRIN1, GRIN2A, GRIN2B, GABRA1, GABRB3), or chromatin/transcriptional regulators active in neurodevelopment (CDKL5, FOXG1, CHD2) disrupts normal neuronal excitability or synaptic signaling. Gene-defined subtypes wired at this node in this entry, beyond the examples above, are CACNA2D1 (the alpha-2-delta-1 auxiliary subunit of CaV1 and CaV2 voltage-gated calcium channels), FGF13/FHF2 (an intracellular regulator of voltage-gated sodium channels), SV2A (a synaptic vesicle glycoprotein and the binding site of levetiracetam), FRRS1L (an AMPA receptor outer-core protein), LGI1 together with its postsynaptic receptor ADAM22, BAIAP2 (dendritic spine morphogenesis and excitatory synapse formation), and ACTL6B (a subunit of the neuron-specific chromatin remodelling complex nBAF). Each functional assignment is taken from the publication cited on that subtype's own has_subtypes row. The DEE-series subtypes added under this parent extend that list with four further voltage-gated channel subunits (SCN3A/Nav1.3, KCNC2/Kv3.2, KCNH5/EAG2-Kv10.2, and the sodium-activated potassium channel KCNT2); the stretch-activated channel TMEM63B; four GABA receptor subunits, namely the GABA-A subunits GABRB2, GABRA2 and GABRA5 together with the metabotropic GABA-B subunit GABBR2; the vesicular GABA transporter SLC32A1; and three further components of the presynaptic vesicle cycle, namely the AAA ATPase NSF, which acts in SNARE complex assembly and disassembly, its beta attachment protein NAPB, and the polyphosphoinositide phosphatase SYNJ1.

SCN1A hgnc:10585 SCN2A hgnc:10588 SCN8A hgnc:10596 KCNQ2 hgnc:6296 STXBP1 hgnc:11444 CDKL5 hgnc:11411 FRRS1L hgnc:1362 ADAM22 hgnc:201 ACTL6B hgnc:160 FGF13 hgnc:3670 CACNA2D1 hgnc:1399 SV2A hgnc:20566 BAIAP2 hgnc:947 LGI1 hgnc:6572 SCN3A hgnc:10590 KCNC2 hgnc:6234 KCNH5 hgnc:6254 KCNT2 hgnc:18866 TMEM63B hgnc:17735 GABRB2 hgnc:4082 GABRA2 hgnc:4076 GABRA5 hgnc:4079 GABBR2 hgnc:4507 SLC32A1 hgnc:11018 NSF hgnc:8016 NAPB hgnc:15751 SYNJ1 hgnc:11503

ion channel activity GO:0005216

Downstream

Neuronal Excitation-Inhibition Imbalance The gene-level lesion alters neuronal excitability or synaptic signalling, shifting the excitation-inhibition balance of the network.

Show evidence (2 references)

PMID:39237642 SUPPORT Human Clinical

"900 genes have been identified as monogenic causes of DEEs and many cell components and processes"

Establishes the extreme monogenic heterogeneity of the DEE umbrella, the defining upstream trigger of this entry.

PMID:35951482 SUPPORT Human Clinical

"Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity."

Enumerates the functional gene classes affected, matching the ion-channel, synaptic, and neurodevelopmental categories described in this node.

Neuronal Excitation-Inhibition Imbalance

Depending on the specific gene and variant, the molecular lesion produces either a gain- or loss-of-function shift in neuronal excitability (e.g. gain-of-function SCN2A/SCN8A sodium-channel variants causing neuronal hyperexcitability versus loss-of-function SCN1A variants preferentially impairing GABAergic interneuron firing), converging on a common circuit-level disruption of the balance between excitatory and inhibitory synaptic drive.

GABAergic interneuron CL:0000617

GABA Signaling Pathway GO:0007214 ↓ DECREASED

Downstream

Hypersynchronous Network Activity and Seizures Excitation-inhibition imbalance drives the seizure arm of the DEE mechanism.

Impaired Synaptic Maturation and Neurodevelopment The same molecular lesion independently disrupts circuit maturation, producing the developmental arm.

Show evidence (1 reference)

PMID:39858526 SUPPORT Human Clinical

"Many genes mutated in DEEs encode ion channels, causing current conduction disruptions known as channelopathies."

Supports the channelopathy arm in which the genetic lesion alters neuronal excitability, the proximate cause of excitation-inhibition imbalance.

Hypersynchronous Network Activity and Seizures

Excitation-inhibition imbalance produces hypersynchronous, epileptiform cortical network activity, manifesting clinically as frequent, often multiple, drug-resistant seizure types with an abnormal interictal EEG background.

neuron CL:0000540

Action Potential GO:0001508 ↑ INCREASED

Downstream

Drug-Resistant Seizures The hypersynchronous network state is what is observed clinically as the antiseizure-medication-refractory seizures that the ILAE operational definition puts at the centre of the DEE concept.

Status Epilepticus Status epilepticus is the failure of a seizure to self-terminate. Convulsive status epilepticus was recorded in 47 per cent and nonconvulsive status epilepticus in 19 per cent of a 510-patient genetic DEE cohort.

Abnormal EEG Background The same hypersynchrony is recorded interictally as frequent epileptiform activity on an abnormal EEG background, which is the electrographic rather than the clinical reading of this node.

Epileptic Encephalopathy Component Ongoing seizures and epileptiform activity themselves degrade cognitive and behavioural function.

Show evidence (1 reference)

PMID:40013914 SUPPORT Human Clinical

"Developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, characterized by drug-resistant seizures and developmental slowing or regression."

The ILAE operational definition identifies drug-resistant seizures as a defining clinical output of the DEE network mechanism.

Impaired Synaptic Maturation and Neurodevelopment

Independent of seizure activity, the same channel or synaptic-gene defect disrupts activity-dependent synaptic pruning, circuit maturation, and neuronal migration/connectivity during critical developmental windows, producing a developmental encephalopathy component that is not fully reversible by seizure control alone.

Downstream

Developmental Encephalopathy Component Disrupted circuit maturation yields developmental delay and intellectual disability independently of seizure burden.

Show evidence (1 reference)

PMID:39858526 SUPPORT Human Clinical

"many other mechanisms have been identified: impaired neurogenesis, metabolic disorders, disruption of dendrite and axon growth, maintenance and synapse formation abnormalities -synaptopathies."

Documents the non-channelopathy, neurodevelopmental mechanisms that constitute this seizure-independent arm of the DEE mechanism.

Epileptic Encephalopathy Component

Frequent seizures and ongoing epileptiform discharges themselves contribute to cognitive slowing, developmental regression, and behavioral disturbance, over and above the effect of the underlying genetic lesion. This component can partially improve with effective seizure control.

Downstream

Developmental Regression What this component adds is deterioration: worsening of development on a background of established impairment, rather than the delay itself. That is why loss of previously acquired skills is routed from here rather than from the developmental component, which the entry treats as the source of the delay.

Show evidence (2 references)

PMID:35951482 SUPPORT Human Clinical

"on a background of developmental impairment that tends to worsen as a consequence of epilepsy"

States the epileptic-encephalopathy component explicitly: the epilepsy itself worsens developmental impairment.

PMID:28276062 SUPPORT Human Clinical

"In an epileptic encephalopathy, the abundant epileptiform activity interferes with development resulting in cognitive slowing and often regression, and sometimes is associated with psychiatric and behavioural consequences. ... A key component of the concept is that amelioration of the..."

The 2017 ILAE classification defines the epileptic-encephalopathy component this node describes: epileptiform activity itself causes cognitive slowing, regression and behavioural consequences, and controlling it may improve development.

Developmental Encephalopathy Component

Developmental delay, intellectual disability, and often autistic features that arise directly from the genetic etiology's disruption of neurodevelopment, and that may be present even before seizure onset or persist despite adequate seizure control.

Downstream

Developmental Delay Delayed acquisition of milestones is the direct expression of this component, and in the DEE concept it may precede seizure onset.

Intellectual Disability The cognitive endpoint of the developmental arm. Its features may persist despite adequate seizure control, which is the clinical observation that makes this arm separable from the epileptic one.

Autistic Behavior Autistic features are routed from the developmental rather than the epileptic arm because they are part of the cognitive and behavioural phenotype of the underlying genetic lesion. The sources cited here name autism spectrum disorder and behavioural deficits as features of the DEE group without attributing them to either arm, so the routing is this entry's model rather than a claim either source makes.

Movement Disorder Movement disorders are routed from the developmental arm because most of the epilepsy-dyskinesia genes map to the same ion-channel and synaptic pathways as the upstream lesion nodes, rather than arising from the seizure burden. The cited review reports co-occurrence and gene-pathway membership; it does not test which arm produces the movement disorder, so this edge is an inference from the entry's two-component model.

Show evidence (1 reference)

PMID:39858526 SUPPORT Human Clinical

"What sets DEEs apart is their complex interplay of epilepsy and developmental delay, often driven by genetic factors. These two aspects influence one another but can develop independently, creating diagnostic and therapeutic challenges."

Directly supports modeling the developmental component as a separate arm that can arise independently of the seizure burden - the conceptual basis for splitting these two nodes.

Genetic Lesion Beyond the Channelopathies

A large share of the genes in which pathogenic variants cause genetic DEE encode neither an ion channel nor a core synaptic protein, and the DEE literature explicitly separates these mechanisms from the channelopathies. The gene-defined subtypes wired at this node in this entry span Rac-GEF-dependent neuronal polarity (DOCK7), actin and protein-phosphatase-1 regulation in cortical migration (PHACTR1), receptor tyrosine kinase signalling (NTRK2), spliceosomal small nuclear RNA (RNU2-2), de-UFMylation (UFSP2), endoplasmic-reticulum stress signalling (RNF13), mitochondrial protein biosynthesis and mitochondrial trafficking (PARS2, TRAK1), purine metabolism and asparagine-linked glycosylation (ITPA, ALG13), endolysosomal acidification (ATP6V0A1), Na+/K+-ATPase pump function and neutral amino-acid transport (ATP1A2, SLC38A3), DNA repair (PNKP), and one gene in the 1q41-q42 microdeletion interval whose molecular function no reference cited here states (FBXO28). The DEE-series subtypes added under this parent extend that list with a Krebs cycle enzyme (MDH2), an endoplasmic-reticulum co-chaperone (CNPY3), a cut homeodomain transcription factor (CUX2), a cohesin subunit (SMC1A), a factor that targets arginine tRNAs for 3-methylcytosine modification (DALRD3), the v-ATPase A subunit (ATP6V1A), a nucleocytoplasmic shuttling RNA-binding protein (CELF2), a trans-Golgi network protein required for peptide hormone processing (HID1), a microtubule-associated serine-threonine kinase (MAST3), an inhibitory component of the mTOR pathway (DEPDC5), the anaphase-promoting complex subunit Cdh1 (FZR1), an ESCRT-II subunit (SNF8), the BRCA1-associated ATM activator (BRAT1), and the neuron-specific beta subunit of the AP-3 vesicle coat adaptor (AP3B2). AP3B2 is placed here rather than at the synaptic node because the AP-3 complex acts in organelle and vesicle biogenesis rather than at the synapse itself. Each functional assignment is taken from the publication cited on that subtype's own has_subtypes row. The node is kept separate from the ion-channel and synaptic lesion node because the two classes reach the shared excitation-inhibition and neurodevelopmental arms by different routes, not because the subtypes here are milder.

DOCK7 hgnc:19190 ITPA hgnc:6176 ALG13 hgnc:30881 NTRK2 hgnc:8032 TRAK1 hgnc:29947 PHACTR1 hgnc:20990 RNF13 hgnc:10057 PARS2 hgnc:30563 ATP1A2 hgnc:800 FBXO28 hgnc:29046 SLC38A3 hgnc:18044 ATP6V0A1 hgnc:865 UFSP2 hgnc:25640 RNU2-2 hgnc:10152 PNKP hgnc:9154 MDH2 hgnc:6971 CNPY3 hgnc:11968 CUX2 hgnc:19347 SMC1A hgnc:11111 DALRD3 hgnc:25536 ATP6V1A hgnc:851 CELF2 hgnc:2550 HID1 hgnc:15736 MAST3 hgnc:19036 DEPDC5 hgnc:18423 FZR1 hgnc:24824 SNF8 hgnc:17028 BRAT1 hgnc:21701 AP3B2 hgnc:567

guanyl-nucleotide exchange factor activity GO:0005085 actin binding GO:0003779 protein phosphatase 1 binding GO:0008157 transmembrane receptor protein tyrosine kinase activity GO:0004714 pre-mRNA binding GO:0036002 deUFMylase activity GO:0071567 ubiquitin protein ligase activity GO:0061630 proline-tRNA ligase activity GO:0004827 kinesin binding GO:0019894 ITP diphosphatase activity GO:0036220 N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity GO:0004577 proton transmembrane transporter activity GO:0015078 P-type sodium:potassium-exchanging transporter activity GO:0005391 L-glutamine transmembrane transporter activity GO:0015186 polynucleotide 3'-phosphatase activity GO:0046403 ATP-dependent polynucleotide 5'-hydroxyl-kinase activity GO:0051734

Downstream

Impaired Synaptic Maturation and Neurodevelopment A lesion in metabolic, transport, proteostasis, RNA-processing, cytoskeletal or genome-maintenance machinery disrupts circuit maturation directly, producing the developmental arm without requiring a primary change in channel conduction.

Neuronal Excitation-Inhibition Imbalance The same non-channel lesions also reach excitation-inhibition balance, either by limiting the supply of neurotransmitter precursors and the ion gradients that neuronal firing depends on, or by altering neuronal excitability directly.

Show evidence (2 references)

PMID:39858526 SUPPORT REVIEW SYNTHESIS Human Clinical

"many other mechanisms have been identified: impaired neurogenesis, metabolic disorders, disruption of dendrite and axon growth, maintenance and synapse formation abnormalities -synaptopathies."

Names the non-channelopathy mechanism classes that this node collects, in the review the entry already uses for the two-component DEE model.

PMID:35951482 SUPPORT REVIEW SYNTHESIS Human Clinical

Supports the breadth of gene functions represented at this node, including cell migration and organization.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Digestive 1

Feeding and Gastrointestinal Difficulties Abnormality of the gastrointestinal tract HP:0011024

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"disorders, gastrointestinal and sleep problems, together with"

Gastrointestinal problems are named among the multisystem comorbidities of the DEE group.

Musculoskeletal 1

Hypotonia HP:0001252

Show evidence (3 references)

PMID:39237642 SUPPORT INDIRECT Human Clinical

"movement and musculoskeletal disorders, gastrointestinal and sleep problems, together with"

Hypotonia falls within the movement and musculoskeletal comorbidity domain named for the DEE group. The review names the domain rather than hypotonia specifically, so the quote reaches this phenotype only by inclusion in that domain.

PMID:37421948 SUPPORT Human Clinical

"early generalized hypotonia evolving to spastic quadriparesis (13/17, 76%)"

Names hypotonia directly, and its evolution to spasticity, in most of a DEE cohort. The cohort is the TMEM63B subtype (DEE118), so it illustrates the umbrella phenotype in one genetic DEE rather than measuring its frequency across the group.

PMID:35914066 SUPPORT REVIEW SYNTHESIS Human Clinical

"abnormal muscle tone (hypotonia and spasticity)"

A second genetic DEE, GRIN2D-related DEE, in which hypotonia and spasticity are both part of the defining clinical characteristics.

Nervous System 8

Developmental Delay VERY_FREQUENT Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"characterised by seizures and frequent epileptiform activity associated with developmental slowing or"

Developmental slowing or regression is a defining, near-universal feature of the DEE group.

Intellectual Disability VERY_FREQUENT HP:0001249

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"Patients have wide-ranging comorbidities including intellectual disability, psychiatric"

Intellectual disability is listed first among the wide-ranging comorbidities of the DEE group.

Drug-Resistant Seizures VERY_FREQUENT HP:0001250

Temporal: CHRONIC Course: PROGRESSIVE Onset: INFANTILE

Sequelae: Premature Mortality

Show evidence (1 reference)

PMID:40013914 SUPPORT Human Clinical

"Developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, characterized by drug-resistant seizures and developmental slowing or regression."

Drug resistance is part of the ILAE operational definition of the DEE group.

Status Epilepticus FREQUENT HP:0002133

Show evidence (2 references)

PMID:36750385 SUPPORT Human Clinical

"The cohort comprised 510 individuals with a genetic DEE, in whom we observed CSE in 47% and NCSE in 19%."

Quantifies convulsive and nonconvulsive status epilepticus in a large cohort restricted to genetic DEE, making it directly on-scope for this umbrella entry.

PMID:36750385 SUPPORT Human Clinical

"The highest proportion of CSE occurred in patients with SCN1A-associated DEEs, including 181/203 (89%; 95% CI 84-93) patients with Dravet syndrome"

Documents the gene-dependent variation in status epilepticus risk, highest in SCN1A-related disease.

Developmental Regression HP:0002376

Show evidence (2 references)

PMID:40013914 SUPPORT Human Clinical

"characterized by drug-resistant seizures and developmental slowing or regression"

Developmental regression is named in the ILAE operational definition of the DEE group.

PMID:40831798 SUPPORT Human Clinical

"It is characterized by early-onset, drug-resistant epilepsy, abnormal electroencephalogram (EEG) findings, and developmental delay or regression."

Independently corroborates developmental regression as a defining feature of DEE.

Abnormal EEG Background EEG abnormality HP:0002353

Show evidence (1 reference)

PMID:35951482 SUPPORT Human Clinical

"characterized by early-onset, often severe epileptic seizures and EEG abnormalities"

EEG abnormality is named as a core characteristic of the DEE group.

Autistic Behavior HP:0000729

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"features, such as autism spectrum disorder and behavioural problems, movement and musculoskeletal"

Autism spectrum disorder is named among the psychiatric comorbidities of the DEE group.

Movement Disorder Abnormality of movement HP:0100022

Show evidence (2 references)

PMID:39237642 SUPPORT Human Clinical

"movement and musculoskeletal disorders, gastrointestinal and sleep problems, together with"

Movement and musculoskeletal disorders are listed among the wide-ranging DEE comorbidities.

PMID:42068099 SUPPORT REVIEW SYNTHESIS Human Clinical

"Across DEE cohorts, movement disorders occurred in roughly one-quarter to over one-half of patients, were often hyperkinetic (notably dystonia and stereotypies), and frequently combined multiple phenomenologies."

Quantifies how often movement disorders occur across DEE cohorts and names their predominant hyperkinetic phenomenology, which the comorbidity-list quote above does not.

Constitutional 1

Premature Mortality Sudden death HP:0001699

Show evidence (2 references)

PMID:36750385 SUPPORT Human Clinical

"There were 42/510 (8%) deaths among the cohort, producing a mortality rate of 6.1 per 1,000 person-years (95% CI 4.4-8.3). Cases of SUDEP accounted for 19/42 (48%) deaths."

Quantifies overall mortality and the SUDEP share in a large genetic DEE cohort.

PMID:39237642 SUPPORT Human Clinical

"disorders, gastrointestinal and sleep problems, together with an increased mortality rate."

An increased mortality rate is an explicit feature of the DEE group.

🧬

Genetic Associations

Genetic Heterogeneity Across Ion Channel and Synaptic Genes

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"genetic cause is found in >50% of patients using next generation sequencing technologies."

Establishes that a genetic etiology is identified in the majority of DEE patients, justifying the genetic DEE umbrella as the dominant subgroup.

KCNQ2

Gene: KCNQ2 hgnc:6296 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:35701389 SUPPORT Human Clinical

"KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes."

Identifies KCNQ2 among the most frequently identified causal genes in a clinical DEE exome cohort.

CDKL5

Gene: CDKL5 hgnc:11411 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:35701389 SUPPORT Human Clinical

"KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes."

Identifies CDKL5 among the most frequently identified causal genes in a clinical DEE exome cohort.

SCN1A

Gene: SCN1A hgnc:10585 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:35701389 SUPPORT Human Clinical

"KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes."

Identifies SCN1A among the most frequently identified causal genes in a clinical DEE exome cohort.

SCN2A

Gene: SCN2A hgnc:10588 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:39613335 SUPPORT Human Clinical

"The most frequently reported genes in the survey were SCN1A (16%), followed by KCNQ2 (5.6%) and SCN2A (5%)."

Establishes SCN2A among the three most frequently implicated genetic DEE genes.

SCN8A

Gene: SCN8A hgnc:10596 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:36750385 SUPPORT Human Clinical

"Four genes were associated with SUDEP: SCN1A, SCN2A, SCN8A, and STXBP1."

Establishes SCN8A as a genetic DEE gene and specifically one carrying SUDEP risk.

PCDH19

Gene: PCDH19 hgnc:14270 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:36750385 SUPPORT Human Clinical

"We included patients with a pathogenic variant in the genes SCN1A, SCN2A, SCN8A, SYNGAP1, NEXMIF, CHD2, PCDH19, STXBP1, GRIN2A, KCNT1, and KCNQ2"

Lists PCDH19 among the frequently observed genetic DEE genes assembled for a dedicated genetic DEE cohort study.

STXBP1

Gene: STXBP1 hgnc:11444 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:35701389 SUPPORT Human Clinical

"KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes."

Identifies STXBP1 among the most frequently identified causal genes in a clinical DEE exome cohort.

DOCK7

Gene: DOCK7 hgnc:19190 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:24814191 SUPPORT Human Clinical

"DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex."

States the neurodevelopmental function through which the DOCK7 lesion reaches the pathograph.

ITPA

Gene: ITPA hgnc:6176 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:35098521 SUPPORT Human Clinical

"We report two additional cases of ITPA-associated neurodegeneration and two pathogenic compound heterozygous variants."

Documents biallelic (compound heterozygous) ITPA variants in further patients.

ALG13

Gene: ALG13 hgnc:30881 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:33410528 SUPPORT Human Clinical

"Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis."

Establishes the recurrent allele, the female predominance, and the normal glycosylation screen.

FRRS1L

Gene: FRRS1L hgnc:1362 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:27236917 SUPPORT Human Clinical

"Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood."

States the glutamatergic mechanism by which the FRRS1L lesion acts.

NTRK2

Gene: NTRK2 hgnc:8032 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:34425480 SUPPORT Human Clinical

"Five cases of NTRK2-related DEE were identified. Four had a previously described recurrent variant in NTRK2 and one had a novel variant."

Establishes NTRK2 as causal for DEE in a reported case series.

ADAM22

Gene: ADAM22 hgnc:201 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:35373813 SUPPORT Human Clinical

"Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy."

States both the recessive gene-disease relationship and the postsynaptic LGI1-receptor function that places it in the synaptic arm.

TRAK1

Gene: TRAK1 hgnc:29947 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:28364549 SUPPORT Human Clinical

"This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder."

Establishes TRAK1 as a neurodevelopmental disease gene acting through mitochondrial dynamics.

PHACTR1

Gene: PHACTR1 hgnc:20990 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:30256902 SUPPORT Model Organism

"Acute knockdown of mouse Phactr1 using in utero electroporation caused defects in cortical neuron migration during corticogenesis, which were rescued by an RNAi-resistant PHACTR1 but not by the four mutants."

Establishes the cortical neuron migration defect through which the PHACTR1 lesion reaches the pathograph, with the mutant alleles failing to rescue.

RNF13

Gene: RNF13 hgnc:10057 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:30595371 SUPPORT Human Clinical

States the gain-of-function ER-stress mechanism by which the RNF13 lesion acts.

PARS2

Gene: PARS2 hgnc:30563 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29915213 SUPPORT Human Clinical

"Our study provides further evidence for validating the role of PARS2 in the pathology of related infantile-onset encephalopathy, contributing to the phenotypic features of this condition, and providing clinical and molecular insight for the diagnosis of this disease entity."

Establishes PARS2 as causal for infantile-onset encephalopathy, in the report that widened its phenotype.

ACTL6B

Gene: ACTL6B hgnc:160 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:30656450 SUPPORT Human Clinical

"Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE."

Establishes ACTL6B as causal for a syndromic DEE.

FGF13

Gene: FGF13 hgnc:3670 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:33245860 SUPPORT Human Clinical

"The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence."

Establishes the FGF13/FHF2 identity and X-linkage recorded for this subtype.

PMID:33245860 SUPPORT In Vitro

"These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants."

Source for the gain-of-function mechanism recorded in the notes, from co-expression of mutant FHF2A with Nav1.6.

PMID:33245860 SUPPORT Human Clinical

"Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy"

Supports the CAUSATIVE relationship of FGF13 to this subtype.

ATP1A2

Gene: ATP1A2 hgnc:800 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:33880529 SUPPORT In Vitro

"We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function."

Establishes loss of Na+/K+-ATPase pump function as the molecular consequence.

FBXO28

Gene: FBXO28 hgnc:29046 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:33280099 SUPPORT Human Clinical

Establishes FBXO28 as a monogenic cause of DEE.

SLC38A3

Gene: SLC38A3 hgnc:18044 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:34605855 SUPPORT Human Clinical

Establishes SLC38A3 as a DEE gene acting through glutamine homeostasis.

ATP6V0A1

Gene: ATP6V0A1 hgnc:865 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:34909687 SUPPORT Human Clinical

Establishes ATP6V0A1 as causal for DEE and records the genotype-phenotype split.

UFSP2

Gene: UFSP2 hgnc:25640 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:33473208 SUPPORT Human Clinical

"Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy."

Establishes the recessive UFSP2 neurodevelopmental phenotype as a distinct disease from the dominant skeletal one.

CACNA2D1

Gene: CACNA2D1 hgnc:1399 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:35293990 SUPPORT Human Clinical

"Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients."

Establishes biallelic CACNA2D1 loss of function as causal, placing the lesion in the calcium-channel arm.

SV2A

Gene: SV2A hgnc:20566 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:26002053 SUPPORT Human Clinical

"Levetiracetam, which binds to SV2A, was not effective as an antiepileptic medication."

Records that the drug whose target this gene encodes did not control the proband's seizures.

PMID:26002053 SUPPORT Human Clinical

"Exome sequencing identified a homozygous arginine to glutamine mutation in amino acid position 383 (R383Q) in exon 5 of the SV2A gene. Both parents were carriers for the R383Q variant, suggesting that R383Q is a recessive mutation."

Source for the single homozygous R383Q variant in one consanguineous family recorded in the notes.

PMID:26002053 SUPPORT Human Clinical

"Our report provides the elusive evidence that an SV2A mutation can be a cause of epilepsy in humans."

Supports the CAUSATIVE relationship, resting on this one family.

RNU2-2

Gene: RNU2-2 hgnc:10152 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:40210679 SUPPORT Human Clinical

"Here, we report that recurrent germline mutations in RNU2-2 (previously known as pseudogene RNU2-2P), a 191-bp gene that encodes the U2-2 snRNA, are responsible for a related disorder."

Establishes the gene, its former pseudogene designation, and its causal role.

BAIAP2

Gene: BAIAP2 hgnc:947 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:41133935 SUPPORT Human Clinical

"Using whole exome/genome sequencing, we identified de novo missense variants in BAIAP2 in six patients with DEEs."

Establishes BAIAP2 as a causal DEE gene.

LGI1

Gene: LGI1 hgnc:6572 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:40455867 SUPPORT Human Clinical

"LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates excitatory synaptic transmission and neuronal excitability in the brain."

States the synaptic mechanism through which the LGI1 lesion reaches neuronal excitability.

PMID:40455867 SUPPORT Human Clinical

Supports the CAUSATIVE relationship of biallelic LGI1 variants to DEE121.

PMID:40455867 SUPPORT In Vitro

"Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding."

Source for the reduced secretion and ADAM22 binding recorded in the notes.

PNKP

Gene: PNKP hgnc:9154 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:20118933 SUPPORT Human Clinical

"we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms."

Establishes PNKP as the causal gene and records the allele-dependent severity.

SCN3A

Gene: SCN3A hgnc:10590 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29466837 SUPPORT Human Clinical

"Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala)."

Establishes SCN3A as causal for DEE62.

KCNC2

Gene: KCNC2 hgnc:6234 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:35314505 SUPPORT Human Clinical

Establishes KCNC2 as causal across a spectrum whose severe pole is DEE103.

KCNH5

Gene: KCNH5 hgnc:6254 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:36307226 SUPPORT Human Clinical

"We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants."

Establishes the KCNH5 variant series behind DEE112.

KCNT2

Gene: KCNT2 hgnc:18866 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29740868 SUPPORT Human Clinical

"We report on 2 females with de novo variants in KCNT2 with West syndrome followed by Lennox-Gastaut syndrome or with DEE with migrating focal seizures."

Establishes KCNT2 as causal for DEE57.

TMEM63B

Gene: TMEM63B hgnc:17735 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:37421948 SUPPORT Human Clinical

Establishes TMEM63B as causal for this DEE and names the channel class.

GABRB2

Gene: GABRB2 hgnc:4082 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29100083 SUPPORT Human Clinical

"By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25."

Establishes GABRB2 as causal for DEE.

GABRA2

Gene: GABRA2 hgnc:4076 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29961870 SUPPORT Human Clinical

Establishes the de novo GABRA2 variant causal for DEE78.

GABRA5

Gene: GABRA5 hgnc:4079 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29961870 SUPPORT Human Clinical

"Using whole-genome sequencing, we identified a novel de novo missense variant in GABRA5 (c.880G > C, p.V294L) in a patient with severe early-onset epilepsy and developmental delay."

Establishes the de novo GABRA5 variant causal for DEE79.

GABBR2

Gene: GABBR2 hgnc:4507 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29100083 SUPPORT Human Clinical

"By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25."

Establishes GABBR2 as causal for DEE.

SLC32A1

Gene: SLC32A1 hgnc:11018 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:36073542 SUPPORT Human Clinical

"Using exome sequencing, we identified four individuals with a developmental and epileptic encephalopathy and de novo missense variants in SLC32A1."

Establishes de novo SLC32A1 variants as causal for DEE114.

NSF

Gene: NSF hgnc:8016 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:31675180 SUPPORT Human Clinical

"Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset."

Establishes NSF as causal for DEE96.

NAPB

Gene: NAPB hgnc:15751 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:26235277 SUPPORT Human Clinical

Establishes the homozygous NAPB lesion causal for DEE107.

SYNJ1

Gene: SYNJ1 hgnc:11503 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:27435091 SUPPORT Human Clinical

Establishes recessive SYNJ1 defects as causal for DEE53.

MDH2

Gene: MDH2 hgnc:6971 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:27989324 SUPPORT Human Clinical

Establishes biallelic MDH2 variants as causal for DEE51.

CNPY3

Gene: CNPY3 hgnc:11968 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29394991 SUPPORT Human Clinical

Establishes biallelic CNPY3 variants as causal for DEE60.

CUX2

Gene: CUX2 hgnc:19347 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29630738 SUPPORT Human Clinical

"We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE)."

Establishes the recurrent CUX2 variant as causal for DEE67.

SMC1A

Gene: SMC1A hgnc:11111 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:28166369 SUPPORT Human Clinical

"Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein."

Establishes truncating SMC1A variants as causal for DEE85.

DALRD3

Gene: DALRD3 hgnc:25536 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:32427860 SUPPORT Human Clinical

"Notably, we identify a homozygous nonsense mutation in the DALRD3 gene that impairs m3C formation in human patients exhibiting developmental delay and early-onset epileptic encephalopathy."

Establishes the homozygous DALRD3 lesion as causal for DEE86 and names the tRNA-modification defect.

ATP6V1A

Gene: ATP6V1A hgnc:851 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29668857 SUPPORT Human Clinical

Establishes de novo ATP6V1A variants as causal for DEE93.

CELF2

Gene: CELF2 hgnc:2550 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:33131106 SUPPORT Human Clinical

Establishes heterozygous CELF2 variants as causal for DEE97.

HID1

Gene: HID1 hgnc:15736 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:33999436 SUPPORT Human Clinical

"Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients."

Establishes biallelic HID1 variants as causal for DEE105.

MAST3

Gene: MAST3 hgnc:19036 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:34185323 SUPPORT Human Clinical

"We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3)."

Establishes de novo MAST3 kinase-domain variants as causal for DEE108.

DEPDC5

Gene: DEPDC5 hgnc:18423 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:36067010 SUPPORT Human Clinical

"We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5."

Establishes germline biallelic DEPDC5 variants as causal for DEE111 and separates them from the heterozygous focal-epilepsy phenotype.

FZR1

Gene: FZR1 hgnc:24824 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:34788397 SUPPORT Human Clinical

Establishes de novo FZR1 variants as causal for DEE109.

SNF8

Gene: SNF8 hgnc:17028 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:38423010 SUPPORT Human Clinical

Establishes biallelic SNF8 variants as causal across the spectrum whose severe pole is DEE115.

BRAT1

Gene: BRAT1 hgnc:21701 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:37344571 SUPPORT Human Clinical

Establishes the BRAT1 genotype-phenotype split that assigns this gene to the lethal phenotype curated here.

AP3B2

Gene: AP3B2 hgnc:567 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:27889060 SUPPORT Human Clinical

"AP3B2 encodes the neuron-specific subunit of the AP-3 complex."

Names the gene product whose loss produces DEE48, and the neuronal restriction that confines the phenotype to the nervous system.

💊

Medical Actions

Anti-Seizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: anticonvulsant agent NCIT:C264

Platform: Small molecule

Broad-spectrum and gene-informed anti-seizure medication selection, guided where possible by the specific ion-channel gain- versus loss-of-function mechanism (e.g. sodium-channel blockers are often beneficial in SCN2A/SCN8A gain-of-function DEE but can worsen seizures in SCN1A-related Dravet syndrome loss-of-function disease).

Mechanism Target:

INHIBITS Hypersynchronous Network Activity and Seizures — Antiseizure medication suppresses the seizure-generating network activity. Which agent helps versus harms is determined by the upstream channel lesion: sodium-channel blockers benefit SCN2A/SCN8A gain-of-function disease but worsen SCN1A loss-of-function Dravet syndrome.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"Understanding the functional consequences of the SCN1A pathogenic variant informs management, as some sodium channel blocker (SCB) antiseizure medications (ASMs) may exacerbate seizures in Dravet syndrome, whereas patients with the non-Dravet, EIDEE phenotype due to GOF variants may respond to..."

Directly supports the gain- versus loss-of-function prescribing logic stated in this mechanism description: sodium-channel blockers exacerbate seizures in SCN1A loss-of-function Dravet syndrome but benefit gain-of-function disease. This is the entry's most clinically consequential claim and is now cited rather than resting on notes.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"Holistic management, which encompasses antiseizure therapies and care for multimorbidities, is determined both by epilepsy syndrome and aetiology."

Supports antiseizure therapy as the pharmacological cornerstone, with choice determined by syndrome and aetiology.

Ketogenic Diet

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Dietary therapy used as an adjunct or alternative treatment for drug-resistant seizures in genetic DEE, with demonstrated efficacy across several DEE subtypes and occasional reduction of pharmacological need.

Mechanism Target:

INHIBITS Hypersynchronous Network Activity and Seizures — Ketogenic dietary therapy suppresses the seizure-generating network activity rather than correcting the upstream genetic lesion.

Show evidence (1 reference)

PMID:40831798 SUPPORT Human Clinical

"The ketogenic diet (KD) is a well-established non-pharmacological treatment for refractory epilepsy and has demonstrated therapeutic efficacy in several DEE subtypes."

Supports the seizure-directed effect of dietary therapy across DEE subtypes.

Show evidence (2 references)

PMID:40831798 SUPPORT Human Clinical

"The ketogenic diet (KD) is a well-established non-pharmacological treatment for refractory epilepsy and has demonstrated therapeutic efficacy in several DEE subtypes."

DEE-specific review establishing ketogenic diet efficacy across DEE subtypes.

PMID:40831798 SUPPORT Human Clinical

"In certain cases, it may reduce or even eliminate the need for pharmacological interventions."

Documents that dietary therapy can reduce antiseizure medication burden in some patients.

Cannabidiol

Action: Pharmacotherapy NCIT:C15986

Agent: cannabidiol CHEBI:69478

Platform: Small molecule

Randomised placebo-controlled trials demonstrated efficacy in Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, with median target-seizure reductions of 38.9%, 41.9%, and 48.6% respectively. One of the few DEE therapies supported by RCT-level evidence.

Mechanism Target:

INHIBITS Hypersynchronous Network Activity and Seizures — Symptomatic suppression of seizure generation; does not address the developmental arm of the mechanism.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"Randomised placebo-controlled trials (RCTs) of cannabidiol demonstrated efficacy in Dravet syndrome , LGS and TSC, with significant median percent reduction s in target seizures"

RCT evidence that the effect is on target seizures, i.e. the seizure node of the pathograph.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"Randomised placebo-controlled trials (RCTs) of cannabidiol demonstrated efficacy in Dravet syndrome , LGS and TSC, with significant median percent reduction s in target seizures"

Establishes RCT-level efficacy of cannabidiol across three DEE syndromes. The reported median seizure reductions of 38.9%, 41.9% and 48.6% follow immediately in the source but are interleaved with inline citation markers, so the quote stops before them.

Fenfluramine

Action: Pharmacotherapy NCIT:C15986

Agent: fenfluramine CHEBI:5000

Platform: Small molecule

Serotonergic agent approved as add-on therapy for Dravet syndrome and subsequently for Lennox-Gastaut syndrome and CDKL5 deficiency disorder. Requires cardiac monitoring given the valvulopathy concerns arising from its former use as an obesity drug.

Mechanism Target:

INHIBITS Hypersynchronous Network Activity and Seizures — Symptomatic suppression of seizure generation via serotonergic modulation.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"The higher dose of fenfluramine was associated with a significantly greater likelihood of achieving a >50% (68% versus 12% placebo) and a >75% reduction (50% versus 2% placebo) in convulsive seizure frequency"

RCT evidence of dose-dependent convulsive-seizure reduction, targeting the seizure node.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

Documents dose-dependent RCT efficacy of fenfluramine as add-on therapy in Dravet syndrome, with the effect sizes quoted.

Stiripentol

Action: Pharmacotherapy NCIT:C15986

Agent: stiripentol NCIT:C152433

Platform: Small molecule

Approved as adjunctive therapy for Dravet syndrome in combination with clobazam, where a randomised controlled trial demonstrated clear efficacy. CHEBI has no stiripentol term, so the agent is bound to NCIT following the documented NCIT-fallback convention for drugs lacking a CHEBI entry.

Mechanism Target:

INHIBITS Hypersynchronous Network Activity and Seizures — Symptomatic suppression of seizure generation, used in combination with clobazam.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"In Dravet syndrome, a RCT of stiripentol demonstrated clear efficacy"

RCT evidence that stiripentol acts on the seizure arm in the archetypal genetic DEE.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"In Dravet syndrome, a RCT of stiripentol demonstrated clear efficacy"

Establishes RCT-level efficacy of stiripentol in the archetypal genetic DEE.

Multidisciplinary Developmental Supportive Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Physical, occupational, and speech therapy along with early intervention services to support developmental outcomes independent of seizure control.

Mechanism Target:

MODULATES Developmental Encephalopathy Component — Developmental and rehabilitative support addresses the developmental arm of the mechanism, which persists independently of seizure control and is therefore not reachable by antiseizure therapy.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"Problems change with age and patients require substantial support throughout life, placing a high psychosocial burden on parents, carers and the community."

Supports lifelong developmental support as the management response to the non-seizure arm of the disease.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"Problems change with age and patients require substantial support throughout life, placing a high psychosocial burden on parents, carers and the community."

Supports lifelong multidisciplinary supportive care as a core management component independent of seizure control.

Precision Medicine Guided by Molecular Diagnosis

Action: Targeted Therapy NCIT:C93352

Platform: Other

Identification of the specific causal gene and the functional direction of the variant (gain- versus loss-of-function) enables aetiology-directed therapy selection and is increasingly the entry point to gene-targeted treatments including antisense oligonucleotides and gene therapy.

Mechanism Target:

MODULATES Genetic Lesion in an Ion Channel or Synaptic Gene — The only entry-level treatment addressing the upstream cause rather than the seizure output. Establishing the specific gene and the functional direction of the variant redirects therapy at the lesion itself, and is the gateway to gene-targeted modalities (antisense oligonucleotides, gene therapy) still in development.

Show evidence (1 reference)

PMID:39237642 SUPPORT Human Clinical

"Identification of the underlying aetiology enables the development of precision medicines to improve the long-term outcome of patients with these devastating diseases."

Supports the aetiology-directed link from molecular diagnosis back to the causal genetic lesion node.

Show evidence (2 references)

PMID:39237642 SUPPORT Human Clinical

"Identification of the underlying aetiology enables the development of precision medicines to improve the long-term outcome of patients with these devastating diseases."

Supports molecular diagnosis as the enabler of precision therapy in the DEE group.

PMID:35701389 SUPPORT Human Clinical

"Finding the molecular cause led to management changes in 36% of patients with DEEs."

Quantifies the clinical actionability of molecular diagnosis in a real-world DEE cohort.

🔬

Diagnosis

Exome or Genome Sequencing

Genome-wide sequencing (exome or genome, ideally as a trio to enable de novo confirmation) is the first-line molecular test given the extreme genetic heterogeneity of the group. Diagnostic yield is substantially higher for seizure onset under two years of age.

Show evidence (2 references)

PMID:35701389 SUPPORT Human Clinical

"Of the 103 patients recruited (54 males, 49 females; aged 2 weeks-17 years), the genetic aetiology was identified in 36 out of 103 (35%) with management implications in 13 out of 36."

Establishes the diagnostic yield of exome sequencing in routine clinical care of children with DEE.

PMID:35701389 SUPPORT Human Clinical

"Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset."

Documents the age-of-onset dependence of diagnostic yield, informing test prioritisation.

📊

Prevalence

Italy (15 tertiary epilepsy centres, molecular diagnoses 2012-2022)

Period Prevalence 2.6 per 100,000 1–9 per 100,000

Genetic-DEE-specific figure derived from molecularly diagnosed patients across 98 genes, accumulated over the 11-year window 2012-2022 and used by the authors as a proxy for the prevalence rate. The source calls this a "mean incidence proportion", but it is a cumulative diagnosed proportion over a defined interval rather than an annual rate, so it is recorded as PERIOD_PREVALENCE with the observation window stated here. This is a lower bound: it counts only patients who received a molecular diagnosis within the surveyed gene panel, so undiagnosed and non-panel genetic DEE are not captured.

Show evidence (1 reference)

PMID:39613335 SUPPORT Human Clinical

"We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions."

The only population-scale estimate specific to genetic DEE rather than DEE of all etiologies.

Wellington region, New Zealand (population-based paediatric cohort)

Point Prevalence 112.0 per 100,000 >1 in 1,000

Point prevalence of DEE among children in a population-based cohort. This figure is for DEE overall rather than the genetic subgroup specifically, which comprises the majority of DEE once sequencing is applied.

Show evidence (1 reference)

PMID:36581463 SUPPORT INDIRECT Human Clinical

"Point prevalence for the broad group of children with epilepsy and developmental impairment was 175/100,000 children (95% CI 149-203; DEE 112 and ID+E 63/100,000 children)."

Reports DEE point prevalence of 112 per 100,000 children. The study measures DEE of all etiologies rather than the genetic subgroup alone, so it bounds this entry's occurrence from above rather than measuring it.

Wellington region, New Zealand (population-based paediatric cohort)

Lifetime Prevalence 169.0 per 100,000 (144.0–199.0) >1 in 1,000

Cumulative incidence of DEE per 100,000 children (approximately 1 in 590), accrued to age 16 years, for DEE overall rather than the genetic subgroup specifically. Recorded as LIFETIME_PREVALENCE rather than ANNUAL_INCIDENCE: the source reports a cumulative proportion affected by age 16, not a rate of new cases per year, and reading it as an annual rate would overstate DEE occurrence by roughly an order of magnitude.

Show evidence (1 reference)

PMID:36581463 SUPPORT INDIRECT Human Clinical

"Cumulative incidence for DEE was 169/100,000 children (95% CI 144-199)"

Reports cumulative incidence of DEE. The measure covers DEE of all etiologies rather than genetic DEE alone, so it bounds this entry's occurrence from above rather than measuring it.

📊

Related Datasets

Excitatory cortical neurons from CDKL5 deficiency disorder patient-derived organoids show early hyperexcitability not identified in neurogenin2 induced neurons [Ampliseq] geo:GSE319080

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy resulting from variants in cyclin-dependent kinase-like 5 (CDKL5) that lead to impaired kinase activity or loss of function. CDD is one of the most common genetic etiologies identified in epilepsy cohorts. To study how CDKL5 variants impact human neuronal activity, gene expression and morphology, CDD patient-derived induced pluripotent stem cells and their isogenic controls were differentiated into excitatory neurons using either an NGN2 induction protocol or a guided cortical organoid differentiation.

human n=12

PMID:40930428

Identified by GEO DataSets index search for Genetic Developmental and Epileptic Encephalopathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability geo:GSE281622

Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how a single disorder differentially affects distinct brain regions by using human patient iPSC-derived cortical- and hippocampal-ganglionic eminence assembloids to model Developmental and Epileptic Encephalopathy 13 (DEE-13), a condition arising from gain-of-function mutations in the SCN8A gene.

human SINGLE CELL RNA SEQ n=6

PMID:40925365

Variability vs. phenotype: Multimodal analysis of Dravet syndrome brain organoids powered by deep learning geo:GSE256142

Dravet Syndrome (DS) is a developmental epileptic encephalopathy (DEE) driven by pathogenic variants in SCN1A gene. Brain organoids (BO) have emerged as reliable models for neurodevelopmental genetic disorders, reproducing human brain developmental milestones and rising as a promising drug testing tool. Here, we determined the underlying molecular DS pathophysiology affecting neuronal connectivity, revealing an early onset excitatory-inhibitory imbalance in maturing DS organoids circuitry. However, neuronal circuitry modeling in BO remains hampered by the notorious inter- and intra-organoid variability.

human BULK RNA SEQ n=18

PMID:41323276

{ }

Source YAML

click to show

name: Genetic Developmental and Epileptic Encephalopathy
creation_date: "2026-07-31T00:09:41Z"
description: >-
  Genetic developmental and epileptic encephalopathy (DEE) is a broad,
  genetically heterogeneous umbrella group of severe early-onset epilepsy
  syndromes in which pathogenic variants in any of more than nine hundred
  genes cause both refractory seizures and developmental impairment that
  exceeds what would be expected from the epileptic activity alone. Under
  the 2017 ILAE classification, "developmental and epileptic encephalopathy"
  recognizes two overlapping but separable contributors to the encephalopathy:
  a developmental component intrinsic to the underlying genetic etiology, and
  an epileptic component in which frequent seizures and epileptiform activity
  themselves worsen cognitive and behavioral outcome. Individual monogenic
  forms (numbered DEE1-DEE121+ in OMIM/MONDO, e.g. SCN1A-related Dravet
  syndrome, STXBP1 encephalopathy, KCNQ2-DEE, SCN2A-DEE, SCN8A-DEE,
  CDKL5 deficiency disorder, SYNGAP1-related DEE) are curated as their own
  dismech entries; this entry captures the mechanisms, phenotypic core, and
  clinical approach shared across the umbrella group.

  Modelling note: this is deliberately curated as an umbrella Disease rather
  than a Grouping over the gene-specific entries. A Grouping cannot carry
  pathophysiology, and the shared two-component DEE mechanism - the very thing
  that makes DEE a coherent concept - is the primary content here. The existing
  Epilepsy and Diabetes_Mellitus entries set the same precedent. Gene-specific
  detail (variant spectra, gene-specific EEG signatures, per-gene natural
  history and treatment response) belongs on the child entries, not here.
  Numbered forms that do not yet have a dismech entry of their own are
  enumerated in has_subtypes instead, each anchored to its MONDO term and to
  its causal gene, so that the concept and the gene are both recorded until a
  full entry exists. A subtype row is therefore a placeholder for a child
  entry, not a substitute for one.
category: Genetic
disease_term:
  preferred_term: genetic developmental and epileptic encephalopathy
  term:
    id: MONDO:0100062
    label: genetic developmental and epileptic encephalopathy
parents:
- Epilepsy
- Neurodevelopmental Disorder
synonyms:
- developmental and epileptic encephalopathy
- hereditary developmental and epileptic encephalopathy
- genetic epileptic encephalopathy
- early-onset epileptic encephalopathy
prevalence:
- population: Italy (15 tertiary epilepsy centres, molecular diagnoses 2012-2022)
  measure_type: PERIOD_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.6
  notes: >-
    Genetic-DEE-specific figure derived from molecularly diagnosed patients
    across 98 genes, accumulated over the 11-year window 2012-2022 and used by
    the authors as a proxy for the prevalence rate. The source calls this a
    "mean incidence proportion", but it is a cumulative diagnosed proportion
    over a defined interval rather than an annual rate, so it is recorded as
    PERIOD_PREVALENCE with the observation window stated here. This is a lower
    bound: it counts only patients who received a molecular diagnosis within the
    surveyed gene panel, so undiagnosed and non-panel genetic DEE are not
    captured.
  evidence:
  - reference: PMID:39613335
    reference_title: National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We included 1568 unique patients and found a mean incidence proportion
      of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values
      across most Italian regions.
    explanation: >-
      The only population-scale estimate specific to genetic DEE rather than DEE
      of all etiologies.
- population: Wellington region, New Zealand (population-based paediatric cohort)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 112.0
  notes: >-
    Point prevalence of DEE among children in a population-based cohort. This
    figure is for DEE overall rather than the genetic subgroup specifically,
    which comprises the majority of DEE once sequencing is applied.
  evidence:
  - reference: PMID:36581463
    reference_title: Epidemiology of Developmental and Epileptic Encephalopathy and of Intellectual Disability and Epilepsy in Children.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Point prevalence for the broad group of children with epilepsy and
      developmental impairment was 175/100,000 children (95% CI 149-203; DEE 112
      and ID+E 63/100,000 children).
    explanation: >-
      Reports DEE point prevalence of 112 per 100,000 children. The study measures
      DEE of all etiologies rather than the genetic subgroup alone, so it bounds
      this entry's occurrence from above rather than measuring it.
- population: Wellington region, New Zealand (population-based paediatric cohort)
  measure_type: LIFETIME_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 169.0
  rate_low: 144.0
  rate_high: 199.0
  notes: >-
    Cumulative incidence of DEE per 100,000 children (approximately 1 in 590),
    accrued to age 16 years, for DEE overall rather than the genetic subgroup
    specifically. Recorded as LIFETIME_PREVALENCE rather than ANNUAL_INCIDENCE:
    the source reports a cumulative proportion affected by age 16, not a rate of
    new cases per year, and reading it as an annual rate would overstate DEE
    occurrence by roughly an order of magnitude.
  evidence:
  - reference: PMID:36581463
    reference_title: Epidemiology of Developmental and Epileptic Encephalopathy and of Intellectual Disability and Epilepsy in Children.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cumulative incidence for DEE was 169/100,000 children (95% CI
      144-199)
    explanation: >-
      Reports cumulative incidence of DEE. The measure covers DEE of all
      etiologies rather than genetic DEE alone, so it bounds this entry's
      occurrence from above rather than measuring it.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Genetic DEE is most commonly regarded as a de novo dominant disease class,
    and the highest-prevalence individual entities (SCN1A, SCN2A, STXBP1,
    KCNQ2, SCN8A) are indeed de novo autosomal dominant, so affected children
    typically have unaffected parents. Parental germline mosaicism gives a small
    but non-zero sibling recurrence risk. Note that this reflects the
    distribution of *cases*: counted by *gene*, more DEE genes follow autosomal
    recessive than dominant inheritance.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic DEEs are most commonly regarded as de novo  dominant disorders ;
      however, more DEE genes follow autosomal recessive than dominant
      inheritance, with a small number
      following X-linked or mitochondrial inheritance patterns
    explanation: >-
      Establishes de novo dominant inheritance as the prevailing mode while
      making explicit the gene-count versus case-count distinction that this
      description records.
  - reference: PMID:39613335
    reference_title: National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic or likely pathogenic variants in genes with an autosomal
      dominant inheritance pattern occurred in 77% (n=1207) patients; 17%
      (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive
      inheritance.
    explanation: >-
      Quantifies the case-level distribution of inheritance modes across 1568
      molecularly diagnosed genetic DEE patients, confirming autosomal dominant
      as the predominant mode by case count.
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Parental mosaicism places parents at an
      increased risk of having a second child with a DEE, as a small population
      of their sperm or ova carry the
      pathogenic variant.
    explanation: >-
      Supports the non-zero sibling recurrence risk stated in this description,
      which would otherwise be an uncited claim.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Counted by gene rather than by case, more DEE genes follow autosomal
    recessive than dominant inheritance. Biallelic forms are individually rarer
    but collectively numerous, and are enriched in consanguineous families and
    among metabolic and glycosylation-pathway DEE genes.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      more DEE genes follow autosomal recessive than dominant inheritance
    explanation: >-
      Directly supports autosomal recessive inheritance as the most common mode
      when DEE genes are counted individually.
  - reference: PMID:39613335
    reference_title: National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      6%
      (n=90) in genes with autosomal recessive inheritance.
    explanation: >-
      Quantifies the autosomal recessive share of molecularly diagnosed genetic
      DEE cases, contrasting with its larger share of the gene count.
- name: X-linked inheritance
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  description: >-
    A small number of genetic DEE genes are X-linked, including CDKL5, PCDH19,
    and ARX, together accounting for 17% of molecularly diagnosed cases.
    X-linked disease and mosaicism complicate cellular targeting for emerging
    gene therapies. PCDH19 departs from the usual X-linked pattern in that
    heterozygous females are affected while hemizygous males are typically
    unaffected transmitting carriers; that observation is recorded in the
    PCDH19 genetic entry, while its mechanistic explanation (cellular
    interference) is left to the PCDH19 Clustering Epilepsy child entry, since
    no source cached here states it.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with a small number
      following X-linked or mitochondrial inheritance patterns
    explanation: >-
      Establishes X-linked inheritance as a recognized but numerically minor
      mode among DEE genes.
  - reference: PMID:39613335
    reference_title: National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      17%
      (n=271) in X-linked genes
    explanation: >-
      Quantifies the X-linked share of molecularly diagnosed genetic DEE cases.
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mosaicism and X-linked disorders further complicate cellular targeting.
    explanation: >-
      Supports the therapeutic-targeting caveat noted for X-linked genetic DEE.
has_subtypes:
- name: DEE6B
  display_name: Developmental and epileptic encephalopathy 6B, non-Dravet (SCN1A)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 6B
    term:
      id: MONDO:0030268
      label: developmental and epileptic encephalopathy 6B
  genes:
  - preferred_term: SCN1A
    term:
      id: hgnc:10585
      label: SCN1A
  description: 'The non-Dravet pole of SCN1A developmental and epileptic encephalopathy. MONDO treats
    this as a class distinct from both Dravet syndrome and SCN1A DEE6A, and the founding cohort argues
    the same clinically: seizure onset at 6 to 12 weeks, profound developmental impairment with no speech
    and no ambulation, and a hyperkinetic movement disorder with prominent oral dyskinesia, a combination
    the authors describe as readily distinguishable from Dravet syndrome. Eight of the nine children carried
    the recurrent missense variant p.Thr226Met. Dravet syndrome itself is curated as the separate Dravet_syndrome
    entry, and SCN1A is carried in this entry''s genetic section and wired to the ion-channel and synaptic
    lesion node, so this row records only the non-Dravet concept.'
  evidence:
  - reference: PMID:28794249
    reference_title: 'Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met
      phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily
      distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile
      seizures plus.
    explanation: Establishes the non-Dravet SCN1A encephalopathy that this subtype term names, and its
      separation from Dravet syndrome.
  - reference: PMID:28794249
    reference_title: 'Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met
      phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures,
      or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory,
      and 7 of 9 required a gastrostomy.
    explanation: Quantifies the onset window and the severity that distinguish this subtype from Dravet
      syndrome.
- name: DEE23
  display_name: Developmental and epileptic encephalopathy 23 (DOCK7)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 23
    term:
      id: MONDO:0014371
      label: developmental and epileptic encephalopathy, 23
  genes:
  - preferred_term: DOCK7
    term:
      id: hgnc:19190
      label: DOCK7
  description: Biallelic truncating DOCK7 variants. The founding report described three girls from
    two nonconsanguineous families with dysmorphic features, early-onset intractable epilepsy, intellectual
    disability and cortical blindness, all compound heterozygous for truncating DOCK7 alleles. DOCK7
    encodes a Rac guanine nucleotide exchange factor implicated in the genesis and polarization of
    newborn pyramidal neurons and in the morphological differentiation of cortical GABAergic interneurons,
    so the lesion is developmental rather than primarily one of channel conduction.
  evidence:
  - reference: PMID:24814191
    reference_title: Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical
      blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe here three girls from two nonconsanguineous families affected by a clinical
      entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual
      disability, and cortical blindness.
    explanation: Establishes the DEE23 clinical entity, including the cortical blindness that distinguishes
      it.
  - reference: PMID:24814191
    reference_title: Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical
      blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sanger sequencing confirmed that all three individuals are compound heterozygotes for
      these truncating mutations in DOCK7.
    explanation: Establishes biallelic truncating DOCK7 variants as the lesion defining this subtype.
- name: DEE35
  display_name: Developmental and epileptic encephalopathy 35 (ITPA)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 35
    term:
      id: MONDO:0014719
      label: developmental and epileptic encephalopathy, 35
  genes:
  - preferred_term: ITPA
    term:
      id: hgnc:6176
      label: ITPA
  description: 'Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency, a purine pathway defect.
    Reported as an infantile-onset epileptic encephalopathy with a lethal course: infantile-onset
    neurodegeneration, progressive microcephaly and epilepsy, with cardiomyopathy in 42% of those
    in whom it was explicitly evaluated. This subtype sits in the metabolic rather than the channelopathy
    arm of the DEE umbrella, and MONDO also files it under inborn disorder of purine metabolism.'
  evidence:
  - reference: PMID:35098521
    reference_title: 'Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants:
      A Case Series and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency associated with mutations
      in the ITPA gene is a recently characterized purine pathway defect that presents with early
      infantile epileptic encephalopathy and lethal course.
    explanation: Establishes ITPA as the causal gene and the early infantile epileptic encephalopathy
      phenotype.
  - reference: PMID:35098521
    reference_title: 'Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants:
      A Case Series and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ITPA-related encephalopathy presents with infantile-onset neurodegeneration, progressive
      microcephaly, and epilepsy.
    explanation: Supports the microcephaly and neurodegenerative course recorded for this subtype.
  - reference: PMID:35098521
    reference_title: 'Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants:
      A Case Series and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiomyopathy was noted in 42% of patients where it was explicitly evaluated (n = 5/12).
    explanation: Source for the cardiomyopathy figure recorded in this subtype's description.
- name: DEE36
  display_name: Developmental and epileptic encephalopathy 36 (ALG13)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 36
    term:
      id: MONDO:0010472
      label: developmental and epileptic encephalopathy, 36
  genes:
  - preferred_term: ALG13
    term:
      id: hgnc:30881
      label: ALG13
  description: X-linked ALG13-related DEE, in almost all reported cases caused by the recurrent de
    novo missense variant p.(Asn107Ser). In a 38-individual series 37 were girls and one was a boy.
    It usually manifests as West syndrome with severe to profound developmental delay. Transferrin
    electrophoresis is normal in most cases, and the cited series leaves open whether this is genuinely
    a congenital disorder of glycosylation, which is how MONDO classifies it.
  evidence:
  - reference: PMID:33410528
    reference_title: The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental
      and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound
      developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser).
    explanation: Establishes the recurrent de novo ALG13 variant and the West syndrome presentation
      of this subtype.
  - reference: PMID:33410528
    reference_title: The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental
      and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Comprehensive functional studies will be able to prove or disprove an association with
      congenital disorder of glycosylation.
    explanation: Records that the glycosylation-disorder classification MONDO applies to this term
      is unsettled in the clinical literature.
  - reference: PMID:33410528
    reference_title: The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental
      and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them
      novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally
      report the phenotype of three individuals carrying other likely pathogenic ALG13 variants.
    explanation: Source for the cohort size and the sex distribution recorded here.
- name: DEE37
  display_name: Developmental and epileptic encephalopathy 37 (FRRS1L)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 37
    term:
      id: MONDO:0014859
      label: developmental and epileptic encephalopathy, 37
  genes:
  - preferred_term: FRRS1L
    term:
      id: hgnc:1362
      label: FRRS1L
  description: Biallelic loss-of-function FRRS1L variants. FRRS1L encodes an AMPA receptor outer-core
    protein, and its loss attenuates AMPA-mediated currents, so this is a postsynaptic glutamatergic
    lesion. The reported phenotype couples epilepsy with prominent choreoathetosis, which is why the
    founding report called it an epileptic-dyskinetic encephalopathy.
  evidence:
  - reference: PMID:27236917
    reference_title: Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe a neurological disorder with epilepsy and prominent choreoathetosis caused
      by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein.
    explanation: Establishes biallelic FRRS1L variants and the epileptic-dyskinetic phenotype of this
      subtype.
  - reference: PMID:27236917
    reference_title: Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities
      of glutamatergic neurotransmission in this monogenic neurological disease of childhood.
    explanation: Supports placing the FRRS1L lesion in the synaptic arm of the DEE mechanism.
- name: DEE48
  display_name: Developmental and epileptic encephalopathy 48 (AP3B2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 48
    term:
      id: MONDO:0015000
      label: developmental and epileptic encephalopathy, 48
  genes:
  - preferred_term: AP3B2
    term:
      id: hgnc:567
      label: AP3B2
  description: Biallelic AP3B2 variants. AP3B2 encodes the neuron-specific beta subunit of the AP-3 vesicle
    coat adaptor complex; the ubiquitous isoform AP3B1 causes Hermansky-Pudlak syndrome type 2 instead,
    so the neuronal restriction of this subunit is what makes the AP3B2 phenotype purely neurological.
    Reverse phenotyping of twelve affected individuals from eight families gave a homogeneous early-onset
    epileptic encephalopathy with severe developmental delay, optic atrophy and postnatal microcephaly,
    and no albinism or haematological involvement.
  evidence:
  - reference: PMID:27889060
    reference_title: Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2
      Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous
      EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy,
      and postnatal microcephaly.
    explanation: Establishes the DEE48 clinical entity and the optic atrophy that characterises it.
  - reference: PMID:27889060
    reference_title: Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2
      Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated
      affected individuals with EOEE associated with developmental impairment and autosomal-recessive
      variants in AP3B2 by means of whole-exome sequencing.
    explanation: Establishes autosomal-recessive AP3B2 variants as the lesion defining this subtype.
- name: DEE51
  display_name: Developmental and epileptic encephalopathy 51 (MDH2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 51
    term:
      id: MONDO:0015025
      label: developmental and epileptic encephalopathy, 51
  genes:
  - preferred_term: MDH2
    term:
      id: hgnc:6971
      label: MDH2
  description: Biallelic MDH2 variants, a Krebs cycle defect. MDH2 encodes mitochondrial malate dehydrogenase,
    which converts malate to oxaloacetate. The three unrelated subjects of the founding report had early-onset
    generalised hypotonia, psychomotor delay and refractory epilepsy with raised lactate in blood and
    cerebrospinal fluid; their fibroblasts showed loss of MDH2 protein with enzymatic activity close to
    null, and accumulation of malate and fumarate. The lesion is therefore metabolic rather than one of
    channel conduction, which is why this subtype gene is wired to the non-channelopathy lesion node.
  evidence:
  - reference: PMID:27989324
    reference_title: Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting
      with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate
      in the blood and cerebrospinal fluid.
    explanation: Establishes the DEE51 clinical entity and biallelic MDH2 variants as its lesion.
  - reference: PMID:27989324
    reference_title: Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional studies in fibroblasts from affected subjects showed both an apparently complete
      loss of MDH2 levels and MDH2 enzymatic activity close to null.
    explanation: Shows the lesion abolishes malate dehydrogenase activity, which is the mechanism this
      subtype contributes.
- name: DEE53
  display_name: Developmental and epileptic encephalopathy 53 (SYNJ1)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 53
    term:
      id: MONDO:0033362
      label: developmental and epileptic encephalopathy, 53
  genes:
  - preferred_term: SYNJ1
    term:
      id: hgnc:11503
      label: SYNJ1
  description: 'Biallelic SYNJ1 variants. SYNJ1 encodes synaptojanin 1, a polyphosphoinositide phosphatase
    with two consecutive phosphatase domains that acts in synaptic vesicle dynamics. The allelic series
    separates two diseases: variants that selectively abolish only the Sac1 domain cause early-onset parkinsonism,
    whereas a critical reduction of the dual phosphatase activity causes this neonatal refractory epilepsy
    with progressive neurological decline. A screen of 543 further patients with epilepsy and intellectual
    disability found no additional pathogenic variants, so SYNJ1 deficiency is rare and tied to a specific
    phenotype.'
  evidence:
  - reference: PMID:27435091
    reference_title: Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures
      and progressive neurological decline.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We performed whole exome or genome sequencing in three independent sib pairs with early onset
      refractory seizures and progressive neurological decline, and identified novel segregating recessive
      SYNJ1 defects.
    explanation: Establishes the DEE53 clinical entity and recessive SYNJ1 variants as its lesion.
  - reference: PMID:27435091
    reference_title: Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures
      and progressive neurological decline.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A genetic follow-up screening in a large cohort of 543 patients with a wide phenotypical
      range of epilepsies and intellectual disability revealed no additional pathogenic variants, showing
      that SYNJ1 deficiency is rare and probably linked to a specific phenotype.
    explanation: Sources the rarity and phenotypic specificity stated in this row description.
- name: DEE57
  display_name: Developmental and epileptic encephalopathy 57 (KCNT2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 57
    term:
      id: MONDO:0033366
      label: developmental and epileptic encephalopathy, 57
  genes:
  - preferred_term: KCNT2
    term:
      id: hgnc:18866
      label: KCNT2
  description: De novo KCNT2 variants. KCNT2 encodes a sodium-activated potassium channel subunit of the
    same subfamily as KCNT1. The two girls of the founding report had West syndrome evolving to Lennox-Gastaut
    syndrome in one and epilepsy of infancy with migrating focal seizures in the other. In vitro analysis
    indicated quinidine-responsive gain of function, and quinidine add-on therapy produced marked clinical
    improvement in one of them, so this subtype shares the pharmacological profile as well as the phenotype
    of KCNT1-related disease.
  evidence:
  - reference: PMID:29740868
    reference_title: De novo gain-of-function variants in KCNT2 as a novel cause of developmental and
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report on 2 females with de novo variants in KCNT2 with West syndrome followed by Lennox-Gastaut
      syndrome or with DEE with migrating focal seizures.
    explanation: Establishes the DEE57 clinical entity and de novo KCNT2 variants as its lesion.
  - reference: PMID:29740868
    reference_title: De novo gain-of-function variants in KCNT2 as a novel cause of developmental and
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After in vitro analysis suggested quinidine-responsive gain-of-function effects, we treated
      1 of the girls with quinidine add-on therapy and achieved marked clinical improvements.
    explanation: Sources both the gain-of-function mechanism and the quinidine response stated in this
      row description.
- name: DEE58
  display_name: Developmental and epileptic encephalopathy 58 (NTRK2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 58
    term:
      id: MONDO:0033367
      label: developmental and epileptic encephalopathy, 58
  genes:
  - preferred_term: NTRK2
    term:
      id: hgnc:8032
      label: NTRK2
  description: NTRK2-related DEE, reported with a recurrent variant in four of the five cases in the
    cited series. The phenotype is early-onset seizures beginning as infantile spasms and later evolving
    to multifocal seizures, with global developmental delay, variable movement disorders, microcephaly
    and optic nerve hypoplasia. HGNC names NTRK2 neurotrophic receptor tyrosine kinase 2, with TRKB
    as an alias symbol, so the lesion is in receptor signalling rather than in channel conduction.
  evidence:
  - reference: PMID:34425480
    reference_title: 'NTRK2-related developmental and epileptic encephalopathy: Report of 5 new cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five cases of NTRK2-related DEE were identified. Four had a previously described recurrent
      variant in NTRK2 and one had a novel variant.
    explanation: Establishes NTRK2 as the causal gene of this subtype and the recurrence of one variant.
  - reference: PMID:34425480
    reference_title: 'NTRK2-related developmental and epileptic encephalopathy: Report of 5 new cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The phenotype was characterized by early-onset seizures (infantile spasms, later evolving
      to multifocal seizures), global developmental delay, variable movement disorders, microcephaly
      and optic nerve hypoplasia.
    explanation: Source for the seizure evolution, microcephaly and optic nerve hypoplasia recorded
      here.
- name: DEE59
  display_name: Developmental and epileptic encephalopathy 59 (GABBR2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 59
    term:
      id: MONDO:0033368
      label: developmental and epileptic encephalopathy, 59
  genes:
  - preferred_term: GABBR2
    term:
      id: hgnc:4507
      label: GABBR2
  description: De novo GABBR2 variants. GABBR2 encodes the type 2 subunit of the metabotropic GABA-B receptor,
    so this subtype sits with the GABA-A receptor subunit subtypes as a lesion of GABAergic inhibition
    rather than of a voltage-gated channel. De novo GABBR2 mutations were reported in two individuals
    in the combined EuroEPINOMICS and Epi4K/EPGP trio cohort, which treated them as suggestive rather
    than statistically established; a later whole-genome study of unexplained DEE provided the causal
    link.
  evidence:
  - reference: PMID:25262651
    reference_title: De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1
      in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each.
    explanation: The first observation of de novo GABBR2 mutations in a DEE trio cohort, which is the
      report OMIM cites for DEE59.
  - reference: PMID:25262651
    reference_title: De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. ... We bring statistical
      evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role
      of three additional genes
    explanation: Sources the statement that the first report treated GABBR2 as suggestive rather than
      established. The three additional genes with suggestive evidence are the three named earlier in
      the same abstract with two de novo carriers each, GABBR2 among them; the statistical evidence in
      that paper is for DNM1, not for GABBR2.
  - reference: PMID:29100083
    reference_title: High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'By combining these strategies, we were able to provide a causal link between DEE and the
      following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25.'
    explanation: Establishes GABBR2 as causal for DEE. The sentence names eight genes, so it supports
      gene-disease causality for each named gene and no gene-specific phenotype claim.
- name: DEE60
  display_name: Developmental and epileptic encephalopathy 60 (CNPY3)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 60
    term:
      id: MONDO:0033369
      label: developmental and epileptic encephalopathy, 60
  genes:
  - preferred_term: CNPY3
    term:
      id: hgnc:11968
      label: CNPY3
  description: Biallelic CNPY3 variants. CNPY3 encodes an endoplasmic reticulum co-chaperone that regulates
    the subcellular distribution and responses of multiple Toll-like receptors, a function outside the
    channel and synaptic classes. The three individuals of the founding report presented as West syndrome
    and all three had hippocampal malrotation; CNPY3 protein was severely reduced in lymphoblastoid cells
    from two of them. Cnpy3-knockout mice showed spastic or dystonic features at rest and enhanced resting
    EEG activity in the fast beta band, which the authors suggest could mimic the fast waves seen in those
    two individuals.
  evidence:
  - reference: PMID:29394991
    reference_title: Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset
      Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have now identified biallelic CNPY3 variants in three individuals with WS; these include
      compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals
      1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3).
    explanation: Establishes the DEE60 clinical entity, presenting as West syndrome, and biallelic CNPY3
      variants as its lesion.
  - reference: PMID:29394991
    reference_title: Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset
      Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Cnpy3-knockout mice exhibited spastic or dystonic features under resting conditions and hyperactivity
      and anxiolytic behavior during the open field test.
    explanation: Model-organism support for CNPY3 loss producing a neurological phenotype.
- name: DEE61
  display_name: Developmental and epileptic encephalopathy 61 (ADAM22)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 61
    term:
      id: MONDO:0033370
      label: developmental and epileptic encephalopathy, 61
  genes:
  - preferred_term: ADAM22
    term:
      id: hgnc:201
      label: ADAM22
  description: 'Biallelic inactivating ADAM22 variants. ADAM22 is the postsynaptic receptor for the
    secreted protein LGI1, and this subtype is the recessive counterpart of the dominant LGI1 epilepsy
    with auditory features. All affected individuals in the cited series had infantile-onset treatment-resistant
    epilepsy. Transfected-cell studies indicated three distinct pathological mechanisms: defective
    cell-membrane expression, impaired LGI1 binding, and impaired interaction with the postsynaptic
    density protein PSD-95.'
  evidence:
  - reference: PMID:35373813
    reference_title: Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset
      refractory epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We refine the phenotype and report 19 additional individuals harbouring compound heterozygous
      or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available.
    explanation: Establishes biallelic inactivating ADAM22 variants in a cohort, defining this subtype.
  - reference: PMID:35373813
    reference_title: Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset
      refractory epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All affected individuals exhibited infantile-onset, treatment-resistant epilepsy.
    explanation: Source for the uniform infantile-onset drug-resistant epilepsy recorded here.
  - reference: PMID:35373813
    reference_title: Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset
      refractory epilepsy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Functional studies in transfected cell lines confirmed the deleteriousness of all identified
      variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane
      expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic
      density protein PSD-95.'
    explanation: Source for the three molecular consequences of ADAM22 loss recorded here.
- name: DEE62
  display_name: Developmental and epileptic encephalopathy 62 (SCN3A)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 62
    term:
      id: MONDO:0033371
      label: developmental and epileptic encephalopathy, 62
  genes:
  - preferred_term: SCN3A
    term:
      id: hgnc:10590
      label: SCN3A
  description: De novo SCN3A variants. SCN3A encodes the Nav1.3 sodium channel alpha subunit, highly expressed
    in brain and, before this report, not linked to early infantile epileptic encephalopathy. The four
    patients carried heterozygous de novo missense variants, and recordings showed gain of channel function
    with a markedly increased slowly inactivating current; phenytoin and lacosamide blocked that slowly
    inactivating component selectively, which is the pharmacological lead the authors draw from the mechanism.
    Variants known or presumed to be inherited did not show gain of function.
  evidence:
  - reference: PMID:29466837
    reference_title: Mutations in SCN3A cause early infantile epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de
      novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala).
    explanation: Establishes the DEE62 clinical entity and de novo SCN3A missense variants as its lesion.
  - reference: PMID:29466837
    reference_title: Mutations in SCN3A cause early infantile epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Electrophysiological recordings of mutant channels revealed prominent gain of channel function,
      with a markedly increased amplitude of the slowly inactivating current component
    explanation: Sources the gain-of-function mechanism stated in this row description.
- name: DEE67
  display_name: Developmental and epileptic encephalopathy 67 (CUX2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 67
    term:
      id: MONDO:0029138
      label: developmental and epileptic encephalopathy, 67
  genes:
  - preferred_term: CUX2
    term:
      id: hgnc:19347
      label: CUX2
  description: The recurrent de novo CUX2 p.Glu590Lys variant. CUX2 is a cut homeodomain transcription
    factor with a role in dendrite branching, spine development and synapse formation in layer II to III
    cortical neurons, so the lesion is transcriptional rather than a channel or synaptic protein defect
    and the gene is wired to the non-channelopathy lesion node. The nine-patient cohort spans a phenotypic
    range with infantile-onset myoclonic DEE at the severe end and generalised epilepsy with severe static
    developmental encephalopathy at the milder end; the variant affects a highly conserved residue in
    the CUT domain predicted to interfere with DNA binding.
  evidence:
  - reference: PMID:29630738
    reference_title: The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental
      and epileptic encephalopathy (DEE).
    explanation: Establishes the DEE67 clinical entity and the recurrent CUX2 variant as its lesion.
  - reference: PMID:29630738
    reference_title: The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly
      generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy
      with severe static developmental encephalopathy at the milder end of the spectrum.
    explanation: Sources the severity range stated in this row description.
- name: DEE68
  display_name: Developmental and epileptic encephalopathy 68 (TRAK1)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 68
    term:
      id: MONDO:0032598
      label: developmental and epileptic encephalopathy, 68
  genes:
  - preferred_term: TRAK1
    term:
      id: hgnc:29947
      label: TRAK1
  description: Biallelic truncating TRAK1 variants. The founding report identified a homozygous splice
    variant in six lethal encephalopathic patients from three unrelated families; patient-derived
    fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced
    membrane potential and diminished respiration. Note that the founding report frames the phenotype
    as a fatal encephalopathy rather than using the DEE label that OMIM 618201 and MONDO later attached
    to this locus.
  evidence:
  - reference: PMID:28364549
    reference_title: Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal
      encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A
      > C), in six lethal encephalopathic patients from three unrelated families.
    explanation: Establishes the biallelic TRAK1 lesion and the lethal encephalopathic phenotype of
      this subtype.
  - reference: PMID:28364549
    reference_title: Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal
      encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial
      distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and
      diminished mitochondrial respiration.
    explanation: Source for the mitochondrial trafficking and respiration defect; the measurements
      are in patient-derived fibroblasts.
- name: DEE70
  display_name: Developmental and epileptic encephalopathy 70 (PHACTR1)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 70
    term:
      id: MONDO:0032663
      label: developmental and epileptic encephalopathy, 70
  genes:
  - preferred_term: PHACTR1
    term:
      id: hgnc:20990
      label: PHACTR1
  description: De novo PHACTR1 variants, whose founding report is titled for their identification
    in West syndrome. Immunoprecipitation showed that the disease variants impair either PHACTR1's
    actin-binding activity or its binding to protein phosphatase 1. In a later nine-patient series
    eight individuals carried missense variants and one a copy-number variant; infantile epileptic
    spasms syndrome was the unifying phenotype of the eight with missense variants, while the copy-number
    patient had a developmental encephalopathy phenotype instead.
  evidence:
  - reference: PMID:38272663
    reference_title: Genotype and phenotype correlation of PHACTR1-related neurological disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients
      with missense variants of PHACTR1.
    explanation: Establishes epileptic spasms as the core phenotype of PHACTR1 missense variants,
      in the largest reported series.
  - reference: PMID:38272663
    reference_title: Genotype and phenotype correlation of PHACTR1-related neurological disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy
      in addition to IESS.
    explanation: Source for the developmental encephalopathy phenotype recorded alongside epileptic
      spasms in this subtype.
  - reference: PMID:30256902
    reference_title: De novo PHACTR1 mutations in West syndrome and their pathophysiological effects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Immunoprecipitation analyses revealed that actin-binding activity of PHACTR1 was impaired
      by the p.Leu500Pro, p.Asn479Ile and p.Ile518Asn mutations while the p.Arg521Cys mutation exhibited
      impaired binding to PP1.
    explanation: Establishes the two molecular consequences of the disease variants, in transfected-cell
      immunoprecipitation assays.
- name: DEE73
  display_name: Developmental and epileptic encephalopathy 73 (RNF13)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 73
    term:
      id: MONDO:0034106
      label: developmental and epileptic encephalopathy, 73
  genes:
  - preferred_term: RNF13
    term:
      id: hgnc:10057
      label: RNF13
  description: De novo heterozygous gain-of-function RNF13 variants. Three unrelated individuals presented
    with congenital microcephaly, infantile epileptic encephalopathy and profound developmental delay.
    RNF13 interacts with the unfolded-protein-response sensor IRE1-alpha, and the variants act by
    increasing signalling through the ER stress response rather than by haploinsufficiency.
  evidence:
  - reference: PMID:30595371
    reference_title: Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly,
      Epileptic Encephalopathy, Blindness, and Failure to Thrive.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three unrelated affected individuals with congenital microcephaly, infantile epileptic
      encephalopathy, and profound developmental delay were found to carry heterozygous variants
    explanation: Establishes the three-patient founding cohort and the congenital microcephaly plus
      infantile epileptic encephalopathy phenotype.
  - reference: PMID:30595371
    reference_title: Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly,
      Epileptic Encephalopathy, Blindness, and Failure to Thrive.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These results indicate that the RNF13 variants confer gain of function to the encoded
      protein and thereby lead to altered signaling of the ER stress response associated with severe
      neurodegeneration in infancy.
    explanation: Establishes the gain-of-function mechanism acting through the ER stress response.
- name: DEE75
  display_name: Developmental and epileptic encephalopathy 75 (PARS2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 75
    term:
      id: MONDO:0032752
      label: developmental and epileptic encephalopathy, 75
  genes:
  - preferred_term: PARS2
    term:
      id: hgnc:30563
      label: PARS2
  description: 'Biallelic PARS2 variants. PARS2 encodes mitochondrial prolyl-tRNA synthetase, one
    of the mitochondrial aminoacyl-tRNA synthetases, and had first been linked to Alpers syndrome
    and infantile-onset neurodegeneration. Reported patients have epileptic spasms with an early treatment
    response, early developmental delay or regression, generalised hypotonia, postnatal microcephaly,
    elevated lactate and progressive cerebral atrophy. A nomenclature hazard is recorded on the NEUROD2-Related_Developmental_and_Epileptic_Encephalopathy
    entry: a publication cited there misapplies the DEE75 number to NEUROD2, which is DEE72.'
  evidence:
  - reference: PMID:29915213
    reference_title: The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As a member of the mt-aaRS family, PARS2 encoding prolyl-tRNA synthetase 2 was recently
      shown to be associated with Alpers syndrome and certain infantile-onset neurodegenerative disorders
      in four patients.
    explanation: Establishes PARS2 as a mitochondrial aminoacyl-tRNA synthetase gene causing infantile-onset
      encephalopathy.
  - reference: PMID:29915213
    reference_title: The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nearly all patients had epileptic spasms with early response to treatment, early developmental
      delay and/or regression followed by generalized hypotonia, postnatal microcephaly, elevated
      lactate levels, and progressive cerebral atrophy.
    explanation: Source for the epileptic spasms, microcephaly, lactate elevation and cerebral atrophy
      recorded here.
- name: DEE76
  display_name: Developmental and epileptic encephalopathy 76 (ACTL6B)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 76
    term:
      id: MONDO:0032768
      label: developmental and epileptic encephalopathy, 76
  genes:
  - preferred_term: ACTL6B
    term:
      id: hgnc:160
      label: ACTL6B
  description: Biallelic ACTL6B variants. ACTL6B encodes a subunit of the neuron-specific chromatin
    remodelling complex nBAF, which is the chromatin-regulator arm of the ion-channel and synaptic
    lesion node this subtype is wired to rather than a channel or synaptic protein in its own right.
    The two siblings in whom the gene was identified had severe DEE with microcephaly,
    spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature and kyphoscoliosis;
    the founding report describes three cases in total.
  evidence:
  - reference: PMID:30656450
    reference_title: Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling
      complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain
      hypomyelination and cerebellar atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this study, we investigated the genetic defects in two siblings who presented with
      severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy,
      short stature, and kyphoscoliosis.
    explanation: Source for the DEE76 phenotype recorded here, including the hypomyelination and cerebellar
      atrophy.
  - reference: PMID:30656450
    reference_title: Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling
      complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain
      hypomyelination and cerebellar atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Whole exome next-generation sequencing (WES) identified in both siblings a homozygous
      non-sense variant in the ACTL6B gene
    explanation: Establishes the biallelic ACTL6B lesion defining this subtype.
- name: DEE78
  display_name: Developmental and epileptic encephalopathy 78 (GABRA2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 78
    term:
      id: MONDO:0032812
      label: developmental and epileptic encephalopathy, 78
  genes:
  - preferred_term: GABRA2
    term:
      id: hgnc:4076
      label: GABRA2
  description: A de novo GABRA2 variant. GABRA2 encodes the alpha2 subunit of the GABA-A receptor, a ligand-gated
    anion channel that regulates neuronal inhibition. The p.Thr292Lys variant was found by targeted resequencing
    of 279 epilepsy patients, in a patient with severe epilepsy and developmental delay. Patch-clamp recordings
    showed it reduced channel expression and produced channels that were tonically open even without GABA,
    so the receptor lesion is not a simple loss of GABA response. DEE78 and DEE79 were established together
    in this one study.
  evidence:
  - reference: PMID:29961870
    reference_title: De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset
      epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Targeted resequencing of 279 additional epilepsy patients identified 19 rare variants from
      nine GABAA receptor genes, including a novel de novo missense variant in GABRA2 (c.875C > A, p.T292K)
      and a recurrent missense variant in GABRB3 (c.902C > T, p.P301L).
    explanation: Establishes the de novo GABRA2 variant that defines this subtype and how it was ascertained.
  - reference: PMID:29961870
    reference_title: De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset
      epilepsy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The GABRA2 p.T292K variant reduced channel expression and produced mutant channels that were
      tonically open, even in the absence of GABA.
    explanation: Gene-specific functional characterisation of the GABRA2 lesion, measured in transfected
      HEK293T cells.
- name: DEE79
  display_name: Developmental and epileptic encephalopathy 79 (GABRA5)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 79
    term:
      id: MONDO:0032813
      label: developmental and epileptic encephalopathy, 79
  genes:
  - preferred_term: GABRA5
    term:
      id: hgnc:4079
      label: GABRA5
  description: A de novo GABRA5 variant. GABRA5 encodes the alpha5 subunit of the GABA-A receptor. The
    index patient was found by whole-genome sequencing and had severe early-onset epilepsy with developmental
    delay. The p.Val294Leu variant produced receptors ten times more sensitive to GABA but with a reduced
    maximal GABA-evoked current because of increased desensitisation, so the net effect is a loss of sustained
    inhibition despite the increased apparent affinity. DEE78 and DEE79 were established together in this
    one study.
  evidence:
  - reference: PMID:29961870
    reference_title: De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset
      epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using whole-genome sequencing, we identified a novel de novo missense variant in GABRA5 (c.880G
      > C, p.V294L) in a patient with severe early-onset epilepsy and developmental delay.
    explanation: Establishes the DEE79 clinical entity and the de novo GABRA5 variant as its lesion.
  - reference: PMID:29961870
    reference_title: De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset
      epilepsy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The GABRA5 p.V294L variant produced receptors that were 10-times more sensitive to GABA but
      had reduced maximal GABA-evoked current due to increased receptor desensitization.
    explanation: Gene-specific functional characterisation of the GABRA5 lesion, measured in transfected
      HEK293T cells.
- name: DEE85
  display_name: Developmental and epileptic encephalopathy 85, with or without midline brain defects (SMC1A)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 85, with or without midline brain defects
    term:
      id: MONDO:0026771
      label: developmental and epileptic encephalopathy, 85, with or without midline brain defects
  genes:
  - preferred_term: SMC1A
    term:
      id: hgnc:11111
      label: SMC1A
  description: 'Heterozygous de novo truncating SMC1A variants, X-linked. SMC1A encodes a core structural
    subunit of the cohesin complex, so this is a cohesinopathy and the gene is wired to the non-channelopathy
    lesion node. The allelic split matters clinically: missense and small in-frame SMC1A changes cause
    about 5 per cent of Cornelia de Lange syndrome, which dismech curates separately, whereas protein-truncating
    changes cause this epilepsy phenotype. All ten cases of the defining series were female, none had
    a clinical diagnosis of Cornelia de Lange syndrome, and the striking feature was seizures occurring
    in clusters associated with developmental regression.'
  evidence:
  - reference: PMID:28166369
    reference_title: 'Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy
      with cluster seizures in females: Detailed phenotyping of 10 new cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations
      identified are predicted to result in premature truncation of the SMC1A protein.
    explanation: Establishes truncating SMC1A variants as the lesion defining this subtype.
  - reference: PMID:28166369
    reference_title: 'Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy
      with cluster seizures in females: Detailed phenotyping of 10 new cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All cases are female, and none had a clinical diagnosis of CdLS.
    explanation: Sources the separation of this subtype from Cornelia de Lange syndrome, which is curated
      as its own dismech entry.
  - reference: PMID:28166369
    reference_title: 'Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy
      with cluster seizures in females: Detailed phenotyping of 10 new cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the majority of cases, a marked preponderance for seizures to occur in clusters was noted.
      Seizure clusters were associated with developmental regression.
    explanation: Sources the cluster-seizure pattern and its link to regression stated in this row description.
- name: DEE86
  display_name: Developmental and epileptic encephalopathy 86 (DALRD3)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 86
    term:
      id: MONDO:0030054
      label: developmental and epileptic encephalopathy, 86
  genes:
  - preferred_term: DALRD3
    term:
      id: hgnc:25536
      label: DALRD3
  description: A homozygous nonsense DALRD3 variant. DALRD3 forms a complex with the METTL2 methyltransferase
    that recognises particular arginine tRNA isoacceptors for 3-methylcytosine modification of the anticodon
    loop, and DALRD3-deficient human cells lose that modification almost completely. The lesion is therefore
    in tRNA modification, placing this subtype with the non-channelopathy mechanisms.
  evidence:
  - reference: PMID:32427860
    reference_title: DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine
      tRNAs for 3-methylcytosine modification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, we identify a homozygous nonsense mutation in the DALRD3 gene that impairs m3C formation
      in human patients exhibiting developmental delay and early-onset epileptic encephalopathy.
    explanation: Establishes the DEE86 clinical entity and the homozygous DALRD3 lesion, together with
      the tRNA-modification defect it causes.
  - reference: PMID:32427860
    reference_title: DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine
      tRNAs for 3-methylcytosine modification.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: DALRD3-deficient human cells exhibit nearly complete loss of the m3C modification in tRNA-Arg
      species.
    explanation: Sources the molecular consequence of DALRD3 loss stated in this row description.
- name: DEE90
  display_name: Developmental and epileptic encephalopathy 90 (FGF13)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 90
    term:
      id: MONDO:0025353
      label: developmental and epileptic encephalopathy, 90
  genes:
  - preferred_term: FGF13
    term:
      id: hgnc:3670
      label: FGF13
  description: X-linked DEE caused by missense variants in the N-terminal domain of the A isoform
    of FHF2, the protein encoded by FGF13. Fibroblast growth factor homologous factors are intracellular
    regulators of voltage-gated sodium channels. Mutant FHF2A co-expressed with wild-type Nav1.6 lost
    the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory
    properties, a gain-of-function effect on excitability. Affected individuals - two sibling pairs
    and three unrelated males - had intractable focal seizures and severe developmental delay from
    infancy.
  evidence:
  - reference: PMID:33245860
    reference_title: Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause
      an X-linked developmental and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe two sibling pairs and three unrelated males who presented in infancy
      with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified
      hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A).
    explanation: Establishes the founding cohort and the FHF2A N-terminal variants defining this subtype.
  - reference: PMID:33245860
    reference_title: Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause
      an X-linked developmental and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental
      and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating
      Nav channel function.
    explanation: States the gene-disease relationship and the sodium-channel regulatory mechanism
      that places this lesion in the channel arm.
  - reference: PMID:33245860
    reference_title: Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause
      an X-linked developmental and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A)
      revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade
      of the channel while retaining pro-excitatory properties.
    explanation: Source for the gain-of-function effect on sodium-channel inactivation recorded here.
- name: DEE92
  display_name: Developmental and epileptic encephalopathy 92 (GABRB2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 92
    term:
      id: MONDO:0020631
      label: developmental and epileptic encephalopathy 92
  genes:
  - preferred_term: GABRB2
    term:
      id: hgnc:4082
      label: GABRB2
  description: De novo GABRB2 variants. GABRB2 encodes the beta2 subunit of the GABA-A receptor. GABRB2
    was one of eight genes given a causal link to DEE by a whole-genome sequencing study of 197 trios
    with unexplained DEE and pharmaco-resistant seizures, combined with targeted sequencing and de-novo-mutation
    enrichment meta-analysis. That study reports gene-disease causality for the set of eight; it does
    not characterise a GABRB2-specific phenotype, so none is asserted here.
  evidence:
  - reference: PMID:29100083
    reference_title: High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'By combining these strategies, we were able to provide a causal link between DEE and the
      following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25.'
    explanation: Establishes GABRB2 as causal for DEE. The sentence names eight genes, so it supports
      gene-disease causality for each named gene and no gene-specific phenotype claim.
  - reference: PMID:29100083
    reference_title: High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant
      seizures and in their unaffected parents.
    explanation: Sources the cohort and design behind that causal link.
- name: DEE93
  display_name: Developmental and epileptic encephalopathy 93 (ATP6V1A)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 93
    term:
      id: MONDO:0020632
      label: developmental and epileptic encephalopathy 93
  genes:
  - preferred_term: ATP6V1A
    term:
      id: hgnc:851
      label: ATP6V1A
  description: 'De novo heterozygous ATP6V1A variants. ATP6V1A encodes the A subunit of the vacuolar proton
    ATPase, the multi-subunit pump that sets organellar pH in all eukaryotic cells and has additional
    roles at the synapse in neurons. Severity in the four founding patients was strikingly variable and
    tracked the variant: two progressed to profound delay with hypotonic or dyskinetic quadriparesis and
    intractable seizures, while two had moderate delay with milder epilepsy. Modelling on v-ATPase structures
    predicted four different mechanisms for the four variants, from perturbed subunit interaction to impaired
    rotation.'
  evidence:
  - reference: PMID:29668857
    reference_title: De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Through whole exome sequencing, we identified de novo heterozygous mutations (p.Pro27Arg,
      p.Asp100Tyr, p.Asp349Asn, p.Asp371Gly) in ATP6V1A, encoding the A subunit of v-ATPase, in four patients
      with developmental encephalopathy with epilepsy.
    explanation: Establishes the DEE93 clinical entity and de novo ATP6V1A variants as its lesion.
  - reference: PMID:29668857
    reference_title: De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early manifestations, observed in all patients, were developmental delay and febrile seizures,
      evolving to encephalopathy with profound delay, hypotonic/dyskinetic quadriparesis and intractable
      multiple seizure types in two patients (p.Pro27Arg, p.Asp100Tyr), and to moderate delay with milder
      epilepsy in the other two (p.Asp349Asn, p.Asp371Gly).
    explanation: Sources the variant-dependent severity range stated in this row description.
- name: DEE96
  display_name: Developmental and epileptic encephalopathy 96 (NSF)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 96
    term:
      id: MONDO:0023659
      label: developmental and epileptic encephalopathy 96
  genes:
  - preferred_term: NSF
    term:
      id: hgnc:8016
      label: NSF
  description: De novo heterozygous NSF variants. NSF is the homo-hexameric AAA ATPase that acts in membrane
    fusion and in assembly and disassembly of the SNARE complex, so the lesion is in the presynaptic vesicle
    cycle and the gene is wired to the ion-channel and synaptic lesion node alongside NAPB, its own beta
    attachment protein. Expressing the mutant allele in the developing Drosophila eye severely disrupted
    eye development where the wild-type allele did not, which the authors read as a dominant negative
    effect.
  evidence:
  - reference: PMID:31675180
    reference_title: De novo NSF mutations cause early infantile epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic
      variants in NSF, that is, epileptic encephalopathy of early infantile onset.
    explanation: Establishes the DEE96 clinical entity and de novo NSF variants as its lesion.
  - reference: PMID:31675180
    reference_title: De novo NSF mutations cause early infantile epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye
      development, while the wild-type allele had no detectable effect under the same conditions.
    explanation: Sources the dominant-negative reading of the NSF lesion stated in this row description.
- name: DEE97
  display_name: Developmental and epileptic encephalopathy 97 (CELF2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 97
    term:
      id: MONDO:0030453
      label: developmental and epileptic encephalopathy 97
  genes:
  - preferred_term: CELF2
    term:
      id: hgnc:2550
      label: CELF2
  description: Heterozygous CELF2 variants that disrupt nuclear localisation. CELF2 encodes a nucleocytoplasmic
    shuttling RNA-binding protein with several roles in RNA processing and in development of the central
    nervous system and heart, so the lesion is post-transcriptional rather than one of channel conduction.
    Four of five individuals had DEE and one had intellectual disability with autistic features. All variants
    except a canonical splice site change clustered within twenty residues of the C-terminus, and mutant
    CELF2 protein was mislocalised outside the nucleus in transfected cells.
  evidence:
  - reference: PMID:33131106
    reference_title: De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental
      and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals
      1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual
      disability and autistic features.'
    explanation: Establishes the DEE97 clinical entity and heterozygous CELF2 variants as its lesion.
  - reference: PMID:33131106
    reference_title: De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental
      and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected
      with mutant CELF2 complementary DNA plasmids.
    explanation: Sources the mislocalisation mechanism stated in this row description.
- name: DEE98
  display_name: Developmental and epileptic encephalopathy 98 (ATP1A2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy, 98
    term:
      id: MONDO:0030472
      label: developmental and epileptic encephalopathy, 98
  genes:
  - preferred_term: ATP1A2
    term:
      id: hgnc:800
      label: ATP1A2
  description: Heterozygous ATP1A2 variants at the severe end of the Na+/K+-ATPase alpha-subunit spectrum.
    The same gene is associated with familial hemiplegic migraine and alternating hemiplegia of childhood,
    which dismech curates in the Familial_Hemiplegic_Migraine entry; this subtype is instead the profound
    phenotype, featuring polymicrogyria or progressive brain atrophy with epilepsy, which caused early
    lethality in seven of 22 patients in the cited cohort. ATP1A2 accounted for six of those 22 patients,
    the remainder carrying ATP1A3 variants. Transfected-cell assays showed severely impaired pump
    activity.
  evidence:
  - reference: PMID:33880529
    reference_title: ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We investigated the genetic causes of developmental and epileptic encephalopathies variably
      associated with malformations of cortical development in a large cohort and identified 22 patients
      with de novo or inherited heterozygous ATP1A2/A3 mutations.
    explanation: Establishes heterozygous ATP1A2 variants as a cause of DEE with cortical malformation.
  - reference: PMID:33880529
    reference_title: ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients,
      five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual).
    explanation: Source for the ATP1A2 share of the cited cohort recorded here.
  - reference: PMID:33880529
    reference_title: ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct
      isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic
      migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism,
      cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar
      ataxia (all ATP1A3).
    explanation: Source for the other ATP1A2 phenotypes this subtype is distinguished from, and for
      the Na+/K+-ATPase alpha-subunit identity. Recorded as BACKGROUND because the citing study established
      the DEE phenotype rather than these earlier associations.
  - reference: PMID:33880529
    reference_title: ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy
      and epilepsy, resulted in early lethality in seven patients (32%).
    explanation: Source for the profound phenotype and the early-lethality figure recorded here.
- name: DEE100
  display_name: Developmental and epileptic encephalopathy 100 (FBXO28)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 100
    term:
      id: MONDO:0030695
      label: developmental and epileptic encephalopathy 100
  genes:
  - preferred_term: FBXO28
    term:
      id: hgnc:29046
      label: FBXO28
  description: Heterozygous FBXO28 variants - missense, nonsense and frameshift - in one of the two
    genes in the 1q41-q42 microdeletion interval already implicated in monogenic disease. Across the
    ten cases assembled in the cited report all had epilepsy and nine of ten had DEE, including infantile
    spasms and a progressive myoclonic epilepsy. The report distinguishes FBXO28 encephalopathy from
    both 1q41-q42 deletion syndrome and WDR26 encephalopathy by more severe intellectual impairment,
    drug-resistant epilepsy and hyperkinetic movement disorders.
  evidence:
  - reference: PMID:33280099
    reference_title: FBXO28 causes developmental and epileptic encephalopathy with profound intellectual
      disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe nine new patients with FBXO28 pathogenic variants (four missense, including
      one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate
      the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile
      spasms (3) and a progressive myoclonic epilepsy (1).
    explanation: Establishes FBXO28 as causal and quantifies the DEE fraction of the reported cohort.
  - reference: PMID:33280099
    reference_title: FBXO28 causes developmental and epileptic encephalopathy with profound intellectual
      disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual
      impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.
    explanation: Supports separating this subtype from the overlapping 1q41-q42 deletion and WDR26
      phenotypes.
  - reference: PMID:33280099
    reference_title: FBXO28 causes developmental and epileptic encephalopathy with profound intellectual
      disability.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic
      disease.
    explanation: Source for FBXO28 lying in the 1q41-q42 microdeletion interval. Recorded as BACKGROUND
      because the citing study set out to test the FBXO28-DEE hypothesis rather than to establish
      the interval.
- name: DEE102
  display_name: Developmental and epileptic encephalopathy 102 (SLC38A3)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 102
    term:
      id: MONDO:0030881
      label: developmental and epileptic encephalopathy 102
  genes:
  - preferred_term: SLC38A3
    term:
      id: hgnc:18044
      label: SLC38A3
  description: 'Biallelic SLC38A3 variants. The gene encodes SNAT3, a sodium-coupled neutral amino
    acid transporter carrying asparagine, histidine and glutamine, the last being the precursor of
    both GABA and glutamate. Ten individuals from seven unrelated families in six countries were reported:
    global developmental delay, intellectual disability, hypotonia and absent speech were common,
    with microcephaly, epilepsy and visual impairment in the majority, and epilepsy drug-resistant
    in half.'
  evidence:
  - reference: PMID:34605855
    reference_title: Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic
      encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental
      disorders identified two siblings with developmental and epileptic encephalopathy and a shared
      deleterious homozygous splicing variant in SLC38A3.
    explanation: Establishes the founding biallelic SLC38A3 observation in DEE.
  - reference: PMID:34605855
    reference_title: Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic
      encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our data support the contention that SLC38A3 is a novel disease gene for developmental
      and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations
      in glutamine homeostasis.
    explanation: States the gene-disease relationship and the glutamine-homeostasis mechanism.
  - reference: PMID:34605855
    reference_title: Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic
      encephalopathy.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal
      transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor
      for the neurotransmitters GABA and glutamate.
    explanation: Source for the SNAT3 transport function and for glutamine being the precursor of
      both GABA and glutamate. Recorded as BACKGROUND because the gene's transport function was established
      before this study.
  - reference: PMID:34605855
    reference_title: Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic
      encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ten individuals from seven unrelated families from six different countries with deleterious
      biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability,
      hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment
      were present in the majority. Epilepsy was drug-resistant in half.
    explanation: Source for the cohort size and the phenotype frequencies recorded here.
- name: DEE103
  display_name: Developmental and epileptic encephalopathy 103 (KCNC2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 103
    term:
      id: MONDO:0030957
      label: developmental and epileptic encephalopathy 103
  genes:
  - preferred_term: KCNC2
    term:
      id: hgnc:6234
      label: KCNC2
  description: 'De novo KCNC2 variants. KCNC2 encodes Kv3.2, a Shaw-related voltage-gated potassium channel
    subunit that supports sustained high-frequency firing. The defining series of eighteen patients spans
    genetic generalised epilepsy, focal epilepsy, myoclonic-atonic epilepsy and DEE, and the functional
    direction tracks severity: gain of function in three severely affected DEE cases and loss of function
    in one milder generalised-epilepsy case. Eight drug-responsive patients became seizure free on valproic
    acid alone or in combination, including severe DEE cases.'
  evidence:
  - reference: PMID:35314505
    reference_title: Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With
      Epilepsy With KCNC2 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including
      genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset
      absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy.
    explanation: Establishes the KCNC2 phenotypic spectrum, of which DEE103 is the severe pole.
  - reference: PMID:35314505
    reference_title: Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With
      Epilepsy With KCNC2 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE
      cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.
    explanation: Sources the direction-of-effect correlation with severity stated in this row description.
  - reference: PMID:35314505
    reference_title: Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With
      Epilepsy With KCNC2 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or
      in combination, including severe DEE cases.
    explanation: Sources the valproate response stated in this row description.
- name: DEE104
  display_name: Developmental and epileptic encephalopathy 104 (ATP6V0A1)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 104
    term:
      id: MONDO:0031021
      label: developmental and epileptic encephalopathy 104
  genes:
  - preferred_term: ATP6V0A1
    term:
      id: hgnc:865
      label: ATP6V0A1
  description: 'ATP6V0A1 encodes the brain-enriched a1 isoform of the V0 domain of the vacuolar H+-ATPase.
    The cited cohort splits by inheritance: five individuals with biallelic variants had early-onset
    progressive myoclonus epilepsy with ataxia, while twelve with de novo missense variants had severe
    developmental and epileptic encephalopathy. The recurrent R740Q change accounts for almost half
    the mutations identified there and impairs acidification of the endolysosomal compartment, causing
    autophagic dysfunction.'
  evidence:
  - reference: PMID:34909687
    reference_title: Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five affected subjects with biallelic variants in this gene presented with a phenotype
      of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo
      missense variants and showed severe developmental and epileptic encephalopathy.
    explanation: Establishes the de novo missense DEE phenotype and its separation from the biallelic
      progressive myoclonus epilepsy phenotype.
  - reference: PMID:34909687
    reference_title: Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently
      associated with developmental delay and epilepsy in four individuals.
    explanation: Records the prior reports that established the gene-disease relationship.
  - reference: PMID:34909687
    reference_title: Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The R740Q mutation, which alone accounts for almost 50% of the mutations identified among
      our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the
      endolysosomal compartment, causing autophagic dysfunction
    explanation: Source for the recurrent R740Q change, its share of the reported mutations, and the
      endolysosomal acidification defect.
- name: DEE105
  display_name: Developmental and epileptic encephalopathy 105 with hypopituitarism (HID1)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 105 with hypopituitarism
    term:
      id: MONDO:0031028
      label: developmental and epileptic encephalopathy 105 with hypopituitarism
  genes:
  - preferred_term: HID1
    term:
      id: hgnc:15736
      label: HID1
  description: Biallelic HID1 variants. HID1 acts in the trans-Golgi network, where precursors of peptide
    hormones are processed, which is why this subtype pairs an epileptic encephalopathy with central
    pituitary insufficiency. Seven individuals from six unrelated families
    shared hypopituitarism with brain atrophy, thin corpus callosum, severe developmental delay and visual
    impairment. Postmortem examination of one patient confirmed cerebral atrophy with enlarged lateral
    ventricles and markedly reduced pituitary hormone expression.
  evidence:
  - reference: PMID:33999436
    reference_title: Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in
      all patients.
    explanation: Establishes biallelic HID1 variants as the lesion defining this subtype.
  - reference: PMID:33999436
    reference_title: Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism
      in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment,
      and epilepsy.
    explanation: Sources the combined endocrine and neurological phenotype that distinguishes DEE105.
  - reference: PMID:33999436
    reference_title: Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly
      reduced expression of pituitary hormones was found in pituitary gland tissue.
    explanation: Sources the neuropathological and pituitary findings stated in this row description.
- name: DEE106
  display_name: Developmental and epileptic encephalopathy 106 (UFSP2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 106
    term:
      id: MONDO:0031052
      label: developmental and epileptic encephalopathy 106
  genes:
  - preferred_term: UFSP2
    term:
      id: hgnc:25640
      label: UFSP2
  description: Homozygosity for the UFSP2 p.V115E variant in eight children from four South Asian
    families with neurodevelopmental delay and epilepsy. UFSP2 encodes UFM1-specific peptidase 2,
    which acts in the UFMylation pathway of protein modification; patient fibroblasts showed reduced
    UFSP2 abundance and increased abundance of UFMylated targets, indicating impaired de-UFMylation.
    The variant residue lies in an N-terminal domain, whereas the variants causing the previously
    known autosomal dominant UFSP2 skeletal dysplasias lie in the catalytic domain.
  evidence:
  - reference: PMID:33473208
    reference_title: A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental
      anomalies and epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Homozygosity for the variant occurred in eight children from four South Asian families
      with neurodevelopmental delay and epilepsy.
    explanation: Establishes the biallelic UFSP2 lesion and the neurodevelopmental-delay-with-epilepsy
      phenotype of this subtype.
  - reference: PMID:33473208
    reference_title: A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental
      anomalies and epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E
      causing a severe syndrome of neurodevelopmental disability and epilepsy.
    explanation: Supports separating this recessive neurodevelopmental subtype from the dominant UFSP2
      skeletal dysplasias.
  - reference: PMID:33473208
    reference_title: A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental
      anomalies and epilepsy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased
      abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than
      UFMylation.
    explanation: Source for the impaired de-UFMylation mechanism recorded here, measured in patient
      fibroblasts.
  - reference: PMID:33473208
    reference_title: A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental
      anomalies and epilepsy.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: Analysis of UFSP2's structure indicated that variants observed in skeletal disorders
      localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved
      in substrate binding.
    explanation: Source for the domain difference that separates this recessive neurodevelopmental
      phenotype from the dominant skeletal one.
- name: DEE107
  display_name: Developmental and epileptic encephalopathy 107 (NAPB)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 107
    term:
      id: MONDO:0031055
      label: developmental and epileptic encephalopathy 107
  genes:
  - preferred_term: NAPB
    term:
      id: hgnc:15751
      label: NAPB
  description: A homozygous nonsense NAPB variant. NAPB encodes the beta attachment protein of N-ethylmaleimide-sensitive
    factor and acts in SNARE complex dissociation and recycling during synaptic vesicle docking, so this
    subtype and DEE96 are lesions at two successive steps of the same machinery. The index patient was
    a girl of Irish Traveller descent with consanguineous parents, with multifocal seizures and profound
    global developmental delay. Napb knockout mice were already known to develop recurrent postnatal seizures
    without structural brain change.
  evidence:
  - reference: PMID:26235277
    reference_title: NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive
      factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of
      the protein.
    explanation: Establishes the homozygous NAPB lesion defining this subtype and the extent of protein
      loss.
  - reference: PMID:26235277
    reference_title: NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report a 6-year-old girl with unexplained EOEE characterized by multifocal seizures
      and profound global developmental delay.
    explanation: Sources the clinical presentation of the index case.
  - reference: PMID:26235277
    reference_title: NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: MODEL_ORGANISM
    snippet: Knockout mouse models of the murine ortholog Napb have been previously reported. These mice
      develop recurrent post-natal epileptic seizures in the absence of structural brain changes.
    explanation: Model-organism support for NAPB loss causing seizures, restated by the citing paper from
      earlier work.
- name: DEE108
  display_name: Developmental and epileptic encephalopathy 108 (MAST3)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 108
    term:
      id: MONDO:0859314
      label: developmental and epileptic encephalopathy 108
  genes:
  - preferred_term: MAST3
    term:
      id: hgnc:19036
      label: MAST3
  description: De novo MAST3 missense variants in the serine-threonine kinase domain. MAST3 is one of
    the microtubule-associated serine-threonine kinases, expressed in excitatory cortical neurons late
    in prenatal development and postnatally. All eleven individuals of the defining series had DEE, eight
    with normal development before seizure onset under two years of age, and fever-triggered and drug-resistant
    seizures in nine each. Transfected cells showed generally lower MAST3 expression with increased phosphorylation
    of its target ARPP-16, which the authors suggest may confer gain of function.
  evidence:
  - reference: PMID:34185323
    reference_title: Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent
      variants p.G510S (n = 5) and p.G515S (n = 3).
    explanation: Establishes the de novo MAST3 kinase-domain variants that define this subtype.
  - reference: PMID:34185323
    reference_title: Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development
      prior to seizure onset at <2 years of age.
    explanation: Sources the DEE phenotype and the normal pre-seizure development stated in this row description.
  - reference: PMID:34185323
    reference_title: Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by
      fever and 9 of 11 patients had drug-resistant seizures.
    explanation: Sources the fever trigger and drug resistance counts stated in this row description.
- name: DEE109
  display_name: Developmental and epileptic encephalopathy 109 (FZR1)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 109
    term:
      id: MONDO:0859325
      label: developmental and epileptic encephalopathy 109
  genes:
  - preferred_term: FZR1
    term:
      id: hgnc:24824
      label: FZR1
  description: De novo loss-of-function FZR1 variants. FZR1 encodes the Cdh1 subunit of the anaphase-promoting
    complex, with roles both in the cell cycle and in post-mitotic neurons, so the lesion is in cell-cycle
    regulation rather than in a channel or synaptic protein. The three individuals found among 250 unrelated
    DEE patients all had childhood-onset generalised epilepsy, intellectual disability, mild ataxia and
    normal head circumference, and two were diagnosed with the myoclonic atonic epilepsy subtype of DEE.
    Drosophila assays using three mutant alleles of the homologue fzr supported the variants being loss
    of function.
  evidence:
  - reference: PMID:34788397
    reference_title: De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies
      and a connection on GeneMatcher led to the identification of three de novo missense variants in
      FZR1.
    explanation: Establishes the de novo FZR1 variants that define this subtype and how they were ascertained.
  - reference: PMID:34788397
    reference_title: De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy,
      intellectual disability, mild ataxia and normal head circumference.
    explanation: Sources the phenotype stated in this row description.
  - reference: PMID:34788397
    reference_title: De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Further, we provide functional evidence that the missense variants are loss-of-function alleles
      using Drosophila neurodevelopment assays.
    explanation: Sources the loss-of-function reading of the FZR1 variants.
- name: DEE110
  display_name: Developmental and epileptic encephalopathy 110 (CACNA2D1)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 110
    term:
      id: MONDO:0859327
      label: developmental and epileptic encephalopathy 110
  genes:
  - preferred_term: CACNA2D1
    term:
      id: hgnc:1399
      label: CACNA2D1
  description: Biallelic loss-of-function CACNA2D1 variants in two unrelated individuals. CACNA2D1
    encodes the α2δ-1 auxiliary subunit of CaV1 and CaV2 voltage-gated calcium channels. Functional
    studies of the missense allele carried by one of the two showed that the amino-acid change severely
    impairs α2δ-1's function as a calcium channel subunit.
  evidence:
  - reference: PMID:35293990
    reference_title: Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report biallelic variants in CACNA2D1, encoding the α2δ-1 protein, in two unrelated
      individuals showing a developmental and epileptic encephalopathy.
    explanation: Establishes biallelic CACNA2D1 variants as the lesion defining this subtype.
  - reference: PMID:35293990
    reference_title: Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental
      disorder in these two patients.
    explanation: States the loss-of-function mechanism and the severity of the resulting neurodevelopmental
      disorder.
  - reference: PMID:35293990
    reference_title: Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our functional studies show that this amino-acid change severely impairs the function
      of α2δ-1 as a calcium channel subunit
    explanation: Source for the functional impairment of the auxiliary subunit recorded here.
- name: DEE111
  display_name: Developmental and epileptic encephalopathy 111 (DEPDC5, biallelic)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 111
    term:
      id: MONDO:0957780
      label: developmental and epileptic encephalopathy 111
  genes:
  - preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  description: 'Germline biallelic missense DEPDC5 variants. DEPDC5 encodes an inhibitory component of
    the mTOR pathway, and the usual germline lesion is a single inactivating heterozygous variant, which
    dismech curates as the separate DEPDC5-Related_Epilepsy entry. This subtype is the biallelic germline
    phenotype, which is a different entity: extensive bilateral polymicrogyria, congenital macrocephaly
    and early-onset refractory epilepsy, rather than a focal lesion produced by a brain-somatic second
    hit. Six of the children were of Irish Traveller origin sharing p.Thr337Arg, and two Tunisian plus
    one Lebanese child shared p.Arg806Cys; five of nine died in infancy or childhood.'
  evidence:
  - reference: PMID:36067010
    reference_title: Germline homozygous missense DEPDC5 variants cause severe refractory early-onset
      epilepsy, macrocephaly and bilateral polymicrogyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5.
    explanation: Establishes the biallelic germline DEPDC5 entity that this subtype term names, as distinct
      from heterozygous DEPDC5-related focal epilepsy.
  - reference: PMID:36067010
    reference_title: Germline homozygous missense DEPDC5 variants cause severe refractory early-onset
      epilepsy, macrocephaly and bilateral polymicrogyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly
      and early-onset refractory epilepsy, in keeping with other mTOR-opathies.
    explanation: Sources the phenotype stated in this row description, and its bilateral rather than focal
      distribution.
  - reference: PMID:36067010
    reference_title: Germline homozygous missense DEPDC5 variants cause severe refractory early-onset
      epilepsy, macrocephaly and bilateral polymicrogyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway.
    explanation: Sources the mTOR hyperactivation mechanism in affected individuals.
- name: DEE112
  display_name: Developmental and epileptic encephalopathy 112 (KCNH5)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 112
    term:
      id: MONDO:0957812
      label: developmental and epileptic encephalopathy 112
  genes:
  - preferred_term: KCNH5
    term:
      id: hgnc:6254
      label: KCNH5
  description: 'De novo KCNH5 missense variants in or near the voltage-sensing and pore domains. KCNH5
    encodes the voltage-gated potassium channel EAG2/Kv10.2. The defining cohort of seventeen patients
    shows that the severity tracks the variant rather than the gene: the recurrent p.Arg333His gave a
    self-limited drug-responsive epilepsy with normal intellect, while the recurrent p.Arg327His gave
    infantile-onset DEE, and two pore-domain variants gave a neonatal movement disorder with early-infantile
    DEE, profound disability and childhood death.'
  evidence:
  - reference: PMID:36307226
    reference_title: Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants
      in the Voltage-Sensing and Pore Domains of KCNH5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant
      p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants.
    explanation: Establishes the KCNH5 variant series behind this subtype.
  - reference: PMID:36307226
    reference_title: Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants
      in the Voltage-Sensing and Pore Domains of KCNH5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal
      or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated
      with infantile-onset DEE.
    explanation: Sources the variant-dependent split between self-limited epilepsy and DEE stated in this
      row description.
- name: DEE113
  display_name: Developmental and epileptic encephalopathy 113 (SV2A)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 113
    term:
      id: MONDO:0958330
      label: developmental and epileptic encephalopathy 113
  genes:
  - preferred_term: SV2A
    term:
      id: hgnc:20566
      label: SV2A
  description: 'SV2A encodes synaptic vesicle glycoprotein 2A, the binding site of levetiracetam.
    The reported lesion is a homozygous R383Q missense change in a multiply consanguineous family:
    the proband had intractable epilepsy, involuntary movements, microcephaly and developmental and
    growth retardation, and an earlier-born brother had a similar course and died at 7 months of age.
    Levetiracetam was not effective in the proband. The evidence base for this subtype is thin - a
    single family, with no independent replication found in a PubMed search on 2026-09-25 using the
    queries ''SV2A biallelic variants developmental and epileptic encephalopathy'' (no hits), ''SV2A
    gene variants patients epilepsy developmental delay cohort'' (no hits) and ''synaptic vesicle
    glycoprotein 2A SV2A homozygous variant patients'' (this report only).'
  evidence:
  - reference: PMID:26002053
    reference_title: Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable
      Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing identified a homozygous arginine to glutamine mutation in amino acid
      position 383 (R383Q) in exon 5 of the SV2A gene.
    explanation: Establishes the single reported biallelic SV2A lesion defining this subtype.
  - reference: PMID:26002053
    reference_title: Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable
      Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our report provides the elusive evidence that an SV2A mutation can be a cause of epilepsy
      in humans.
    explanation: States the gene-disease claim, and its wording marks how new and singular the observation
      was.
  - reference: PMID:26002053
    reference_title: Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable
      Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both parents were multiply consanguineous and an earlier-born brother of the proband
      had a similar course and died at 7 months of age.
    explanation: Source for the consanguinity and the affected sibling, the whole of the reported
      family evidence for this subtype.
  - reference: PMID:26002053
    reference_title: Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable
      Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We investigated a patient with intractable epilepsy, involuntary movements, microcephaly,
      and developmental and growth retardation.
    explanation: Source for the proband's phenotype recorded here.
- name: DEE114
  display_name: Developmental and epileptic encephalopathy 114 (SLC32A1)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 114
    term:
      id: MONDO:0958331
      label: developmental and epileptic encephalopathy 114
  genes:
  - preferred_term: SLC32A1
    term:
      id: hgnc:11018
      label: SLC32A1
  description: 'De novo missense SLC32A1 variants. SLC32A1 encodes the vesicular GABA transporter, which
    loads GABA into synaptic vesicles, so the lesion is presynaptic and inhibitory. Inherited missense
    variants in the same gene had already been linked to genetic epilepsy with febrile seizures plus,
    and this report establishes that de novo missense variants instead cause a DEE. Two mechanisms were
    demonstrated in a murine neuronal culture model: three variants lining the putative GABA transport
    pathway reduced quantal size, consistent with impaired vesicle filling, while an N-terminal variant
    left quantal size intact but raised presynaptic release probability.'
  evidence:
  - reference: PMID:36073542
    reference_title: De Novo Missense Variants in SLC32A1 Cause a Developmental and Epileptic Encephalopathy
      Due to Impaired GABAergic Neurotransmission.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using exome sequencing, we identified four individuals with a developmental and epileptic
      encephalopathy and de novo missense variants in SLC32A1.
    explanation: Establishes the DEE114 clinical entity and de novo SLC32A1 variants as its lesion.
  - reference: PMID:36073542
    reference_title: De Novo Missense Variants in SLC32A1 Cause a Developmental and Epileptic Encephalopathy
      Due to Impaired GABAergic Neurotransmission.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The main phenotype comprises moderate-to-severe intellectual disability, infantile-onset
      epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement
      disorder.
    explanation: Sources the phenotype stated in this row description, including the movement disorder.
  - reference: PMID:36073542
    reference_title: De Novo Missense Variants in SLC32A1 Cause a Developmental and Epileptic Encephalopathy
      Due to Impaired GABAergic Neurotransmission.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In silico modeling and functional analyses reveal that three of these variants, which are
      located in helices that line the putative GABA transport pathway, result in reduced quantal size,
      consistent with impaired filling of synaptic vesicles with GABA.
    explanation: Sources the vesicle-filling mechanism, measured in a murine neuronal cell culture model.
- name: DEE115
  display_name: Developmental and epileptic encephalopathy 115 (SNF8)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 115
    term:
      id: MONDO:0968946
      label: developmental and epileptic encephalopathy 115
  genes:
  - preferred_term: SNF8
    term:
      id: hgnc:17028
      label: SNF8
  description: Biallelic SNF8 variants, the severe pole of the SNF8 disease spectrum. SNF8 encodes a subunit
    of ESCRT-II, one of the three complexes of the endosomal sorting machinery required for membrane remodelling
    and autophagy. The milder pole of the same spectrum, with intellectual disability and childhood-onset
    optic atrophy or ataxia, is curated as the separate SNF8-Related_Neurodevelopmental_Disorder entry,
    which lists this concept as an allelic differential diagnosis; all mildly affected individuals shared
    the hypomorphic variant p.Val102Ile. The DEE concept itself is curated here as a subtype row rather
    than as its own entry.
  evidence:
  - reference: PMID:38423010
    reference_title: Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental
      and epileptic encephalopathy to syndromic optic atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The phenotypic spectrum included four individuals with severe developmental and epileptic
      encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental
      arrest, and early death.
    explanation: Establishes the DEE115 clinical entity as the severe pole of the SNF8 spectrum.
  - reference: PMID:38423010
    reference_title: Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental
      and epileptic encephalopathy to syndromic optic atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative
      features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit
      SNF8.'
    explanation: Establishes biallelic SNF8 variants as the lesion and SNF8 as an ESCRT-II subunit.
  - reference: PMID:38423010
    reference_title: Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental
      and epileptic encephalopathy to syndromic optic atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile).
    explanation: Sources the allele that separates the mild pole, curated elsewhere, from this severe
      pole.
- name: DEE118
  display_name: Developmental and epileptic encephalopathy 118 (TMEM63B)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 118
    term:
      id: MONDO:0979238
      label: developmental and epileptic encephalopathy 118
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0800503
        label: TMEM63B-related developmental and epileptic encephalopathy with anemia
      mapping_predicate: skos:exactMatch
      mapping_source: MONDO
      mapping_justification: 'MONDO carries two classes for one disease. MONDO:0800503 and MONDO:0979238
        are both direct children of MONDO:0100062, both assert RO:0004003 hgnc:17735 TMEM63B, and both
        trace to the same founding report: the OMIM summary for OMIM:621250, which MONDO:0979238 xrefs,
        attributes the phenotype to Vetro et al. 2023 (PMID:37421948), and the haematological abnormality
        that MONDO:0800503 is named after is the feature that report describes in 12 of 17 individuals.
        The two classes differ only in provenance, MONDO:0800503 carrying GARD:0027306 and MONDO:0979238
        carrying OMIM:621250 and GARD:0028112, and neither definition refers to the other or gives a reason
        for a split.'
  genes:
  - preferred_term: TMEM63B
    term:
      id: hgnc:17735
      label: TMEM63B
  description: 'Heterozygous, almost always de novo, missense or in-frame TMEM63B variants affecting conserved
    transmembrane residues. TMEM63B encodes a stretch-activated ion channel, and the mutated channels
    carried an inward leak cation current even under isotonic conditions while responding poorly to a
    hypo-osmotic challenge. Two features set this subtype apart from the other channel subtypes here:
    the brain changes are progressive and neurodegenerative rather than static, and haematological abnormalities
    such as macrocytosis and haemolysis occurred in twelve of seventeen individuals, some needing transfusion.
    The recurrent p.Val44Met accounted for seven of the seventeen.'
  evidence:
  - reference: PMID:37421948
    reference_title: Stretch-activated ion channel TMEM63B associates with developmental and epileptic
      encephalopathies and progressive neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic
      encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated
      with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of
      TMEM63B, encoding for a highly conserved stretch-activated ion channel.
    explanation: Establishes the clinical entity, the heterozygous TMEM63B lesion, and the progressive
      neurodegenerative course.
  - reference: PMID:37421948
    reference_title: Stretch-activated ion channel TMEM63B associates with developmental and epileptic
      encephalopathies and progressive neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 12 individuals, hematological abnormalities co-occurred, such as macrocytosis and hemolysis,
      requiring blood transfusions in some.
    explanation: Sources the haematological involvement, which is the feature the duplicate MONDO class
      named in this row mappings block is named after.
  - reference: PMID:37421948
    reference_title: Stretch-activated ion channel TMEM63B associates with developmental and epileptic
      encephalopathies and progressive neurodegeneration.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we modeled six variants (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr,
      and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, in transfected
      Neuro2a cells and demonstrated inward leak cation currents across the mutated channel even in isotonic
      conditions
    explanation: Sources the leak-current mechanism stated in this row description.
- name: DEE119
  display_name: Developmental and epileptic encephalopathy 119 (RNU2-2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 119
    term:
      id: MONDO:1060177
      label: developmental and epileptic encephalopathy 119
  genes:
  - preferred_term: RNU2-2
    term:
      id: hgnc:10152
      label: RNU2-2P
  description: Recurrent de novo single-nucleotide mutations at positions 4 and 35 of RNU2-2, a 191-bp
    gene encoding the U2-2 small nuclear RNA of the major spliceosome. Twenty-five cases were assembled
    in the founding report, which estimates the disorder's prevalence at about 20% that of the related
    RNU4-2 syndrome. The phenotype is intellectual disability, autistic behaviour, microcephaly, hypotonia,
    epilepsy and hyperventilation, with a severe and complex seizure phenotype in all cases. Notably,
    mutant U2-2 was expressed in patient blood without detectable missplicing, so the mechanism downstream
    of the snRNA lesion is not yet established. This is the only non-protein-coding causal gene among
    the subtypes recorded here.
  evidence:
  - reference: PMID:40210679
    reference_title: Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental
      disorder with prominent epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: By genetic association, we identified recurrent de novo single-nucleotide mutations at
      nucleotide positions 4 and 35 of RNU2-2 in nine cases.
    explanation: Establishes the recurrent de novo RNU2-2 lesion defining this subtype.
  - reference: PMID:40210679
    reference_title: Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental
      disorder with prominent epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The disorder is characterized by intellectual disability, autistic behavior, microcephaly,
      hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype.
    explanation: Source for the phenotype and the uniformly severe seizure picture recorded here.
  - reference: PMID:40210679
    reference_title: Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental
      disorder with prominent epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We replicated this finding in 16 additional cases, bringing the total to 25. We estimate
      that RNU2-2 syndrome has a prevalence of ~20% that of RNU4-2 syndrome.
    explanation: Source for the total case count and the prevalence estimate relative to RNU4-2 syndrome.
  - reference: PMID:40210679
    reference_title: Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental
      disorder with prominent epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite mutant U2-2 being expressed in patient blood samples, we found no evidence of
      missplicing.
    explanation: Source for the negative missplicing result, which is why the mechanism downstream
      of the snRNA lesion is recorded as unestablished.
- name: DEE120
  display_name: Developmental and epileptic encephalopathy 120 (BAIAP2)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 120
    term:
      id: MONDO:0980948
      label: developmental and epileptic encephalopathy 120
  genes:
  - preferred_term: BAIAP2
    term:
      id: hgnc:947
      label: BAIAP2
  description: De novo missense BAIAP2 variants in six patients. BAIAP2 acts in dendritic spine morphogenesis
    and excitatory synapse formation, and the reported variants cluster in the multiple phosphorylation
    site region that maintains the protein's autoinhibited conformation through 14-3-3 binding. All
    six patients had severe infantile or early childhood onset epilepsy, refractory in four, with
    language and motor delay and varying degrees of intellectual disability. Neurons expressing the
    variants were more excitable through enhanced excitatory synaptogenesis, which the authors read
    as gain of function.
  evidence:
  - reference: PMID:41133935
    reference_title: De novo missense variants in BAIAP2 are associated with developmental and epileptic
      encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using whole exome/genome sequencing, we identified de novo missense variants in BAIAP2
      in six patients with DEEs.
    explanation: Establishes de novo BAIAP2 missense variants as the lesion defining this subtype.
  - reference: PMID:41133935
    reference_title: De novo missense variants in BAIAP2 are associated with developmental and epileptic
      encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) plays a crucial
      role in dendritic spine morphogenesis and excitatory synapse formation.
    explanation: States the synaptic function that places this lesion in the synaptic arm of the mechanism.
  - reference: PMID:41133935
    reference_title: De novo missense variants in BAIAP2 are associated with developmental and epileptic
      encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All six patients exhibited severe infantile or early childhood onset epilepsy, with refractory
      seizures in four individuals.
    explanation: Source for the seizure onset and refractoriness recorded here.
  - reference: PMID:41133935
    reference_title: De novo missense variants in BAIAP2 are associated with developmental and epileptic
      encephalopathies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Electrophysiological recordings revealed that neurons expressing BAIAP2 variants exhibited
      increased excitability, due to enhanced excitatory synaptogenesis.
    explanation: Source for the gain-of-function effect on excitability, measured in cultured neurons.
  - reference: PMID:41133935
    reference_title: De novo missense variants in BAIAP2 are associated with developmental and epileptic
      encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The missense variants were clustered within the multiple phosphorylation site region
      that is critical for the autoinhibited conformation of BAIAP2 through 14-3-3 binding.
    explanation: Source for the variant clustering and the autoinhibition mechanism recorded here.
- name: DEE121
  display_name: Developmental and epileptic encephalopathy 121 (LGI1)
  classification: molecular
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 121
    term:
      id: MONDO:0980966
      label: developmental and epileptic encephalopathy 121
  genes:
  - preferred_term: LGI1
    term:
      id: hgnc:6572
      label: LGI1
  description: Biallelic LGI1 variants - the recessive counterpart of the dominant LGI1 disease, autosomal
    dominant epilepsy with auditory features, which dismech curates as the separate Autosomal_Dominant_Epilepsy_with_Auditory_Features
    entry. Six individuals from four consanguineous families had DEE with neonatal or infantile-onset
    epilepsy and global developmental delay or intellectual disability; five of the six died in infancy
    or prematurely. All variants reduced LGI1 secretion and ADAM22 binding, and residual LGI1 function
    correlated with clinical severity. LGI1 is the ligand for ADAM22, so DEE121 and the ADAM22 subtype
    DEE61 are two ends of one pathway.
  evidence:
  - reference: PMID:40455867
    reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy
      via the LGI1-ADAM22/23 pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Through international genetic data sharing, we identified the first ultra-rare biallelic
      LGI1 variants in six individuals from four consanguineous families. Affected individuals presented
      DEE with neonatal/infantile-onset epilepsy (n = 6/6), global developmental delay/intellectual
      disability (n = 6/6) and infant/premature death (n = 5/6).
    explanation: Establishes biallelic LGI1 variants as a cause of DEE and records the cohort and
      its mortality.
  - reference: PMID:40455867
    reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy
      via the LGI1-ADAM22/23 pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates
      excitatory synaptic transmission and neuronal excitability in the brain.
    explanation: States the synaptic function shared with the ADAM22 subtype DEE61.
  - reference: PMID:40455867
    reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy
      via the LGI1-ADAM22/23 pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding.
      Residual LGI1 function levels correlated with clinical severity, ranging from infantile lethality
      to intermediate phenotypes.
    explanation: Source for the reduced secretion and ADAM22 binding, and for the correlation between
      residual function and severity.
  - reference: PMID:40455867
    reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy
      via the LGI1-ADAM22/23 pathway.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: Monoallelic pathogenic variants in LGI1 cause autosomal dominant epilepsy with auditory
      features with onset in childhood/adolescence.
    explanation: Source for the dominant LGI1 phenotype that this recessive subtype is distinguished
      from, and for the same distinction drawn on the ADAM22 subtype DEE61. Recorded as BACKGROUND
      because the citing study established the recessive phenotype, not the dominant one.
- name: MCSZ
  display_name: Microcephaly, seizures, and developmental delay (PNKP)
  classification: molecular
  subtype_term:
    preferred_term: microcephaly, seizures, and developmental delay
    term:
      id: MONDO:0013254
      label: microcephaly, seizures, and developmental delay
  genes:
  - preferred_term: PNKP
    term:
      id: hgnc:9154
      label: PNKP
  description: 'Biallelic PNKP variants. This is the one subtype recorded here that MONDO does not
    number in the DEE series: it is filed under both microcephaly and genetic developmental and epileptic
    encephalopathy, and carries EIEE10 only as a related synonym. The founding report mapped the locus
    to 19q13.33 and described an autosomal recessive disease of microcephaly, early-onset intractable
    seizures and developmental delay, with a splicing allele giving a milder course. PNKP encodes
    polynucleotide kinase 3''-phosphatase; unlike other human DNA repair defects, PNKP variants universally
    cause severe seizures. Allelic PNKP disorders are curated elsewhere in dismech, notably Charcot-Marie-Tooth_Disease_Type_2B2.'
  evidence:
  - reference: PMID:20118933
    reference_title: Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe a previously unknown autosomal recessive disease characterized by microcephaly,
      early-onset, intractable seizures and developmental delay (denoted MCSZ).
    explanation: Establishes the MCSZ entity and its autosomal recessive inheritance.
  - reference: PMID:20118933
    reference_title: Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Unlike other DNA repair defects that affect humans, PNKP mutations universally cause
      severe seizures.
    explanation: Supports treating this DNA-repair disorder as a member of the DEE umbrella rather
      than only a microcephaly syndrome.

- name: RMFSL
  display_name: Neonatal-onset encephalopathy with rigidity and seizures (BRAT1)
  classification: molecular
  subtype_term:
    preferred_term: neonatal-onset encephalopathy with rigidity and seizures
    term:
      id: MONDO:0013784
      label: neonatal-onset encephalopathy with rigidity and seizures
  genes:
  - preferred_term: BRAT1
    term:
      id: hgnc:21701
      label: BRAT1
  description: 'Biallelic BRAT1 variants, also called lethal neonatal rigidity and multifocal seizure
    syndrome. BRAT1 is the BRCA1-associated ATM activator. The sibling pair in the first report cited
    here carried compound heterozygous variants, one of them affecting a conserved residue in the CIDE-N
    domain that regulates the DNA fragmentation pathway of apoptosis. BRAT1 produces two distinct phenotypes,
    and which one a genotype gives is largely predictable: in a 97-patient cohort every one of 46 genotypes
    made up of biallelic nonsense, frameshift or in-frame indel variants gave this lethal rigidity and
    multifocal-seizure phenotype, whereas genotypes including at least one missense variant gave the non-lethal
    cerebellar-atrophy phenotype in 28 of 34. Fifty-nine of the 97 had the phenotype this row names, and
    93 per cent of those died prematurely.'
  evidence:
  - reference: PMID:25319849
    reference_title: Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia
      and microcephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: They had intractable seizures from neonatal period, dysmorphic features and hypertonia. Progressive
      microcephaly was also observed.
    explanation: Clinical presentation of the sibling pair reported in this paper, who carried compound
      heterozygous BRAT1 variants.
  - reference: PMID:25319849
    reference_title: Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia
      and microcephaly.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: Homozygous frameshift BRAT1 mutations were found in patients with lethal neonatal rigidity
      and multifocal seizure syndrome (MIM# 614498).
    explanation: Identifies BRAT1 as the gene of the OMIM entity this subtype term names. The citing paper
      restates this from the earlier reports rather than establishing it.
  - reference: PMID:37344571
    reference_title: 'BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations
      from 97 patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift
      or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46;
      100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS
      (28/34; 82%).
    explanation: Sources the genotype-phenotype split between this lethal phenotype and the non-lethal
      BRAT1 phenotype.
  - reference: PMID:37344571
    reference_title: 'BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations
      from 97 patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no
      psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died
      prematurely (93%).
    explanation: Sources the cohort share and the feature frequencies stated in this row description.
pathophysiology:
- name: Genetic Lesion in an Ion Channel or Synaptic Gene
  biological_scale: MOLECULAR
  description: >-
    A de novo or inherited pathogenic variant in one of a large and growing
    set of genes encoding voltage-gated ion channels (e.g. SCN1A, SCN2A,
    SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1E, HCN1), presynaptic vesicle-cycle
    and neurotransmitter-release machinery (STXBP1, DNM1, SNAP25, CPLX1,
    UNC13A), postsynaptic glutamate or GABA receptors (GRIN1, GRIN2A,
    GRIN2B, GABRA1, GABRB3), or chromatin/transcriptional regulators active
    in neurodevelopment (CDKL5, FOXG1, CHD2) disrupts normal neuronal
    excitability or synaptic signaling.

    Gene-defined subtypes wired at this node in this entry, beyond the examples
    above, are CACNA2D1 (the alpha-2-delta-1 auxiliary subunit of CaV1 and CaV2
    voltage-gated calcium channels), FGF13/FHF2 (an intracellular regulator of
    voltage-gated sodium channels), SV2A (a synaptic vesicle glycoprotein and the
    binding site of levetiracetam), FRRS1L (an AMPA receptor outer-core protein),
    LGI1 together with its postsynaptic receptor ADAM22, BAIAP2 (dendritic spine
    morphogenesis and excitatory synapse formation), and ACTL6B (a subunit of the
    neuron-specific chromatin remodelling complex nBAF). Each functional
    assignment is taken from the publication cited on that subtype's own
    has_subtypes row.

    The DEE-series subtypes added under this parent extend that list with four
    further voltage-gated channel subunits (SCN3A/Nav1.3, KCNC2/Kv3.2,
    KCNH5/EAG2-Kv10.2, and the sodium-activated potassium channel KCNT2); the
    stretch-activated channel TMEM63B; four GABA receptor subunits, namely the
    GABA-A subunits GABRB2, GABRA2 and GABRA5 together with the metabotropic
    GABA-B subunit GABBR2; the vesicular GABA transporter SLC32A1; and three
    further components of the presynaptic vesicle cycle, namely the AAA ATPase
    NSF, which acts in SNARE complex assembly and disassembly, its beta
    attachment protein NAPB, and the polyphosphoinositide phosphatase SYNJ1.
  molecular_functions:
  - preferred_term: ion channel activity
    term:
      id: GO:0005216
      label: monoatomic ion channel activity
  genes:
  - preferred_term: SCN1A
    term:
      id: hgnc:10585
      label: SCN1A
  - preferred_term: SCN2A
    term:
      id: hgnc:10588
      label: SCN2A
  - preferred_term: SCN8A
    term:
      id: hgnc:10596
      label: SCN8A
  - preferred_term: KCNQ2
    term:
      id: hgnc:6296
      label: KCNQ2
  - preferred_term: STXBP1
    term:
      id: hgnc:11444
      label: STXBP1
  - preferred_term: CDKL5
    term:
      id: hgnc:11411
      label: CDKL5
  - preferred_term: FRRS1L
    term:
      id: hgnc:1362
      label: FRRS1L
  - preferred_term: ADAM22
    term:
      id: hgnc:201
      label: ADAM22
  - preferred_term: ACTL6B
    term:
      id: hgnc:160
      label: ACTL6B
  - preferred_term: FGF13
    term:
      id: hgnc:3670
      label: FGF13
  - preferred_term: CACNA2D1
    term:
      id: hgnc:1399
      label: CACNA2D1
  - preferred_term: SV2A
    term:
      id: hgnc:20566
      label: SV2A
  - preferred_term: BAIAP2
    term:
      id: hgnc:947
      label: BAIAP2
  - preferred_term: LGI1
    term:
      id: hgnc:6572
      label: LGI1
  - preferred_term: SCN3A
    term:
      id: hgnc:10590
      label: SCN3A
  - preferred_term: KCNC2
    term:
      id: hgnc:6234
      label: KCNC2
  - preferred_term: KCNH5
    term:
      id: hgnc:6254
      label: KCNH5
  - preferred_term: KCNT2
    term:
      id: hgnc:18866
      label: KCNT2
  - preferred_term: TMEM63B
    term:
      id: hgnc:17735
      label: TMEM63B
  - preferred_term: GABRB2
    term:
      id: hgnc:4082
      label: GABRB2
  - preferred_term: GABRA2
    term:
      id: hgnc:4076
      label: GABRA2
  - preferred_term: GABRA5
    term:
      id: hgnc:4079
      label: GABRA5
  - preferred_term: GABBR2
    term:
      id: hgnc:4507
      label: GABBR2
  - preferred_term: SLC32A1
    term:
      id: hgnc:11018
      label: SLC32A1
  - preferred_term: NSF
    term:
      id: hgnc:8016
      label: NSF
  - preferred_term: NAPB
    term:
      id: hgnc:15751
      label: NAPB
  - preferred_term: SYNJ1
    term:
      id: hgnc:11503
      label: SYNJ1
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      900 genes have been identified as monogenic causes of DEEs and many cell
      components and processes
    explanation: >-
      Establishes the extreme monogenic heterogeneity of the DEE umbrella, the
      defining upstream trigger of this entry.
  - reference: PMID:35951482
    reference_title: 'Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic DEEs have been associated with mutations in many genes involved in
      different functions including cell migration, proliferation, and
      organization, neuronal excitability, and synapse transmission and
      plasticity.
    explanation: >-
      Enumerates the functional gene classes affected, matching the ion-channel,
      synaptic, and neurodevelopmental categories described in this node.
  downstream:
  - target: Neuronal Excitation-Inhibition Imbalance
    description: >-
      The gene-level lesion alters neuronal excitability or synaptic signalling,
      shifting the excitation-inhibition balance of the network.
    evidence:
    - reference: PMID:35951482
      reference_title: 'Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Genetic DEEs have been associated with mutations in many genes involved
        in different functions including cell migration, proliferation, and
        organization, neuronal excitability, and synapse transmission and
        plasticity.
      explanation: >-
        Connects the causal genes to neuronal excitability and synaptic
        transmission, the substrate of excitation-inhibition balance.
- name: Neuronal Excitation-Inhibition Imbalance
  biological_scale: CELLULAR
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance"
  description: >-
    Depending on the specific gene and variant, the molecular lesion produces
    either a gain- or loss-of-function shift in neuronal excitability (e.g.
    gain-of-function SCN2A/SCN8A sodium-channel variants causing neuronal
    hyperexcitability versus loss-of-function SCN1A variants preferentially
    impairing GABAergic interneuron firing), converging on a common circuit-level
    disruption of the balance between excitatory and inhibitory synaptic drive.
  cell_types:
  - preferred_term: GABAergic interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: GABA Signaling Pathway
    term:
      id: GO:0007214
      label: gamma-aminobutyric acid signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:39858526
    reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many genes mutated in DEEs encode ion channels, causing current conduction
      disruptions known as channelopathies.
    explanation: >-
      Supports the channelopathy arm in which the genetic lesion alters neuronal
      excitability, the proximate cause of excitation-inhibition imbalance.
  downstream:
  - target: Hypersynchronous Network Activity and Seizures
    description: >-
      Excitation-inhibition imbalance drives the seizure arm of the DEE
      mechanism.
    evidence:
    - reference: PMID:39858526
      reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Many genes mutated in DEEs encode ion channels, causing current
        conduction disruptions known as channelopathies.
      explanation: >-
        Links the channel-level conduction disruption to the epileptic output of
        the disease.
  - target: Impaired Synaptic Maturation and Neurodevelopment
    description: >-
      The same molecular lesion independently disrupts circuit maturation,
      producing the developmental arm.
    evidence:
    - reference: PMID:39858526
      reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These two aspects
        influence one another but can develop independently, creating diagnostic
        and therapeutic challenges.
      explanation: >-
        Supports branching the mechanism into two arms that can develop
        independently of one another.
- name: Hypersynchronous Network Activity and Seizures
  biological_scale: TISSUE
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
  description: >-
    Excitation-inhibition imbalance produces hypersynchronous, epileptiform
    cortical network activity, manifesting clinically as frequent,
    often multiple, drug-resistant seizure types with an abnormal
    interictal EEG background.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Action Potential
    term:
      id: GO:0001508
      label: action potential
    modifier: INCREASED
  evidence:
  - reference: PMID:40013914
    reference_title: Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental and epileptic encephalopathies (DEEs) are the most severe
      group of epilepsies, characterized by drug-resistant seizures and
      developmental slowing or regression.
    explanation: >-
      The ILAE operational definition identifies drug-resistant seizures as a
      defining clinical output of the DEE network mechanism.
  downstream:
  - target: Drug-Resistant Seizures
    causal_link_type: DIRECT
    description: >-
      The hypersynchronous network state is what is observed clinically as the
      antiseizure-medication-refractory seizures that the ILAE operational
      definition puts at the centre of the DEE concept.
    evidence:
    - reference: PMID:40013914
      reference_title: Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Developmental and epileptic encephalopathies (DEEs) are the most severe
        group of epilepsies, characterized by drug-resistant seizures and
        developmental slowing or regression.
      explanation: >-
        Names drug-resistant seizures as the defining clinical output of the DEE
        mechanism, which is what this edge asserts.
  - target: Status Epilepticus
    causal_link_type: DIRECT
    description: >-
      Status epilepticus is the failure of a seizure to self-terminate.
      Convulsive status epilepticus was recorded in 47 per cent and
      nonconvulsive status epilepticus in 19 per cent of a 510-patient genetic
      DEE cohort.
    evidence:
    - reference: PMID:36750385
      reference_title: Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The cohort comprised 510 individuals with a genetic DEE, in whom we
        observed CSE in 47% and NCSE in 19%.
      explanation: >-
        Quantifies status epilepticus as an outcome of the seizure mechanism in a
        cohort restricted to genetic DEE.
  - target: Abnormal EEG Background
    causal_link_type: DIRECT
    description: >-
      The same hypersynchrony is recorded interictally as frequent epileptiform
      activity on an abnormal EEG background, which is the electrographic rather
      than the clinical reading of this node.
    evidence:
    - reference: PMID:35951482
      reference_title: 'Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        characterized by early-onset, often severe epileptic seizures and EEG
        abnormalities
      explanation: >-
        Pairs the seizures and the EEG abnormality as joint characteristics of
        the DEE group, which is what this edge asserts.
  - target: Epileptic Encephalopathy Component
    description: >-
      Ongoing seizures and epileptiform activity themselves degrade cognitive
      and behavioural function.
    evidence:
    - reference: PMID:35951482
      reference_title: 'Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        on a background of developmental impairment that tends to worsen as a
        consequence of epilepsy
      explanation: >-
        States that the epilepsy itself worsens developmental impairment, the
        defining claim of this causal edge.
- name: Impaired Synaptic Maturation and Neurodevelopment
  biological_scale: TISSUE
  description: >-
    Independent of seizure activity, the same channel or synaptic-gene
    defect disrupts activity-dependent synaptic pruning, circuit
    maturation, and neuronal migration/connectivity during critical
    developmental windows, producing a developmental encephalopathy
    component that is not fully reversible by seizure control alone.
  evidence:
  - reference: PMID:39858526
    reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      many other mechanisms have been identified: impaired neurogenesis,
      metabolic disorders, disruption of dendrite and axon growth, maintenance
      and synapse formation abnormalities -synaptopathies.
    explanation: >-
      Documents the non-channelopathy, neurodevelopmental mechanisms that
      constitute this seizure-independent arm of the DEE mechanism.
  downstream:
  - target: Developmental Encephalopathy Component
    description: >-
      Disrupted circuit maturation yields developmental delay and intellectual
      disability independently of seizure burden.
    evidence:
    - reference: PMID:39858526
      reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        many other mechanisms have been identified: impaired neurogenesis,
        metabolic disorders, disruption of dendrite and axon growth, maintenance
        and synapse formation abnormalities -synaptopathies.
      explanation: >-
        Identifies the neurodevelopmental mechanisms that generate the
        developmental encephalopathy component.
- name: Epileptic Encephalopathy Component
  biological_scale: ORGANISM
  description: >-
    Frequent seizures and ongoing epileptiform discharges themselves
    contribute to cognitive slowing, developmental regression, and
    behavioral disturbance, over and above the effect of the underlying
    genetic lesion. This component can partially improve with effective
    seizure control.
  evidence:
  - reference: PMID:35951482
    reference_title: 'Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      on a background of developmental impairment that tends to worsen as a
      consequence of epilepsy
    explanation: >-
      States the epileptic-encephalopathy component explicitly: the epilepsy
      itself worsens developmental impairment.
  - reference: PMID:28276062
    reference_title: 'ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In an epileptic encephalopathy, the abundant epileptiform activity
      interferes with development resulting in cognitive slowing and often
      regression, and sometimes is associated with psychiatric and behavioural
      consequences. ... A key component of the concept is that amelioration of
      the epileptiform activity may have the potential to improve the
      developmental consequences of the disorder.
    explanation: >-
      The 2017 ILAE classification defines the epileptic-encephalopathy
      component this node describes: epileptiform activity itself causes
      cognitive slowing, regression and behavioural consequences, and
      controlling it may improve development.
  downstream:
  - target: Developmental Regression
    causal_link_type: DIRECT
    description: >-
      What this component adds is deterioration: worsening of development on a
      background of established impairment, rather than the delay itself. That is
      why loss of previously acquired skills is routed from here rather than from
      the developmental component, which the entry treats as the source of the
      delay.
    evidence:
    - reference: PMID:35951482
      reference_title: 'Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        on a background of developmental impairment that tends to worsen as a
        consequence of epilepsy
      explanation: >-
        States that the epilepsy itself worsens developmental impairment, which is
        the deterioration this edge asserts.
- name: Developmental Encephalopathy Component
  biological_scale: ORGANISM
  description: >-
    Developmental delay, intellectual disability, and often autistic
    features that arise directly from the genetic etiology's disruption of
    neurodevelopment, and that may be present even before seizure onset or
    persist despite adequate seizure control.
  evidence:
  - reference: PMID:39858526
    reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      What sets DEEs apart is their complex interplay of epilepsy and
      developmental delay, often driven by genetic factors. These two aspects
      influence one another but can develop independently, creating diagnostic
      and therapeutic challenges.
    explanation: >-
      Directly supports modeling the developmental component as a separate arm
      that can arise independently of the seizure burden - the conceptual basis
      for splitting these two nodes.
  downstream:
  - target: Developmental Delay
    causal_link_type: DIRECT
    description: >-
      Delayed acquisition of milestones is the direct expression of this
      component, and in the DEE concept it may precede seizure onset.
    evidence:
    - reference: PMID:39858526
      reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Developmental and epileptic encephalopathies (DEEs) are a group of
        neuropediatric diseases associated with epileptic seizures, severe delay
        or regression of psychomotor development, and cognitive and behavioral
        deficits.
      explanation: >-
        Names severe delay of psychomotor development as a defining feature of the
        DEE group, alongside and separable from the seizures.
  - target: Intellectual Disability
    causal_link_type: DIRECT
    description: >-
      The cognitive endpoint of the developmental arm. Its features may persist
      despite adequate seizure control, which is the clinical observation that
      makes this arm separable from the epileptic one.
    evidence:
    - reference: PMID:39858526
      reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Developmental and epileptic encephalopathies (DEEs) are a group of
        neuropediatric diseases associated with epileptic seizures, severe delay
        or regression of psychomotor development, and cognitive and behavioral
        deficits.
      explanation: >-
        Names cognitive deficits as a defining feature of the DEE group, alongside
        and separable from the seizures.
    - reference: PMID:39858526
      reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: Intellectual disability is severe and complicates potential treatment.
      explanation: >-
        Characterises the severity of the intellectual disability this edge
        produces.
  - target: Autistic Behavior
    causal_link_type: UNKNOWN
    description: >-
      Autistic features are routed from the developmental rather than the
      epileptic arm because they are part of the cognitive and behavioural
      phenotype of the underlying genetic lesion. The sources cited here name
      autism spectrum disorder and behavioural deficits as features of the DEE
      group without attributing them to either arm, so the routing is this
      entry's model rather than a claim either source makes.
    evidence:
    - reference: PMID:39858526
      reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.'
      supports: SUPPORT
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Developmental and epileptic encephalopathies (DEEs) are a group of
        neuropediatric diseases associated with epileptic seizures, severe delay
        or regression of psychomotor development, and cognitive and behavioral
        deficits.
      explanation: >-
        Names behavioural deficits as a feature of the DEE group. It does not
        separate the developmental from the epileptic contribution, hence INDIRECT.
    - reference: PMID:39237642
      reference_title: Developmental and epileptic encephalopathies.
      supports: SUPPORT
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients have wide-ranging comorbidities including intellectual
        disability, psychiatric features, such as autism spectrum disorder and
        behavioural problems, movement and musculoskeletal disorders,
        gastrointestinal and sleep problems, together with  an increased
        mortality rate.
      explanation: >-
        Names autism spectrum disorder among the comorbidities of the DEE group.
        The review states co-occurrence and attributes no mechanism, hence INDIRECT.
  - target: Movement Disorder
    causal_link_type: UNKNOWN
    description: >-
      Movement disorders are routed from the developmental arm because most of
      the epilepsy-dyskinesia genes map to the same ion-channel and synaptic
      pathways as the upstream lesion nodes, rather than arising from the seizure
      burden. The cited review reports co-occurrence and gene-pathway membership;
      it does not test which arm produces the movement disorder, so this edge is
      an inference from the entry's two-component model.
    evidence:
    - reference: PMID:42068099
      reference_title: Movement Disorders in Developmental and Epileptic Encephalopathies.
      supports: SUPPORT
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Across DEE cohorts, movement disorders occurred in roughly one-quarter to
        over one-half of patients, were often hyperkinetic (notably dystonia and
        stereotypies), and frequently combined multiple phenomenologies.
      explanation: >-
        Quantifies movement disorders across DEE cohorts and gives their
        predominant hyperkinetic character. The review reports co-occurrence
        rather than a mechanism, hence INDIRECT.
    - reference: PMID:42068099
      reference_title: Movement Disorders in Developmental and Epileptic Encephalopathies.
      supports: SUPPORT
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Eight cohort studies and multiple tier 2-3 series and reviews yielded 245
        single-gene associations, most mapping to ion channel and synaptic
        signaling pathways.
      explanation: >-
        Places the epilepsy-dyskinesia gene set in the same ion-channel and
        synaptic classes as this entry's upstream lesion nodes, which is the basis
        for routing the movement disorder from the developmental arm.
- name: Genetic Lesion Beyond the Channelopathies
  biological_scale: MOLECULAR
  description: A large share of the genes in which pathogenic variants cause genetic DEE encode neither
    an ion channel nor a core synaptic protein, and the DEE literature explicitly separates these mechanisms
    from the channelopathies. The gene-defined subtypes wired at this node in this entry span Rac-GEF-dependent
    neuronal polarity (DOCK7), actin and protein-phosphatase-1 regulation in cortical migration (PHACTR1),
    receptor tyrosine kinase signalling (NTRK2), spliceosomal small nuclear RNA (RNU2-2), de-UFMylation
    (UFSP2), endoplasmic-reticulum stress signalling (RNF13), mitochondrial protein biosynthesis and
    mitochondrial trafficking (PARS2, TRAK1), purine metabolism and asparagine-linked glycosylation
    (ITPA, ALG13), endolysosomal acidification (ATP6V0A1), Na+/K+-ATPase pump function and neutral amino-acid
    transport (ATP1A2, SLC38A3), DNA repair (PNKP), and one gene in the 1q41-q42 microdeletion interval
    whose molecular function no reference cited here states (FBXO28). The DEE-series subtypes added
    under this parent extend that list with a Krebs cycle enzyme (MDH2), an endoplasmic-reticulum
    co-chaperone (CNPY3), a cut homeodomain transcription factor (CUX2), a cohesin subunit (SMC1A),
    a factor that targets arginine tRNAs for 3-methylcytosine modification (DALRD3), the v-ATPase A
    subunit (ATP6V1A), a nucleocytoplasmic shuttling RNA-binding protein (CELF2), a trans-Golgi network
    protein required for peptide hormone processing (HID1), a microtubule-associated serine-threonine
    kinase (MAST3), an inhibitory component of the mTOR pathway (DEPDC5), the anaphase-promoting complex
    subunit Cdh1 (FZR1), an ESCRT-II subunit (SNF8), the BRCA1-associated ATM activator (BRAT1), and the
    neuron-specific beta subunit of the AP-3 vesicle coat adaptor (AP3B2). AP3B2 is placed here rather
    than at the synaptic node because the AP-3 complex acts in organelle and vesicle biogenesis rather
    than at the synapse itself. Each functional assignment is
    taken from the publication cited on that subtype's own has_subtypes row. The node is kept separate
    from the ion-channel and synaptic lesion node because the two classes reach the shared excitation-inhibition
    and neurodevelopmental arms by different routes, not because the subtypes here are milder.
  molecular_functions:
  - preferred_term: guanyl-nucleotide exchange factor activity
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
  - preferred_term: actin binding
    term:
      id: GO:0003779
      label: actin binding
  - preferred_term: protein phosphatase 1 binding
    term:
      id: GO:0008157
      label: protein phosphatase 1 binding
  - preferred_term: transmembrane receptor protein tyrosine kinase activity
    term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
  - preferred_term: pre-mRNA binding
    term:
      id: GO:0036002
      label: pre-mRNA binding
  - preferred_term: deUFMylase activity
    term:
      id: GO:0071567
      label: deUFMylase activity
  - preferred_term: ubiquitin protein ligase activity
    term:
      id: GO:0061630
      label: ubiquitin protein ligase activity
  - preferred_term: proline-tRNA ligase activity
    term:
      id: GO:0004827
      label: proline-tRNA ligase activity
  - preferred_term: kinesin binding
    term:
      id: GO:0019894
      label: kinesin binding
  - preferred_term: ITP diphosphatase activity
    term:
      id: GO:0036220
      label: ITP diphosphatase activity
  - preferred_term: N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity
    term:
      id: GO:0004577
      label: N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity
  - preferred_term: proton transmembrane transporter activity
    term:
      id: GO:0015078
      label: proton transmembrane transporter activity
  - preferred_term: P-type sodium:potassium-exchanging transporter activity
    term:
      id: GO:0005391
      label: P-type sodium:potassium-exchanging transporter activity
  - preferred_term: L-glutamine transmembrane transporter activity
    term:
      id: GO:0015186
      label: L-glutamine transmembrane transporter activity
  - preferred_term: polynucleotide 3'-phosphatase activity
    term:
      id: GO:0046403
      label: polynucleotide 3'-phosphatase activity
  - preferred_term: ATP-dependent polynucleotide 5'-hydroxyl-kinase activity
    term:
      id: GO:0051734
      label: ATP-dependent polynucleotide 5'-hydroxyl-kinase activity
  evidence:
  - reference: PMID:39858526
    reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability
      Beyond Channelopathies.'
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: 'many other mechanisms have been identified: impaired neurogenesis, metabolic disorders,
      disruption of dendrite and axon growth, maintenance and synapse formation abnormalities -synaptopathies.'
    explanation: Names the non-channelopathy mechanism classes that this node collects, in the review
      the entry already uses for the two-component DEE model.
  - reference: PMID:35951482
    reference_title: 'Developmental and epileptic encephalopathies: from genetic heterogeneity to
      phenotypic continuum.'
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic DEEs have been associated with mutations in many genes involved in different
      functions including cell migration, proliferation, and organization, neuronal excitability,
      and synapse transmission and plasticity.
    explanation: Supports the breadth of gene functions represented at this node, including cell migration
      and organization.
  downstream:
  - target: Impaired Synaptic Maturation and Neurodevelopment
    description: A lesion in metabolic, transport, proteostasis, RNA-processing, cytoskeletal or genome-maintenance
      machinery disrupts circuit maturation directly, producing the developmental arm without requiring
      a primary change in channel conduction.
    evidence:
    - reference: PMID:39858526
      reference_title: 'Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability
        Beyond Channelopathies.'
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: 'many other mechanisms have been identified: impaired neurogenesis, metabolic disorders,
        disruption of dendrite and axon growth, maintenance and synapse formation abnormalities -synaptopathies.'
      explanation: States that impaired neurogenesis, metabolic disorders and disrupted dendrite and
        axon growth are DEE mechanisms, which is the claim this edge makes.
  - target: Neuronal Excitation-Inhibition Imbalance
    description: The same non-channel lesions also reach excitation-inhibition balance, either by
      limiting the supply of neurotransmitter precursors and the ion gradients that neuronal firing
      depends on, or by altering neuronal excitability directly.
    evidence:
    - reference: PMID:35951482
      reference_title: 'Developmental and epileptic encephalopathies: from genetic heterogeneity to
        phenotypic continuum.'
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: Genetic DEEs have been associated with mutations in many genes involved in different
        functions including cell migration, proliferation, and organization, neuronal excitability,
        and synapse transmission and plasticity.
      explanation: Places neuronal excitability among the functions disrupted by the wider set of
        genetic DEE genes, supporting this edge from a non-channel lesion.
  genes:
  - preferred_term: DOCK7
    term:
      id: hgnc:19190
      label: DOCK7
  - preferred_term: ITPA
    term:
      id: hgnc:6176
      label: ITPA
  - preferred_term: ALG13
    term:
      id: hgnc:30881
      label: ALG13
  - preferred_term: NTRK2
    term:
      id: hgnc:8032
      label: NTRK2
  - preferred_term: TRAK1
    term:
      id: hgnc:29947
      label: TRAK1
  - preferred_term: PHACTR1
    term:
      id: hgnc:20990
      label: PHACTR1
  - preferred_term: RNF13
    term:
      id: hgnc:10057
      label: RNF13
  - preferred_term: PARS2
    term:
      id: hgnc:30563
      label: PARS2
  - preferred_term: ATP1A2
    term:
      id: hgnc:800
      label: ATP1A2
  - preferred_term: FBXO28
    term:
      id: hgnc:29046
      label: FBXO28
  - preferred_term: SLC38A3
    term:
      id: hgnc:18044
      label: SLC38A3
  - preferred_term: ATP6V0A1
    term:
      id: hgnc:865
      label: ATP6V0A1
  - preferred_term: UFSP2
    term:
      id: hgnc:25640
      label: UFSP2
  - preferred_term: RNU2-2
    term:
      id: hgnc:10152
      label: RNU2-2P
  - preferred_term: PNKP
    term:
      id: hgnc:9154
      label: PNKP
  - preferred_term: MDH2
    term:
      id: hgnc:6971
      label: MDH2
  - preferred_term: CNPY3
    term:
      id: hgnc:11968
      label: CNPY3
  - preferred_term: CUX2
    term:
      id: hgnc:19347
      label: CUX2
  - preferred_term: SMC1A
    term:
      id: hgnc:11111
      label: SMC1A
  - preferred_term: DALRD3
    term:
      id: hgnc:25536
      label: DALRD3
  - preferred_term: ATP6V1A
    term:
      id: hgnc:851
      label: ATP6V1A
  - preferred_term: CELF2
    term:
      id: hgnc:2550
      label: CELF2
  - preferred_term: HID1
    term:
      id: hgnc:15736
      label: HID1
  - preferred_term: MAST3
    term:
      id: hgnc:19036
      label: MAST3
  - preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  - preferred_term: FZR1
    term:
      id: hgnc:24824
      label: FZR1
  - preferred_term: SNF8
    term:
      id: hgnc:17028
      label: SNF8
  - preferred_term: BRAT1
    term:
      id: hgnc:21701
      label: BRAT1
  - preferred_term: AP3B2
    term:
      id: hgnc:567
      label: AP3B2

phenotypes:
- name: Developmental Delay
  category: Neurologic
  description: >-
    Developmental slowing or frank regression, which by definition of the DEE
    concept may precede, coincide with, or follow seizure onset.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterised by seizures and frequent epileptiform activity associated
      with developmental slowing or
    explanation: >-
      Developmental slowing or regression is a defining, near-universal feature
      of the DEE group.
- name: Intellectual Disability
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients have wide-ranging comorbidities including intellectual
      disability, psychiatric
    explanation: >-
      Intellectual disability is listed first among the wide-ranging
      comorbidities of the DEE group.
- name: Drug-Resistant Seizures
  category: Neurologic
  description: >-
    Multiple seizure types that are typically refractory to antiseizure
    medication, a defining feature of the DEE group.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    temporality: CHRONIC
    clinical_course: PROGRESSIVE
    onset:
      onset_category: INFANTILE
      notes: >-
        Onset is gene-dependent, spanning neonatal (KCNQ2, STXBP1, SCN2A/SCN8A
        gain-of-function) through early infantile (SCN1A, CDKL5) to later
        infancy and early childhood (PCDH19). Infantile onset is the modal
        category across the group.
  evidence:
  - reference: PMID:40013914
    reference_title: Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental and epileptic encephalopathies (DEEs) are the most severe
      group of epilepsies, characterized by drug-resistant seizures and
      developmental slowing or regression.
    explanation: >-
      Drug resistance is part of the ILAE operational definition of the DEE
      group.
  sequelae:
  - target: Premature Mortality
    causal_link_type: DIRECT
    description: >-
      Sudden unexpected death in epilepsy accounted for 19 of 42 deaths in a
      510-patient genetic DEE cohort, so ongoing seizures are a proximate route
      from this phenotype to premature death.
    evidence:
    - reference: PMID:36750385
      reference_title: Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cases of SUDEP accounted for 19/42 (48%) deaths.
      explanation: >-
        Quantifies the share of deaths attributable to sudden unexpected death in
        epilepsy, which is the seizure-mediated route this edge asserts.
- name: Status Epilepticus
  category: Neurologic
  description: >-
    Convulsive and nonconvulsive status epilepticus are frequent and
    life-threatening complications, affecting roughly half and one fifth of
    patients respectively across genetic DEE cohorts, with the highest burden in
    SCN1A-related disease.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Status epilepticus
    term:
      id: HP:0002133
      label: Status epilepticus
  evidence:
  - reference: PMID:36750385
    reference_title: Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cohort comprised 510 individuals with a genetic DEE, in whom we
      observed CSE in 47% and NCSE in 19%.
    explanation: >-
      Quantifies convulsive and nonconvulsive status epilepticus in a large
      cohort restricted to genetic DEE, making it directly on-scope for this
      umbrella entry.
  - reference: PMID:36750385
    reference_title: Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The highest proportion of CSE occurred in
      patients with SCN1A-associated DEEs, including 181/203 (89%; 95% CI 84-93)
      patients with Dravet syndrome
    explanation: >-
      Documents the gene-dependent variation in status epilepticus risk, highest
      in SCN1A-related disease.
- name: Developmental Regression
  category: Neurologic
  description: >-
    Loss of previously acquired developmental skills, distinct from static
    delay. Regression is the more severe pole of the developmental
    encephalopathy component and is part of the operational definition of DEE.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:40013914
    reference_title: Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by drug-resistant seizures and developmental slowing
      or regression
    explanation: >-
      Developmental regression is named in the ILAE operational definition of
      the DEE group.
  - reference: PMID:40831798
    reference_title: Progress of ketogenic diet in the treatment of developmental epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It
      is characterized by early-onset, drug-resistant epilepsy, abnormal
      electroencephalogram (EEG) findings, and developmental delay or regression.
    explanation: >-
      Independently corroborates developmental regression as a defining feature
      of DEE.
- name: Abnormal EEG Background
  category: Neurologic
  description: >-
    Frequent epileptiform activity and abnormal interictal EEG background;
    specific patterns (burst-suppression, hypsarrhythmia) are gene- and
    age-dependent.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:35951482
    reference_title: 'Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by early-onset, often severe epileptic seizures and EEG
      abnormalities
    explanation: >-
      EEG abnormality is named as a core characteristic of the DEE group.
- name: Hypotonia
  category: Neurologic
  description: >-
    Truncal and appendicular hypotonia is a common early motor finding,
    frequently evolving to spasticity in severely affected children.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      movement and musculoskeletal
      disorders, gastrointestinal and sleep problems, together with
    explanation: >-
      Hypotonia falls within the movement and musculoskeletal comorbidity domain
      named for the DEE group. The review names the domain rather than hypotonia
      specifically, so the quote reaches this phenotype only by inclusion in that
      domain.
  - reference: PMID:37421948
    reference_title: Stretch-activated ion channel TMEM63B associates with developmental and epileptic
      encephalopathies and progressive neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: early generalized hypotonia evolving to spastic quadriparesis (13/17, 76%)
    explanation: >-
      Names hypotonia directly, and its evolution to spasticity, in most of a
      DEE cohort. The cohort is the TMEM63B subtype (DEE118), so it illustrates
      the umbrella phenotype in one genetic DEE rather than measuring its
      frequency across the group.
  - reference: PMID:35914066
    reference_title: GRIN2D-Related Developmental and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: abnormal muscle tone (hypotonia and spasticity)
    explanation: >-
      A second genetic DEE, GRIN2D-related DEE, in which hypotonia and spasticity
      are both part of the defining clinical characteristics.
- name: Autistic Behavior
  category: Neurologic
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      features, such as autism spectrum disorder and behavioural problems,
      movement and musculoskeletal
    explanation: >-
      Autism spectrum disorder is named among the psychiatric comorbidities of
      the DEE group.
- name: Movement Disorder
  category: Neurologic
  description: >-
    Movement and musculoskeletal problems are a recognized comorbidity domain
    of the DEE group, prominent in specific genetic forms such as
    GNAO1-related DEE.
  phenotype_term:
    preferred_term: Abnormality of movement
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      movement and musculoskeletal
      disorders, gastrointestinal and sleep problems, together with
    explanation: >-
      Movement and musculoskeletal disorders are listed among the wide-ranging
      DEE comorbidities.
  - reference: PMID:42068099
    reference_title: Movement Disorders in Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Across DEE cohorts, movement disorders occurred in roughly one-quarter to
      over one-half of patients, were often hyperkinetic (notably dystonia and
      stereotypies), and frequently combined multiple phenomenologies.
    explanation: >-
      Quantifies how often movement disorders occur across DEE cohorts and names
      their predominant hyperkinetic phenomenology, which the comorbidity-list
      quote above does not.
- name: Feeding and Gastrointestinal Difficulties
  category: Gastrointestinal
  description: >-
    Gastrointestinal problems including feeding difficulty and reflux, often
    requiring gastrostomy in severely affected children.
  phenotype_term:
    preferred_term: Abnormality of the gastrointestinal tract
    term:
      id: HP:0011024
      label: Abnormality of the gastrointestinal tract
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      disorders, gastrointestinal and sleep problems, together with
    explanation: >-
      Gastrointestinal problems are named among the multisystem comorbidities of
      the DEE group.
- name: Premature Mortality
  category: Neurologic
  description: >-
    Markedly elevated premature mortality, with sudden unexpected death in
    epilepsy (SUDEP) the leading identifiable cause in genetic DEE cohorts.
  phenotype_term:
    preferred_term: Sudden death
    term:
      id: HP:0001699
      label: Sudden death
  evidence:
  - reference: PMID:36750385
    reference_title: Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were 42/510 (8%) deaths among the cohort, producing a mortality
      rate of 6.1 per 1,000 person-years (95% CI 4.4-8.3). Cases of SUDEP
      accounted for 19/42 (48%) deaths.
    explanation: >-
      Quantifies overall mortality and the SUDEP share in a large genetic DEE
      cohort.
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      disorders, gastrointestinal and sleep problems, together with  an
      increased mortality rate.
    explanation: >-
      An increased mortality rate is an explicit feature of the DEE group.
genetic:
- name: Genetic Heterogeneity Across Ion Channel and Synaptic Genes
  notes: >-
    Pathogenic variants causing genetic DEE have been reported in more than nine
    hundred genes; the most frequent recurring categories are voltage-gated ion
    channel genes (SCN1A, SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1), presynaptic
    vesicle-cycle genes (STXBP1, DNM1, SNAP25), and postsynaptic
    neurotransmitter-receptor genes (GRIN1, GRIN2A, GRIN2B), with most cases
    arising from de novo dominant variants. Individual gene-defined forms are
    curated as separate dismech entries.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genetic cause is found in >50% of patients using next generation
      sequencing technologies.
    explanation: >-
      Establishes that a genetic etiology is identified in the majority of DEE
      patients, justifying the genetic DEE umbrella as the dominant subgroup.
- name: KCNQ2
  gene_term:
    preferred_term: KCNQ2
    term:
      id: hgnc:6296
      label: KCNQ2
  relationship_type: CAUSATIVE
  notes: >-
    Kv7.2 voltage-gated potassium channel subunit underlying the neuronal
    M-current; among the most frequently identified genes in DEE diagnostic
    cohorts.
  case_fractions:
  - population: Italian national genetic DEE survey (1568 molecularly diagnosed patients, 2012-2022)
    case_fraction_percent: 5.6
    cohort_size: 1568
    notes: Second most frequently reported gene in the Italian national survey.
    evidence:
    - reference: PMID:39613335
      reference_title: National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most frequently reported genes in the survey were SCN1A (16%),
        followed by KCNQ2 (5.6%) and SCN2A (5%).
      explanation: >-
        Quantifies the KCNQ2 share of molecularly diagnosed genetic DEE cases.
  evidence:
  - reference: PMID:35701389
    reference_title: Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.
    explanation: >-
      Identifies KCNQ2 among the most frequently identified causal genes in a
      clinical DEE exome cohort.
- name: CDKL5
  gene_term:
    preferred_term: CDKL5
    term:
      id: hgnc:11411
      label: CDKL5
  relationship_type: CAUSATIVE
  notes: >-
    X-linked serine/threonine kinase required for activity-dependent synaptic
    maturation; loss of function causes CDKL5 deficiency disorder, an exemplar
    of the seizure-independent developmental arm of DEE.
  evidence:
  - reference: PMID:35701389
    reference_title: Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.
    explanation: >-
      Identifies CDKL5 among the most frequently identified causal genes in a
      clinical DEE exome cohort.
- name: SCN1A
  gene_term:
    preferred_term: SCN1A
    term:
      id: hgnc:10585
      label: SCN1A
  relationship_type: CAUSATIVE
  notes: >-
    Nav1.1 voltage-gated sodium channel, predominantly expressed in GABAergic
    interneurons; haploinsufficiency causes Dravet syndrome, the archetypal
    genetic DEE, via interneuron disinhibition. The single most frequently
    implicated gene in molecularly diagnosed genetic DEE cohorts.
  case_fractions:
  - population: Italian national genetic DEE survey (1568 molecularly diagnosed patients, 2012-2022)
    case_fraction_percent: 16.0
    cohort_size: 1568
    notes: Most frequently reported gene in the Italian national survey.
    evidence:
    - reference: PMID:39613335
      reference_title: National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most frequently reported genes in the survey were SCN1A (16%),
        followed by KCNQ2 (5.6%) and SCN2A (5%).
      explanation: >-
        Quantifies the SCN1A share of molecularly diagnosed genetic DEE cases.
  evidence:
  - reference: PMID:35701389
    reference_title: Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.
    explanation: >-
      Identifies SCN1A among the most frequently identified causal genes in a
      clinical DEE exome cohort.
- name: SCN2A
  gene_term:
    preferred_term: SCN2A
    term:
      id: hgnc:10588
      label: SCN2A
  relationship_type: CAUSATIVE
  notes: >-
    Nav1.2 voltage-gated sodium channel, predominantly in excitatory neurons.
    Illustrates the gain- versus loss-of-function dichotomy that drives
    genotype-guided prescribing: gain-of-function variants cause severe
    early-infantile DEE responsive to sodium-channel blockers, whereas
    loss-of-function variants give a later-onset, autism-predominant phenotype.
  case_fractions:
  - population: Italian national genetic DEE survey (1568 molecularly diagnosed patients, 2012-2022)
    case_fraction_percent: 5.0
    cohort_size: 1568
    notes: Third most frequently reported gene in the Italian national survey.
    evidence:
    - reference: PMID:39613335
      reference_title: National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most frequently reported genes in the survey were SCN1A (16%),
        followed by KCNQ2 (5.6%) and SCN2A (5%).
      explanation: >-
        Quantifies the SCN2A share of molecularly diagnosed genetic DEE cases.
  evidence:
  - reference: PMID:39613335
    reference_title: National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequently reported genes in the survey were SCN1A (16%),
      followed by KCNQ2 (5.6%) and SCN2A (5%).
    explanation: >-
      Establishes SCN2A among the three most frequently implicated genetic DEE
      genes.
- name: SCN8A
  gene_term:
    preferred_term: SCN8A
    term:
      id: hgnc:10596
      label: SCN8A
  relationship_type: CAUSATIVE
  notes: >-
    Nav1.6 voltage-gated sodium channel; DEE-causing variants are typically
    gain-of-function, and like SCN2A this makes sodium-channel blockers
    rational rather than contraindicated. One of four genes associated with
    SUDEP in a large genetic DEE cohort.
  evidence:
  - reference: PMID:36750385
    reference_title: Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four genes were associated with SUDEP: SCN1A, SCN2A,
      SCN8A, and STXBP1.
    explanation: >-
      Establishes SCN8A as a genetic DEE gene and specifically one carrying
      SUDEP risk.
- name: PCDH19
  gene_term:
    preferred_term: PCDH19
    term:
      id: hgnc:14270
      label: PCDH19
  relationship_type: CAUSATIVE
  notes: >-
    X-linked protocadherin-19. Notable for a female-restricted inheritance
    pattern in which heterozygous females are affected and hemizygous males are
    typically unaffected transmitting carriers; the mechanism is curated on the
    PCDH19 Clustering Epilepsy child entry.
  evidence:
  - reference: PMID:36750385
    reference_title: Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We included patients
      with a pathogenic variant in the genes SCN1A, SCN2A, SCN8A, SYNGAP1,
      NEXMIF, CHD2, PCDH19, STXBP1, GRIN2A, KCNT1, and KCNQ2
    explanation: >-
      Lists PCDH19 among the frequently observed genetic DEE genes assembled for
      a dedicated genetic DEE cohort study.
- name: STXBP1
  gene_term:
    preferred_term: STXBP1
    term:
      id: hgnc:11444
      label: STXBP1
  relationship_type: CAUSATIVE
  notes: >-
    Syntaxin-binding protein 1 (Munc18-1), a core regulator of SNARE-mediated
    synaptic vesicle fusion; haploinsufficiency impairs both excitatory and
    inhibitory neurotransmitter release.
  evidence:
  - reference: PMID:35701389
    reference_title: Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.
    explanation: >-
      Identifies STXBP1 among the most frequently identified causal genes in a
      clinical DEE exome cohort.
- name: DOCK7
  gene_term:
    preferred_term: DOCK7
    term:
      id: hgnc:19190
      label: DOCK7
  relationship_type: CAUSATIVE
  subtype: DEE23
  notes: HGNC names this gene dedicator of cytokinesis 7. Biallelic truncating variants cause DEE23;
    the cited report describes DOCK7 as a Rac guanine nucleotide exchange factor implicated in the
    genesis and polarization of newborn pyramidal neurons and in the differentiation of cortical GABAergic
    interneurons.
  evidence:
  - reference: PMID:24814191
    reference_title: Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical
      blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in
      the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation
      of GABAergic interneurons in the developing cortex.
    explanation: States the neurodevelopmental function through which the DOCK7 lesion reaches the
      pathograph.
- name: ITPA
  gene_term:
    preferred_term: ITPA
    term:
      id: hgnc:6176
      label: ITPA
  relationship_type: CAUSATIVE
  subtype: DEE35
  notes: HGNC names this gene inosine triphosphatase. Biallelic variants cause a purine pathway defect
    presenting as early infantile epileptic encephalopathy with a lethal course.
  evidence:
  - reference: PMID:35098521
    reference_title: 'Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants:
      A Case Series and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two additional cases of ITPA-associated neurodegeneration and two pathogenic
      compound heterozygous variants.
    explanation: Documents biallelic (compound heterozygous) ITPA variants in further patients.
- name: ALG13
  gene_term:
    preferred_term: ALG13
    term:
      id: hgnc:30881
      label: ALG13
  relationship_type: CAUSATIVE
  subtype: DEE36
  notes: HGNC names this gene ALG13 UDP-N-acetylglucosaminyltransferase subunit. The recurrent de
    novo p.(Asn107Ser) missense variant accounts for most reported ALG13-related DEE, predominantly
    in females, with normal transferrin electrophoresis.
  evidence:
  - reference: PMID:33410528
    reference_title: The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental
      and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser),
      with normal transferrin electrophoresis.
    explanation: Establishes the recurrent allele, the female predominance, and the normal glycosylation
      screen.
- name: FRRS1L
  gene_term:
    preferred_term: FRRS1L
    term:
      id: hgnc:1362
      label: FRRS1L
  relationship_type: CAUSATIVE
  subtype: DEE37
  notes: AMPA receptor outer-core protein. Biallelic loss-of-function variants attenuate AMPA-mediated
    currents and cause an epileptic-dyskinetic encephalopathy with prominent choreoathetosis.
  evidence:
  - reference: PMID:27236917
    reference_title: Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities
      of glutamatergic neurotransmission in this monogenic neurological disease of childhood.
    explanation: States the glutamatergic mechanism by which the FRRS1L lesion acts.
- name: NTRK2
  gene_term:
    preferred_term: NTRK2
    term:
      id: hgnc:8032
      label: NTRK2
  relationship_type: CAUSATIVE
  subtype: DEE58
  notes: HGNC names this gene neurotrophic receptor tyrosine kinase 2, with TRKB as an alias symbol.
    A recurrent variant accounts for most reported cases of NTRK2-related DEE, which presents with
    infantile spasms evolving to multifocal seizures, microcephaly and optic nerve hypoplasia.
  evidence:
  - reference: PMID:34425480
    reference_title: 'NTRK2-related developmental and epileptic encephalopathy: Report of 5 new cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five cases of NTRK2-related DEE were identified. Four had a previously described recurrent
      variant in NTRK2 and one had a novel variant.
    explanation: Establishes NTRK2 as causal for DEE in a reported case series.
- name: ADAM22
  gene_term:
    preferred_term: ADAM22
    term:
      id: hgnc:201
      label: ADAM22
  relationship_type: CAUSATIVE
  subtype: DEE61
  notes: Postsynaptic receptor for LGI1. Biallelic inactivating variants cause DEE61 through loss
    of membrane expression, impaired LGI1 binding, or impaired interaction with PSD-95; the same trans-synaptic
    complex is affected in the LGI1 subtype DEE121.
  evidence:
  - reference: PMID:35373813
    reference_title: Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset
      refractory epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic
      cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1
      (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy.
    explanation: States both the recessive gene-disease relationship and the postsynaptic LGI1-receptor
      function that places it in the synaptic arm.
- name: TRAK1
  gene_term:
    preferred_term: TRAK1
    term:
      id: hgnc:29947
      label: TRAK1
  relationship_type: CAUSATIVE
  subtype: DEE68
  notes: HGNC names this gene trafficking kinesin protein 1; the cited report describes the TRAK family's
    role in lysosomal and mitochondrial trafficking. Biallelic truncating variants cause a fatal infantile
    encephalopathy, and patient fibroblasts show disordered mitochondrial distribution, motility and
    respiration.
  evidence:
  - reference: PMID:28364549
    reference_title: Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal
      encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first
      report of this gene in association with a severe neurodevelopmental disorder.
    explanation: Establishes TRAK1 as a neurodevelopmental disease gene acting through mitochondrial
      dynamics.
- name: PHACTR1
  gene_term:
    preferred_term: PHACTR1
    term:
      id: hgnc:20990
      label: PHACTR1
  relationship_type: CAUSATIVE
  subtype: DEE70
  notes: HGNC names this gene phosphatase and actin regulator 1. De novo missense variants cause infantile
    epileptic spasms syndrome; the variants impair either actin binding or binding to protein phosphatase
    1, and mouse knockdown shows defective cortical neuron migration.
  evidence:
  - reference: PMID:30256902
    reference_title: De novo PHACTR1 mutations in West syndrome and their pathophysiological effects.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Acute knockdown of mouse Phactr1 using in utero electroporation caused defects in cortical
      neuron migration during corticogenesis, which were rescued by an RNAi-resistant PHACTR1 but
      not by the four mutants.
    explanation: Establishes the cortical neuron migration defect through which the PHACTR1 lesion
      reaches the pathograph, with the mutant alleles failing to rescue.
- name: RNF13
  gene_term:
    preferred_term: RNF13
    term:
      id: hgnc:10057
      label: RNF13
  relationship_type: CAUSATIVE
  subtype: DEE73
  notes: HGNC names this gene ring finger protein 13; the cited report describes it as an IRE1-alpha-interacting
    protein. De novo heterozygous gain-of-function variants increase ER stress signalling and stress-induced
    apoptosis, causing congenital microcephaly with infantile epileptic encephalopathy and blindness.
  evidence:
  - reference: PMID:30595371
    reference_title: Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly,
      Epileptic Encephalopathy, Blindness, and Failure to Thrive.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These results indicate that the RNF13 variants confer gain of function to the encoded
      protein and thereby lead to altered signaling of the ER stress response associated with severe
      neurodegeneration in infancy.
    explanation: States the gain-of-function ER-stress mechanism by which the RNF13 lesion acts.
- name: PARS2
  gene_term:
    preferred_term: PARS2
    term:
      id: hgnc:30563
      label: PARS2
  relationship_type: CAUSATIVE
  subtype: DEE75
  notes: Prolyl-tRNA synthetase 2, a member of the mitochondrial aminoacyl-tRNA synthetase family
    that the cited report describes as critical to protein biosynthesis. Biallelic variants cause
    an infantile-onset encephalopathy with epileptic spasms, postnatal microcephaly, elevated lactate
    and progressive cerebral atrophy.
  evidence:
  - reference: PMID:29915213
    reference_title: The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our study provides further evidence for validating the role of PARS2 in the pathology
      of related infantile-onset encephalopathy, contributing to the phenotypic features of this condition,
      and providing clinical and molecular insight for the diagnosis of this disease entity.
    explanation: Establishes PARS2 as causal for infantile-onset encephalopathy, in the report that
      widened its phenotype.
- name: ACTL6B
  gene_term:
    preferred_term: ACTL6B
    term:
      id: hgnc:160
      label: ACTL6B
  relationship_type: CAUSATIVE
  subtype: DEE76
  notes: HGNC names this gene actin like 6B; the cited report describes it as a subunit of the neuron-specific
    nBAF chromatin remodelling complex. Biallelic variants cause early-onset severe DEE with brain
    hypomyelination and cerebellar atrophy.
  evidence:
  - reference: PMID:30656450
    reference_title: Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling
      complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain
      hypomyelination and cerebellar atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we provide additional genetic and clinical data on three new cases that support
      the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.
    explanation: Establishes ACTL6B as causal for a syndromic DEE.
- name: FGF13
  gene_term:
    preferred_term: FGF13
    term:
      id: hgnc:3670
      label: FGF13
  relationship_type: CAUSATIVE
  subtype: DEE90
  notes: Fibroblast growth factor homologous factor 2 (FHF2), whose FHF2A isoform the cited report
    identifies as a regulator of Nav channel function; the gene is X-linked. Missense variants in
    the N-terminal domain of FHF2A act through gain of function on neuronal excitability.
  evidence:
  - reference: PMID:33245860
    reference_title: Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause
      an X-linked developmental and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce
      multiple protein isoforms that differ in their N-terminal sequence.
    explanation: Establishes the FGF13/FHF2 identity and X-linkage recorded for this subtype.
  - reference: PMID:33245860
    reference_title: Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause
      an X-linked developmental and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These gain-of-function effects are likely to increase neuronal excitability consistent
      with the epileptic potential of FHF2 variants.
    explanation: Source for the gain-of-function mechanism recorded in the notes, from co-expression
      of mutant FHF2A with Nav1.6.
  - reference: PMID:33245860
    reference_title: Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause
      an X-linked developmental and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental
      and epileptic encephalopathy
    explanation: Supports the CAUSATIVE relationship of FGF13 to this subtype.
- name: ATP1A2
  gene_term:
    preferred_term: ATP1A2
    term:
      id: hgnc:800
      label: ATP1A2
  relationship_type: CAUSATIVE
  subtype: DEE98
  notes: One of the two Na+/K+-ATPase alpha-subunit isoforms implicated in this spectrum. Heterozygous
    variants that severely impair pump activity cause a profound epileptic encephalopathy with polymicrogyria
    or progressive brain atrophy, distinct from the familial hemiplegic migraine and alternating hemiplegia
    phenotypes curated in other dismech entries.
  evidence:
  - reference: PMID:33880529
    reference_title: ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump
      activity, consistent with severe loss of function.
    explanation: Establishes loss of Na+/K+-ATPase pump function as the molecular consequence.
- name: FBXO28
  gene_term:
    preferred_term: FBXO28
    term:
      id: hgnc:29046
      label: FBXO28
  relationship_type: CAUSATIVE
  subtype: DEE100
  notes: HGNC names this gene F-box protein 28. It is one of the two genes in the 1q41-q42 microdeletion
    interval already implicated in monogenic disease, and heterozygous variants cause DEE with profound
    intellectual disability and hyperkinetic movement disorders.
  evidence:
  - reference: PMID:33280099
    reference_title: FBXO28 causes developmental and epileptic encephalopathy with profound intellectual
      disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe nine new patients with FBXO28 pathogenic variants (four missense, including
      one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate
      the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile
      spasms (3) and a progressive myoclonic epilepsy (1).
    explanation: Establishes FBXO28 as a monogenic cause of DEE.
- name: SLC38A3
  gene_term:
    preferred_term: SLC38A3
    term:
      id: hgnc:18044
      label: SLC38A3
  relationship_type: CAUSATIVE
  subtype: DEE102
  notes: SNAT3, a sodium-coupled neutral amino acid transporter. Biallelic variants perturb glutamine
    homeostasis; glutamine is the precursor of both GABA and glutamate, which is how this transport
    lesion reaches excitation-inhibition balance.
  evidence:
  - reference: PMID:34605855
    reference_title: Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic
      encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our data support the contention that SLC38A3 is a novel disease gene for developmental
      and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations
      in glutamine homeostasis.
    explanation: Establishes SLC38A3 as a DEE gene acting through glutamine homeostasis.
- name: ATP6V0A1
  gene_term:
    preferred_term: ATP6V0A1
    term:
      id: hgnc:865
      label: ATP6V0A1
  relationship_type: CAUSATIVE
  subtype: DEE104
  notes: Subunit a1 of the V0 domain of the vacuolar H+-ATPase, the brain-enriched isoform. De novo
    missense variants cause severe DEE, while biallelic variants give progressive myoclonus epilepsy
    with ataxia; the recurrent R740Q change impairs endolysosomal acidification.
  evidence:
  - reference: PMID:34909687
    reference_title: Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five affected subjects with biallelic variants in this gene presented with a phenotype
      of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo
      missense variants and showed severe developmental and epileptic encephalopathy.
    explanation: Establishes ATP6V0A1 as causal for DEE and records the genotype-phenotype split.
- name: UFSP2
  gene_term:
    preferred_term: UFSP2
    term:
      id: hgnc:25640
      label: UFSP2
  relationship_type: CAUSATIVE
  subtype: DEE106
  notes: UFM1-specific peptidase 2, a de-UFMylating enzyme. Homozygosity for the N-terminal-domain
    p.V115E variant causes a severe neurodevelopmental disability with epilepsy, distinct from the
    autosomal dominant skeletal dysplasias caused by catalytic-domain variants.
  evidence:
  - reference: PMID:33473208
    reference_title: A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental
      anomalies and epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E
      causing a severe syndrome of neurodevelopmental disability and epilepsy.
    explanation: Establishes the recessive UFSP2 neurodevelopmental phenotype as a distinct disease
      from the dominant skeletal one.
- name: CACNA2D1
  gene_term:
    preferred_term: CACNA2D1
    term:
      id: hgnc:1399
      label: CACNA2D1
  relationship_type: CAUSATIVE
  subtype: DEE110
  notes: α2δ-1 auxiliary subunit of CaV1 and CaV2 voltage-gated calcium channels. Biallelic loss-of-function
    variants severely impair its function as a calcium channel subunit and cause early-onset DEE.
  evidence:
  - reference: PMID:35293990
    reference_title: Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental
      disorder in these two patients.
    explanation: Establishes biallelic CACNA2D1 loss of function as causal, placing the lesion in
      the calcium-channel arm.
- name: SV2A
  gene_term:
    preferred_term: SV2A
    term:
      id: hgnc:20566
      label: SV2A
  relationship_type: CAUSATIVE
  subtype: DEE113
  notes: Synaptic vesicle glycoprotein 2A and the binding site of levetiracetam. A single homozygous
    R383Q missense variant in one consanguineous family is the whole reported basis of this subtype;
    levetiracetam was ineffective in the proband.
  evidence:
  - reference: PMID:26002053
    reference_title: Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable
      Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Levetiracetam, which binds to SV2A, was not effective as an antiepileptic medication.
    explanation: Records that the drug whose target this gene encodes did not control the proband's
      seizures.
  - reference: PMID:26002053
    reference_title: Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable
      Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing identified a homozygous arginine to glutamine mutation in amino acid position
      383 (R383Q) in exon 5 of the SV2A gene. Both parents were carriers for the R383Q variant, suggesting
      that R383Q is a recessive mutation.
    explanation: Source for the single homozygous R383Q variant in one consanguineous family recorded
      in the notes.
  - reference: PMID:26002053
    reference_title: Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable
      Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our report provides the elusive evidence that an SV2A mutation can be a cause of epilepsy
      in humans.
    explanation: Supports the CAUSATIVE relationship, resting on this one family.
- name: RNU2-2
  gene_term:
    preferred_term: RNU2-2
    term:
      id: hgnc:10152
      label: RNU2-2P
  relationship_type: CAUSATIVE
  subtype: DEE119
  notes: U2-2 small nuclear RNA of the major spliceosome. HGNC renamed this locus from RNU2-2P to
    RNU2-2 on 2024-11-15 (live HGNC REST lookup for HGNC:10152 returns symbol RNU2-2 with RNU2-2P
    as a previous symbol); the OBO HGNC build this repository validates against still carries RNU2-2P,
    so term.label is the build's label while preferred_term is the current approved symbol. Recurrent
    de novo variants at nucleotide positions 4 and 35 cause DEE119; no missplicing was detected in
    patient blood.
  evidence:
  - reference: PMID:40210679
    reference_title: Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental
      disorder with prominent epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report that recurrent germline mutations in RNU2-2 (previously known as pseudogene
      RNU2-2P), a 191-bp gene that encodes the U2-2 snRNA, are responsible for a related disorder.
    explanation: Establishes the gene, its former pseudogene designation, and its causal role.
- name: BAIAP2
  gene_term:
    preferred_term: BAIAP2
    term:
      id: hgnc:947
      label: BAIAP2
  relationship_type: CAUSATIVE
  subtype: DEE120
  notes: Brain-specific angiogenesis inhibitor 1-associated protein 2, acting in dendritic spine morphogenesis
    and excitatory synapse formation. De novo missense variants clustered in the multiple phosphorylation
    site region act by gain of function, increasing excitatory synaptogenesis and neuronal excitability.
  evidence:
  - reference: PMID:41133935
    reference_title: De novo missense variants in BAIAP2 are associated with developmental and epileptic
      encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using whole exome/genome sequencing, we identified de novo missense variants in BAIAP2
      in six patients with DEEs.
    explanation: Establishes BAIAP2 as a causal DEE gene.
- name: LGI1
  gene_term:
    preferred_term: LGI1
    term:
      id: hgnc:6572
      label: LGI1
  relationship_type: CAUSATIVE
  subtype: DEE121
  notes: Leucine-rich glioma-inactivated protein 1, a secreted ligand for ADAM22 and ADAM23. Biallelic
    variants that reduce secretion and ADAM22 binding cause DEE121; monoallelic variants cause autosomal
    dominant epilepsy with auditory features, curated in the Autosomal_Dominant_Epilepsy_with_Auditory_Features
    entry.
  evidence:
  - reference: PMID:40455867
    reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy
      via the LGI1-ADAM22/23 pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates
      excitatory synaptic transmission and neuronal excitability in the brain.
    explanation: States the synaptic mechanism through which the LGI1 lesion reaches neuronal excitability.
  - reference: PMID:40455867
    reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy
      via the LGI1-ADAM22/23 pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Through international genetic data sharing, we identified the first ultra-rare biallelic
      LGI1 variants in six individuals from four consanguineous families. Affected individuals presented
      DEE with neonatal/infantile-onset epilepsy (n = 6/6)
    explanation: Supports the CAUSATIVE relationship of biallelic LGI1 variants to DEE121.
  - reference: PMID:40455867
    reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy
      via the LGI1-ADAM22/23 pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding.
    explanation: Source for the reduced secretion and ADAM22 binding recorded in the notes.
- name: PNKP
  gene_term:
    preferred_term: PNKP
    term:
      id: hgnc:9154
      label: PNKP
  relationship_type: CAUSATIVE
  subtype: MCSZ
  notes: Polynucleotide kinase 3'-phosphatase. Biallelic variants cause MCSZ; a splicing allele is
    associated with a milder course. The allelic PNKP peripheral-nerve phenotype is curated in Charcot-Marie-Tooth_Disease_Type_2B2.
  evidence:
  - reference: PMID:20118933
    reference_title: Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations
      in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in
      contrast, a splicing mutation is associated with more moderate symptoms.
    explanation: Establishes PNKP as the causal gene and records the allele-dependent severity.

- name: SCN3A
  gene_term:
    preferred_term: SCN3A
    term:
      id: hgnc:10590
      label: SCN3A
  relationship_type: CAUSATIVE
  subtype: DEE62
  notes: HGNC names this gene sodium voltage-gated channel alpha subunit 3. The cited report identifies
    Nav1.3 as highly expressed in brain and previously unlinked to early infantile epileptic encephalopathy;
    de novo missense variants produce gain of channel function.
  evidence:
  - reference: PMID:29466837
    reference_title: Mutations in SCN3A cause early infantile epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de
      novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala).
    explanation: Establishes SCN3A as causal for DEE62.
- name: KCNC2
  gene_term:
    preferred_term: KCNC2
    term:
      id: hgnc:6234
      label: KCNC2
  relationship_type: CAUSATIVE
  subtype: DEE103
  notes: HGNC names this gene potassium voltage-gated channel subfamily C member 2. The cited report describes
    Kv3.2 as a Shaw-related voltage-gated potassium channel subunit important for sustained high-frequency
    firing; the DEE pole of the KCNC2 spectrum is associated with gain of function.
  evidence:
  - reference: PMID:35314505
    reference_title: Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With
      Epilepsy With KCNC2 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including
      genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset
      absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy.
    explanation: Establishes KCNC2 as causal across a spectrum whose severe pole is DEE103.
- name: KCNH5
  gene_term:
    preferred_term: KCNH5
    term:
      id: hgnc:6254
      label: KCNH5
  relationship_type: CAUSATIVE
  subtype: DEE112
  notes: HGNC names this gene potassium voltage-gated channel subfamily H member 5. The cited report describes
    KCNH5 as encoding the voltage-gated potassium channel EAG2/Kv10.2; the DEE phenotype is associated
    with specific recurrent variants rather than with the gene as a whole.
  evidence:
  - reference: PMID:36307226
    reference_title: Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants
      in the Voltage-Sensing and Pore Domains of KCNH5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant
      p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants.
    explanation: Establishes the KCNH5 variant series behind DEE112.
- name: KCNT2
  gene_term:
    preferred_term: KCNT2
    term:
      id: hgnc:18866
      label: KCNT2
  relationship_type: CAUSATIVE
  subtype: DEE57
  notes: HGNC names this gene potassium sodium-activated channel subfamily T member 2. The paralogue of
    KCNT1. De novo variants act by gain of function and were quinidine-responsive in vitro and in one
    treated patient.
  evidence:
  - reference: PMID:29740868
    reference_title: De novo gain-of-function variants in KCNT2 as a novel cause of developmental and
      epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report on 2 females with de novo variants in KCNT2 with West syndrome followed by Lennox-Gastaut
      syndrome or with DEE with migrating focal seizures.
    explanation: Establishes KCNT2 as causal for DEE57.
- name: TMEM63B
  gene_term:
    preferred_term: TMEM63B
    term:
      id: hgnc:17735
      label: TMEM63B
  relationship_type: CAUSATIVE
  subtype: DEE118
  notes: HGNC names this gene transmembrane protein 63B. The cited report describes TMEM63B as a highly
    conserved stretch-activated ion channel; the mutated channels carry an inward leak cation current
    under isotonic conditions.
  evidence:
  - reference: PMID:37421948
    reference_title: Stretch-activated ion channel TMEM63B associates with developmental and epileptic
      encephalopathies and progressive neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic
      encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated
      with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of
      TMEM63B, encoding for a highly conserved stretch-activated ion channel.
    explanation: Establishes TMEM63B as causal for this DEE and names the channel class.
- name: GABRB2
  gene_term:
    preferred_term: GABRB2
    term:
      id: hgnc:4082
      label: GABRB2
  relationship_type: CAUSATIVE
  subtype: DEE92
  notes: HGNC names this gene gamma-aminobutyric acid type A receptor subunit beta2. One of eight genes
    given a causal link to DEE by the cited whole-genome study of unexplained DEE trios. That study characterises
    no GABRB2-specific phenotype.
  evidence:
  - reference: PMID:29100083
    reference_title: High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'By combining these strategies, we were able to provide a causal link between DEE and the
      following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25.'
    explanation: Establishes GABRB2 as causal for DEE.
- name: GABRA2
  gene_term:
    preferred_term: GABRA2
    term:
      id: hgnc:4076
      label: GABRA2
  relationship_type: CAUSATIVE
  subtype: DEE78
  notes: HGNC names this gene gamma-aminobutyric acid type A receptor subunit alpha2. The cited report
    describes GABA-A receptors as ligand-gated anion channels regulating neuronal inhibition; the p.Thr292Lys
    variant reduced channel expression and left the channel tonically open in the absence of GABA.
  evidence:
  - reference: PMID:29961870
    reference_title: De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset
      epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Targeted resequencing of 279 additional epilepsy patients identified 19 rare variants from
      nine GABAA receptor genes, including a novel de novo missense variant in GABRA2 (c.875C > A, p.T292K)
      and a recurrent missense variant in GABRB3 (c.902C > T, p.P301L).
    explanation: Establishes the de novo GABRA2 variant causal for DEE78.
- name: GABRA5
  gene_term:
    preferred_term: GABRA5
    term:
      id: hgnc:4079
      label: GABRA5
  relationship_type: CAUSATIVE
  subtype: DEE79
  notes: HGNC names this gene gamma-aminobutyric acid type A receptor subunit alpha5. The p.Val294Leu
    variant raises GABA sensitivity tenfold but reduces the maximal GABA-evoked current through increased
    desensitisation, so the net effect is loss of sustained inhibition.
  evidence:
  - reference: PMID:29961870
    reference_title: De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset
      epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using whole-genome sequencing, we identified a novel de novo missense variant in GABRA5 (c.880G
      > C, p.V294L) in a patient with severe early-onset epilepsy and developmental delay.
    explanation: Establishes the de novo GABRA5 variant causal for DEE79.
- name: GABBR2
  gene_term:
    preferred_term: GABBR2
    term:
      id: hgnc:4507
      label: GABBR2
  relationship_type: CAUSATIVE
  subtype: DEE59
  notes: HGNC names this gene gamma-aminobutyric acid type B receptor subunit 2. The metabotropic GABA-B
    receptor subunit, so a lesion of GABAergic inhibition rather than of a voltage-gated channel. First
    seen in two DEE trios as suggestive evidence; the causal link came from a later whole-genome study.
  evidence:
  - reference: PMID:29100083
    reference_title: High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'By combining these strategies, we were able to provide a causal link between DEE and the
      following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25.'
    explanation: Establishes GABBR2 as causal for DEE.
- name: SLC32A1
  gene_term:
    preferred_term: SLC32A1
    term:
      id: hgnc:11018
      label: SLC32A1
  relationship_type: CAUSATIVE
  subtype: DEE114
  notes: HGNC names this gene solute carrier family 32 member 1. The cited report names SLC32A1 as the
    gene encoding the vesicular GABA transporter. Inherited missense variants cause genetic epilepsy with
    febrile seizures plus; de novo missense variants cause this DEE.
  evidence:
  - reference: PMID:36073542
    reference_title: De Novo Missense Variants in SLC32A1 Cause a Developmental and Epileptic Encephalopathy
      Due to Impaired GABAergic Neurotransmission.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using exome sequencing, we identified four individuals with a developmental and epileptic
      encephalopathy and de novo missense variants in SLC32A1.
    explanation: Establishes de novo SLC32A1 variants as causal for DEE114.
- name: NSF
  gene_term:
    preferred_term: NSF
    term:
      id: hgnc:8016
      label: NSF
  relationship_type: CAUSATIVE
  subtype: DEE96
  notes: HGNC names this gene N-ethylmaleimide sensitive factor, vesicle fusing ATPase. The cited report
    describes NSF as critical for intracellular vesicle transport underlying neurotransmitter release,
    and reads the de novo variants as dominant negative on the strength of a Drosophila eye assay.
  evidence:
  - reference: PMID:31675180
    reference_title: De novo NSF mutations cause early infantile epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic
      variants in NSF, that is, epileptic encephalopathy of early infantile onset.
    explanation: Establishes NSF as causal for DEE96.
- name: NAPB
  gene_term:
    preferred_term: NAPB
    term:
      id: hgnc:15751
      label: NAPB
  relationship_type: CAUSATIVE
  subtype: DEE107
  notes: HGNC names this gene NSF attachment protein beta. The beta attachment protein of NSF. The cited
    report places it in SNARE complex dissociation and recycling during synaptic vesicle docking, so NAPB
    and NSF are lesions at successive steps of one machinery.
  evidence:
  - reference: PMID:26235277
    reference_title: NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive
      factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of
      the protein.
    explanation: Establishes the homozygous NAPB lesion causal for DEE107.
- name: SYNJ1
  gene_term:
    preferred_term: SYNJ1
    term:
      id: hgnc:11503
      label: SYNJ1
  relationship_type: CAUSATIVE
  subtype: DEE53
  notes: HGNC names this gene synaptojanin 1. A polyphosphoinositide phosphatase with two phosphatase
    domains acting in synaptic vesicle dynamics. Variants abolishing only Sac1 activity cause early-onset
    parkinsonism; a critical reduction of the dual activity causes this DEE.
  evidence:
  - reference: PMID:27435091
    reference_title: Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures
      and progressive neurological decline.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We performed whole exome or genome sequencing in three independent sib pairs with early onset
      refractory seizures and progressive neurological decline, and identified novel segregating recessive
      SYNJ1 defects.
    explanation: Establishes recessive SYNJ1 defects as causal for DEE53.
- name: MDH2
  gene_term:
    preferred_term: MDH2
    term:
      id: hgnc:6971
      label: MDH2
  relationship_type: CAUSATIVE
  subtype: DEE51
  notes: HGNC names this gene malate dehydrogenase 2. Mitochondrial malate dehydrogenase, which converts
    malate to oxaloacetate in the Krebs cycle. Patient fibroblasts lost MDH2 protein with enzymatic activity
    close to null and accumulated malate and fumarate.
  evidence:
  - reference: PMID:27989324
    reference_title: Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting
      with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate
      in the blood and cerebrospinal fluid.
    explanation: Establishes biallelic MDH2 variants as causal for DEE51.
- name: CNPY3
  gene_term:
    preferred_term: CNPY3
    term:
      id: hgnc:11968
      label: CNPY3
  relationship_type: CAUSATIVE
  subtype: DEE60
  notes: HGNC names this gene canopy FGF signaling regulator 3. An endoplasmic reticulum co-chaperone
    that regulates the subcellular distribution and responses of multiple Toll-like receptors. Protein
    was severely reduced in lymphoblastoid cells from two affected siblings.
  evidence:
  - reference: PMID:29394991
    reference_title: Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset
      Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have now identified biallelic CNPY3 variants in three individuals with WS; these include
      compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals
      1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3).
    explanation: Establishes biallelic CNPY3 variants as causal for DEE60.
- name: CUX2
  gene_term:
    preferred_term: CUX2
    term:
      id: hgnc:19347
      label: CUX2
  relationship_type: CAUSATIVE
  subtype: DEE67
  notes: HGNC names this gene cut like homeobox 2. A cut homeodomain transcription factor with a role
    in dendrite branching, spine development and synapse formation in layer II to III cortical neurons.
    The recurrent p.Glu590Lys variant lies in the CUT domain and is predicted to interfere with DNA binding.
  evidence:
  - reference: PMID:29630738
    reference_title: The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental
      and epileptic encephalopathy (DEE).
    explanation: Establishes the recurrent CUX2 variant as causal for DEE67.
- name: SMC1A
  gene_term:
    preferred_term: SMC1A
    term:
      id: hgnc:11111
      label: SMC1A
  relationship_type: CAUSATIVE
  subtype: DEE85
  notes: HGNC names this gene structural maintenance of chromosomes 1A. A core structural subunit of the
    cohesin complex, so this is a cohesinopathy. Missense and small in-frame changes cause about 5 per
    cent of Cornelia de Lange syndrome, curated separately; protein-truncating changes cause this X-linked
    epilepsy phenotype.
  evidence:
  - reference: PMID:28166369
    reference_title: 'Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy
      with cluster seizures in females: Detailed phenotyping of 10 new cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations
      identified are predicted to result in premature truncation of the SMC1A protein.
    explanation: Establishes truncating SMC1A variants as causal for DEE85.
- name: DALRD3
  gene_term:
    preferred_term: DALRD3
    term:
      id: hgnc:25536
      label: DALRD3
  relationship_type: CAUSATIVE
  subtype: DEE86
  notes: HGNC names this gene DALR anticodon binding domain containing 3. Forms a complex with the METTL2
    methyltransferase that selects particular arginine tRNA isoacceptors for 3-methylcytosine modification
    of the anticodon loop.
  evidence:
  - reference: PMID:32427860
    reference_title: DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine
      tRNAs for 3-methylcytosine modification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, we identify a homozygous nonsense mutation in the DALRD3 gene that impairs m3C formation
      in human patients exhibiting developmental delay and early-onset epileptic encephalopathy.
    explanation: Establishes the homozygous DALRD3 lesion as causal for DEE86 and names the tRNA-modification
      defect.
- name: ATP6V1A
  gene_term:
    preferred_term: ATP6V1A
    term:
      id: hgnc:851
      label: ATP6V1A
  relationship_type: CAUSATIVE
  subtype: DEE93
  notes: HGNC names this gene ATPase H+ transporting V1 subunit A. The A subunit of the vacuolar proton
    ATPase, which sets organellar pH and has additional roles at the neuronal synapse. Severity in the
    founding four patients tracked the individual variant.
  evidence:
  - reference: PMID:29668857
    reference_title: De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Through whole exome sequencing, we identified de novo heterozygous mutations (p.Pro27Arg,
      p.Asp100Tyr, p.Asp349Asn, p.Asp371Gly) in ATP6V1A, encoding the A subunit of v-ATPase, in four patients
      with developmental encephalopathy with epilepsy.
    explanation: Establishes de novo ATP6V1A variants as causal for DEE93.
- name: CELF2
  gene_term:
    preferred_term: CELF2
    term:
      id: hgnc:2550
      label: CELF2
  relationship_type: CAUSATIVE
  subtype: DEE97
  notes: HGNC names this gene CUGBP Elav-like family member 2. A nucleocytoplasmic shuttling RNA-binding
    protein with roles in RNA processing and in development of the central nervous system and heart. The
    pathogenic variants cluster at the C-terminal nuclear localisation signal and mislocalise the protein
    out of the nucleus.
  evidence:
  - reference: PMID:33131106
    reference_title: De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental
      and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals
      1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual
      disability and autistic features.'
    explanation: Establishes heterozygous CELF2 variants as causal for DEE97.
- name: HID1
  gene_term:
    preferred_term: HID1
    term:
      id: hgnc:15736
      label: HID1
  relationship_type: CAUSATIVE
  subtype: DEE105
  notes: HGNC names this gene HID1 domain containing. Acts in the trans-Golgi network where peptide hormone
    precursors are processed, which is why the biallelic lesion pairs an epileptic encephalopathy with
    central pituitary insufficiency.
  evidence:
  - reference: PMID:33999436
    reference_title: Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in
      all patients.
    explanation: Establishes biallelic HID1 variants as causal for DEE105.
- name: MAST3
  gene_term:
    preferred_term: MAST3
    term:
      id: hgnc:19036
      label: MAST3
  relationship_type: CAUSATIVE
  subtype: DEE108
  notes: HGNC names this gene microtubule associated serine/threonine kinase 3. One of the microtubule-associated
    serine-threonine kinases, expressed in excitatory cortical neurons late in prenatal development and
    postnatally. Transfected cells showed increased phosphorylation of the MAST3 target ARPP-16, read
    as gain of function.
  evidence:
  - reference: PMID:34185323
    reference_title: Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent
      variants p.G510S (n = 5) and p.G515S (n = 3).
    explanation: Establishes de novo MAST3 kinase-domain variants as causal for DEE108.
- name: DEPDC5
  gene_term:
    preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  relationship_type: CAUSATIVE
  subtype: DEE111
  notes: HGNC names this gene DEP domain containing 5, GATOR1 subcomplex subunit. An inhibitory component
    of the mTOR pathway. The common germline lesion is a single inactivating heterozygous variant, curated
    as the separate DEPDC5-Related_Epilepsy entry; the biallelic germline lesion curated here gives bilateral
    polymicrogyria with macrocephaly instead of a focal lesion.
  evidence:
  - reference: PMID:36067010
    reference_title: Germline homozygous missense DEPDC5 variants cause severe refractory early-onset
      epilepsy, macrocephaly and bilateral polymicrogyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5.
    explanation: Establishes germline biallelic DEPDC5 variants as causal for DEE111 and separates them
      from the heterozygous focal-epilepsy phenotype.
- name: FZR1
  gene_term:
    preferred_term: FZR1
    term:
      id: hgnc:24824
      label: FZR1
  relationship_type: CAUSATIVE
  subtype: DEE109
  notes: HGNC names this gene fizzy and cell division cycle 20 related 1. Encodes Cdh1, a substrate-recognition
    subunit of the anaphase-promoting complex, with roles in the cell cycle and in post-mitotic neurons.
    Drosophila assays supported the patient variants being loss of function.
  evidence:
  - reference: PMID:34788397
    reference_title: De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies
      and a connection on GeneMatcher led to the identification of three de novo missense variants in
      FZR1.
    explanation: Establishes de novo FZR1 variants as causal for DEE109.
- name: SNF8
  gene_term:
    preferred_term: SNF8
    term:
      id: hgnc:17028
      label: SNF8
  relationship_type: CAUSATIVE
  subtype: DEE115
  notes: HGNC names this gene SNF8 subunit of ESCRT-II. A subunit of ESCRT-II, one of the three endosomal
    sorting complexes required for membrane remodelling and autophagy. The milder pole of the SNF8 spectrum
    is curated as SNF8-Related_Neurodevelopmental_Disorder.
  evidence:
  - reference: PMID:38423010
    reference_title: Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental
      and epileptic encephalopathy to syndromic optic atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative
      features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit
      SNF8.'
    explanation: Establishes biallelic SNF8 variants as causal across the spectrum whose severe pole is
      DEE115.
- name: BRAT1
  gene_term:
    preferred_term: BRAT1
    term:
      id: hgnc:21701
      label: BRAT1
  relationship_type: CAUSATIVE
  subtype: RMFSL
  notes: 'HGNC names this gene BRCA1 associated ATM activator 1. Biallelic variants give two distinct
    phenotypes, and the genotype largely predicts which: nonsense, frameshift or in-frame indel genotypes
    give the lethal rigidity and multifocal-seizure phenotype, while genotypes including a missense variant
    usually give the non-lethal cerebellar-atrophy phenotype.'
  evidence:
  - reference: PMID:37344571
    reference_title: 'BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations
      from 97 patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift
      or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46;
      100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS
      (28/34; 82%).
    explanation: Establishes the BRAT1 genotype-phenotype split that assigns this gene to the lethal phenotype
      curated here.
- name: AP3B2
  gene_term:
    preferred_term: AP3B2
    term:
      id: hgnc:567
      label: AP3B2
  relationship_type: CAUSATIVE
  subtype: DEE48
  notes: HGNC names this gene adaptor related protein complex 3 subunit beta 2. The neuron-specific beta
    subunit of the AP-3 vesicle coat adaptor complex. The ubiquitous isoform AP3B1 causes Hermansky-Pudlak
    syndrome type 2 instead, which is why the AP3B2 phenotype is purely neurological.
  evidence:
  - reference: PMID:27889060
    reference_title: Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2
      Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: AP3B2 encodes the neuron-specific subunit of the AP-3 complex.
    explanation: Names the gene product whose loss produces DEE48, and the neuronal restriction that confines
      the phenotype to the nervous system.
treatments:
- name: Anti-Seizure Medication
  description: >-
    Broad-spectrum and gene-informed anti-seizure medication selection,
    guided where possible by the specific ion-channel gain- versus
    loss-of-function mechanism (e.g. sodium-channel blockers are often
    beneficial in SCN2A/SCN8A gain-of-function DEE but can worsen seizures
    in SCN1A-related Dravet syndrome loss-of-function disease).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Hypersynchronous Network Activity and Seizures
    treatment_effect: INHIBITS
    description: >-
      Antiseizure medication suppresses the seizure-generating network activity.
      Which agent helps versus harms is determined by the upstream channel
      lesion: sodium-channel blockers benefit SCN2A/SCN8A gain-of-function
      disease but worsen SCN1A loss-of-function Dravet syndrome.
    evidence:
    - reference: PMID:39237642
      reference_title: Developmental and epileptic encephalopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Understanding the functional consequences of the SCN1A pathogenic
        variant informs management, as some sodium channel blocker (SCB)
        antiseizure medications (ASMs) may exacerbate seizures in Dravet
        syndrome, whereas patients with the non-Dravet, EIDEE phenotype due to
        GOF variants may respond to SCB, such as carbamazepine and phenytoin
      explanation: >-
        Directly supports the gain- versus loss-of-function prescribing logic
        stated in this mechanism description: sodium-channel blockers exacerbate
        seizures in SCN1A loss-of-function Dravet syndrome but benefit
        gain-of-function disease. This is the entry's most clinically
        consequential claim and is now cited rather than resting on notes.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Holistic management, which
      encompasses antiseizure therapies and care for multimorbidities, is
      determined both by epilepsy syndrome and aetiology.
    explanation: >-
      Supports antiseizure therapy as the pharmacological cornerstone, with
      choice determined by syndrome and aetiology.
- name: Ketogenic Diet
  description: >-
    Dietary therapy used as an adjunct or alternative treatment for
    drug-resistant seizures in genetic DEE, with demonstrated efficacy across
    several DEE subtypes and occasional reduction of pharmacological need.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Hypersynchronous Network Activity and Seizures
    treatment_effect: INHIBITS
    description: >-
      Ketogenic dietary therapy suppresses the seizure-generating network
      activity rather than correcting the upstream genetic lesion.
    evidence:
    - reference: PMID:40831798
      reference_title: Progress of ketogenic diet in the treatment of developmental epileptic encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The ketogenic diet
        (KD) is a well-established non-pharmacological treatment for refractory
        epilepsy and has demonstrated therapeutic efficacy in several DEE
        subtypes.
      explanation: >-
        Supports the seizure-directed effect of dietary therapy across DEE
        subtypes.
  evidence:
  - reference: PMID:40831798
    reference_title: Progress of ketogenic diet in the treatment of developmental epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ketogenic diet
      (KD) is a well-established non-pharmacological treatment for refractory
      epilepsy and has demonstrated therapeutic efficacy in several DEE
      subtypes.
    explanation: >-
      DEE-specific review establishing ketogenic diet efficacy across DEE
      subtypes.
  - reference: PMID:40831798
    reference_title: Progress of ketogenic diet in the treatment of developmental epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In certain
      cases, it may reduce or even eliminate the need for pharmacological
      interventions.
    explanation: >-
      Documents that dietary therapy can reduce antiseizure medication burden in
      some patients.
- name: Cannabidiol
  description: >-
    Randomised placebo-controlled trials demonstrated efficacy in Dravet
    syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, with
    median target-seizure reductions of 38.9%, 41.9%, and 48.6% respectively.
    One of the few DEE therapies supported by RCT-level evidence.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cannabidiol
      term:
        id: CHEBI:69478
        label: cannabidiol
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Hypersynchronous Network Activity and Seizures
    treatment_effect: INHIBITS
    description: >-
      Symptomatic suppression of seizure generation; does not address the
      developmental arm of the mechanism.
    evidence:
    - reference: PMID:39237642
      reference_title: Developmental and epileptic encephalopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Randomised placebo-controlled trials (RCTs) of cannabidiol demonstrated
        efficacy
        in Dravet syndrome , LGS and TSC, with significant median percent
        reduction s in target seizures
      explanation: >-
        RCT evidence that the effect is on target seizures, i.e. the seizure
        node of the pathograph.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Randomised placebo-controlled trials (RCTs) of cannabidiol demonstrated
      efficacy
      in Dravet syndrome , LGS and TSC, with significant median percent
      reduction s in target seizures
    explanation: >-
      Establishes RCT-level efficacy of cannabidiol across three DEE syndromes.
      The reported median seizure reductions of 38.9%, 41.9% and 48.6% follow
      immediately in the source but are interleaved with inline citation
      markers, so the quote stops before them.
- name: Fenfluramine
  description: >-
    Serotonergic agent approved as add-on therapy for Dravet syndrome and
    subsequently for Lennox-Gastaut syndrome and CDKL5 deficiency disorder.
    Requires cardiac monitoring given the valvulopathy concerns arising from its
    former use as an obesity drug.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fenfluramine
      term:
        id: CHEBI:5000
        label: fenfluramine
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Hypersynchronous Network Activity and Seizures
    treatment_effect: INHIBITS
    description: >-
      Symptomatic suppression of seizure generation via serotonergic modulation.
    evidence:
    - reference: PMID:39237642
      reference_title: Developmental and epileptic encephalopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The higher
        dose of fenfluramine was associated with a significantly greater
        likelihood of achieving a >50% (68% versus 12% placebo) and a >75%
        reduction (50% versus 2% placebo) in convulsive seizure frequency
      explanation: >-
        RCT evidence of dose-dependent convulsive-seizure reduction, targeting
        the seizure node.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The higher
      dose of fenfluramine was associated with a significantly greater
      likelihood of achieving a >50% (68% versus 12% placebo) and a >75%
      reduction (50% versus 2% placebo) in convulsive seizure frequency
    explanation: >-
      Documents dose-dependent RCT efficacy of fenfluramine as add-on therapy in
      Dravet syndrome, with the effect sizes quoted.
- name: Stiripentol
  description: >-
    Approved as adjunctive therapy for Dravet syndrome in combination with
    clobazam, where a randomised controlled trial demonstrated clear efficacy.
    CHEBI has no stiripentol term, so the agent is bound to NCIT following the
    documented NCIT-fallback convention for drugs lacking a CHEBI entry.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: stiripentol
      term:
        id: NCIT:C152433
        label: Stiripentol
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Hypersynchronous Network Activity and Seizures
    treatment_effect: INHIBITS
    description: >-
      Symptomatic suppression of seizure generation, used in combination with
      clobazam.
    evidence:
    - reference: PMID:39237642
      reference_title: Developmental and epileptic encephalopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In Dravet syndrome, a RCT of stiripentol demonstrated clear efficacy
      explanation: >-
        RCT evidence that stiripentol acts on the seizure arm in the archetypal
        genetic DEE.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Dravet syndrome, a RCT of stiripentol demonstrated clear efficacy
    explanation: >-
      Establishes RCT-level efficacy of stiripentol in the archetypal genetic
      DEE.
- name: Multidisciplinary Developmental Supportive Care
  description: >-
    Physical, occupational, and speech therapy along with early
    intervention services to support developmental outcomes independent
    of seizure control.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Developmental Encephalopathy Component
    treatment_effect: MODULATES
    description: >-
      Developmental and rehabilitative support addresses the developmental arm
      of the mechanism, which persists independently of seizure control and is
      therefore not reachable by antiseizure therapy.
    evidence:
    - reference: PMID:39237642
      reference_title: Developmental and epileptic encephalopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Problems
        change with age and patients require substantial support throughout
        life, placing a high psychosocial burden on parents, carers and the
        community.
      explanation: >-
        Supports lifelong developmental support as the management response to
        the non-seizure arm of the disease.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Problems
      change with age and patients require substantial support throughout life,
      placing a high psychosocial burden on parents, carers and the community.
    explanation: >-
      Supports lifelong multidisciplinary supportive care as a core management
      component independent of seizure control.
- name: Precision Medicine Guided by Molecular Diagnosis
  description: >-
    Identification of the specific causal gene and the functional direction of
    the variant (gain- versus loss-of-function) enables aetiology-directed
    therapy selection and is increasingly the entry point to gene-targeted
    treatments including antisense oligonucleotides and gene therapy.
  treatment_term:
    preferred_term: Targeted Therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  therapeutic_modality: OTHER
  target_mechanisms:
  - target: Genetic Lesion in an Ion Channel or Synaptic Gene
    treatment_effect: MODULATES
    description: >-
      The only entry-level treatment addressing the upstream cause rather than
      the seizure output. Establishing the specific gene and the functional
      direction of the variant redirects therapy at the lesion itself, and is
      the gateway to gene-targeted modalities (antisense oligonucleotides, gene
      therapy) still in development.
    evidence:
    - reference: PMID:39237642
      reference_title: Developmental and epileptic encephalopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Identification of the underlying aetiology enables the development of
        precision medicines to improve the long-term outcome of patients with
        these devastating diseases.
      explanation: >-
        Supports the aetiology-directed link from molecular diagnosis back to
        the causal genetic lesion node.
  evidence:
  - reference: PMID:39237642
    reference_title: Developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of the underlying aetiology enables the development of
      precision medicines to improve the long-term outcome of patients with
      these devastating diseases.
    explanation: >-
      Supports molecular diagnosis as the enabler of precision therapy in the
      DEE group.
  - reference: PMID:35701389
    reference_title: Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finding the molecular cause led to management changes in 36% of patients
      with DEEs.
    explanation: >-
      Quantifies the clinical actionability of molecular diagnosis in a
      real-world DEE cohort.
diagnosis:
- name: Exome or Genome Sequencing
  description: >-
    Genome-wide sequencing (exome or genome, ideally as a trio to enable de novo
    confirmation) is the first-line molecular test given the extreme genetic
    heterogeneity of the group. Diagnostic yield is substantially higher for
    seizure onset under two years of age.
  evidence:
  - reference: PMID:35701389
    reference_title: Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 103 patients recruited (54 males, 49 females; aged
      2 weeks-17 years), the genetic aetiology was identified in 36 out of 103
      (35%) with management implications in 13 out of 36.
    explanation: >-
      Establishes the diagnostic yield of exome sequencing in routine clinical
      care of children with DEE.
  - reference: PMID:35701389
    reference_title: Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic aetiology was identified in 41% of children with seizure onset
      under 2 years, compared to 18% with older onset.
    explanation: >-
      Documents the age-of-onset dependence of diagnostic yield, informing test
      prioritisation.
references:
- reference: PMID:39237642
  title: Developmental and epileptic encephalopathies.
- reference: PMID:35951482
  title: >-
    Developmental and epileptic encephalopathies: from genetic heterogeneity to
    phenotypic continuum.
- reference: PMID:40013914
  title: >-
    Operational definition of developmental and epileptic encephalopathies to
    underpin the design of therapeutic trials.
- reference: PMID:28276062
  title: >-
    ILAE classification of the epilepsies: Position paper of the ILAE Commission
    for Classification and Terminology.
datasets:
- accession: geo:GSE319080
  title: Excitatory cortical neurons from CDKL5 deficiency disorder patient-derived organoids show early hyperexcitability not identified in neurogenin2 induced neurons [Ampliseq]
  description: CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy resulting from variants in cyclin-dependent kinase-like 5 (CDKL5) that lead to impaired kinase activity or loss of function. CDD is one of the most common genetic etiologies identified in epilepsy cohorts. To study how CDKL5 variants impact human neuronal activity, gene expression and morphology, CDD patient-derived induced pluripotent stem cells and their isogenic controls were differentiated into excitatory neurons using either an NGN2 induction protocol or a guided cortical organoid differentiation.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 12
  publication: PMID:40930428
  notes: Identified by GEO DataSets index search for Genetic Developmental and Epileptic Encephalopathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE281622
  title: Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability
  description: Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how a single disorder differentially affects distinct brain regions by using human patient iPSC-derived cortical- and hippocampal-ganglionic eminence assembloids to model Developmental and Epileptic Encephalopathy 13 (DEE-13), a condition arising from gain-of-function mutations in the SCN8A gene.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 6
  publication: PMID:40925365
  notes: Identified by GEO DataSets index search for Genetic Developmental and Epileptic Encephalopathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE256142
  title: 'Variability vs. phenotype: Multimodal analysis of Dravet syndrome brain organoids powered by deep learning'
  description: Dravet Syndrome (DS) is a developmental epileptic encephalopathy (DEE) driven by pathogenic variants in SCN1A gene. Brain organoids (BO) have emerged as reliable models for neurodevelopmental genetic disorders, reproducing human brain developmental milestones and rising as a promising drug testing tool. Here, we determined the underlying molecular DS pathophysiology affecting neuronal connectivity, revealing an early onset excitatory-inhibitory imbalance in maturing DS organoids circuitry. However, neuronal circuitry modeling in BO remains hampered by the notorious inter- and intra-organoid variability.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 18
  publication: PMID:41323276
  notes: Identified by GEO DataSets index search for Genetic Developmental and Epileptic Encephalopathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
notes: >-
  Two MONDO classes that are direct children of this entry's disease_term are
  deliberately given no has_subtypes row. MONDO:0100079 (developmental and
  epileptic encephalopathy, 6A) asserts RO:0004003 HGNC:10585 SCN1A and is
  linked to MONDO:0100135 (Dravet syndrome) by
  mondo#disease_shares_features_of; dismech curates the SCN1A developmental and
  epileptic encephalopathy phenotype as the separate Dravet_syndrome entry,
  which is bound to MONDO:0100135, and SCN1A is carried in this entry's genetic
  section and wired to the pathograph, so a subtype row for MONDO:0100079 would
  duplicate an existing entry rather than record anything new. Whether those two
  MONDO classes describe one concept and should be merged is a question for
  MONDO rather than one this entry should settle. MONDO:0032880 (developmental
  and epileptic encephalopathy, 82, GOT2) already has its own dismech entry,
  Developmental_And_Epileptic_Encephalopathy_82, and likewise gets no subtype
  row here.

  MONDO:0700339 (DNM1-encephalopathy and neurodevelopmental disorder) is given no
  has_subtypes row for the same reason as the two classes above. It is the
  gene-scoped parent of MONDO:0014598 (developmental and epileptic
  encephalopathy, 31A), which carries "DNM1-encephalopathy and neurodevelopmental
  disorder" as an exact synonym and is bound as the disease_term of the separate
  DNM1_Encephalopathy entry, so the disease this class denotes is curated there.

  MONDO carries two classes for one disease in the TMEM63B series.
  MONDO:0979238 (developmental and epileptic encephalopathy 118) is bound as the
  DEE118 subtype row, and MONDO:0800503 (TMEM63B-related developmental and
  epileptic encephalopathy with anemia) is recorded on that same row as a
  skos:exactMatch; the mapping_justification there sets out the shared gene,
  shared founding report and shared haematological feature on which that
  judgement rests.

  PCDH19 is the one gene in the genetic section that is not wired to a
  pathophysiology node. Its record notes that the female-restricted mechanism is
  curated on the PCDH19 clustering epilepsy child entry, and no reference cited
  in this entry characterises the protein's function, so a node assignment here
  would not be sourced.

  GeneReviews baseline: just check-genereviews matches this entry against
  NBK582335, "GRIN2D-Related Developmental and Epileptic Encephalopathy"
  (PMID:35914066), through this entry's synonym "developmental and epileptic
  encephalopathy". That chapter is about GRIN2D and is not this umbrella's
  chapter. Searching the committed Bookshelf index
  (cache/bookshelf/genereviews.csv, snapshot 2026-09-10) case-insensitively for
  "epileptic encephalopath" returns that one chapter and no other, so
  GeneReviews has no chapter for the DEE umbrella itself; its DEE coverage is
  per-gene, and the gene-specific chapters belong on the child entries.

📚

References & Deep Research

References

PMID:39237642

Developmental and epileptic encephalopathies.

No top-level findings curated for this source.

PMID:35951482

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.

No top-level findings curated for this source.

PMID:40013914

Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials.

No top-level findings curated for this source.

PMID:28276062

ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Genetic Developmental and Epileptic Encephalopathy · 2026-07-31T00:45:00Z · View source

Created the umbrella entry for genetic DEE [MONDO:0100062], verified by direct OAK lookup and distinct from the ~40 gene-specific DEE entries already in the KB, which MONDO places as its children. Duplicate preflight across origin/main, PRs and issues found no existing coverage. Deep research providers: falcon [Edison] and claude_code, both run via `just research-disorder`. Reports and citations committed under research/. Both reports agreed on the core mechanism; falcon additionally cautioned against assigning an unverified umbrella identifier, and the claude_code report misidentified the umbrella MONDO as MONDO:0010246 -- the OAK-verified MONDO:0100062 was used instead. Modeled the two-component DEE mechanism from the 2017 ILAE classification: a genetic lesion in an ion-channel or synaptic gene drives excitation-inhibition imbalance, which branches into a seizure/epileptic-encephalopathy arm and an independent impaired-neurodevelopment arm. Conforms to the epilepsy_excitation_inhibition_imbalance module at the E/I-imbalance and hyperexcitability nodes. Curated 48 evidence items across pathophysiology nodes, causal edges, phenotypes, genetic, prevalence, inheritance, diagnosis and treatments. Added four causative genes -- SCN1A, KCNQ2, SCN2A, STXBP1 -- with per-gene case fractions from the Italian national survey [PMID:39613335], plus a genetic-DEE-specific prevalence figure from the same source and DEE-overall figures from the New Zealand population cohort [PMID:36581463], marked PARTIAL since they cover DEE of all etiologies. Corrected two claims during curation: the gene count was raised from "over one hundred" to "more than nine hundred" per PMID:39237642, and the inheritance section was reworked to distinguish gene-count from case-count -- more DEE genes follow autosomal recessive than dominant inheritance, while 77 percent of diagnosed cases involve autosomal dominant genes. Validation: `just validate` passes for schema, terms and references. All 48 snippets were independently verified as exact whitespace-normalized substrings of their cached PubMed abstracts via a standalone check, an earlier note in this record claimed `just validate-references` was a no-op false-green because it reports "Total checks: 0"; that was wrong. A deliberate-corruption test showed it correctly rejects fabricated snippets against both abstract-only and full-text caches -- "Total checks" counts issues found, not snippets examined. Compliance 98.2 percent global / 99.1 percent weighted.

Claude Code ▸

Genetic Developmental and Epileptic Encephalopathy (DEE) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 31 citations 2026-07-31T00:19:29.167947

Genetic Developmental and Epileptic Encephalopathy (DEE) — Comprehensive Research Report

1. Disease Information

Overview. Developmental and Epileptic Encephalopathy (DEE) is a diagnostic category — not a single disease — formalized by the ILAE 2017 Classification and refined by the ILAE Task Force on Nosology and Definitions in 2022, which split early-onset epilepsy syndromes into (a) self-limited epilepsies with age-related spontaneous remission and (b) DEEs, in which seizures and/or the underlying epileptiform activity itself contribute to a progressive or static encephalopathy with developmental impairment that is independent of (and often precedes) seizure onset. "Genetic DEE" denotes the subset — now understood to be the majority of DEE cases once modern sequencing is applied — in which a single-gene (monogenic) or, less commonly, oligogenic/copy-number variant is the etiology, as opposed to structural (malformations, HIE, stroke), metabolic, infectious, or immune causes. DEEs are the most severe end of the developmental and epileptic spectrum: drug-resistant seizures of multiple types, epileptiform EEG abnormalities, and intellectual disability/developmental regression, typically presenting in infancy or early childhood. (MedLink Neurology; Nature Reviews Disease Primers 2024, Scheffer et al., DOI:10.1038/s41572-024-00546-6; Epilepsy Foundation)

Key identifiers. - OMIM Phenotypic Series: PS308350 — "Developmental and epileptic encephalopathy," an umbrella series currently listing 123 numbered entries (DEE1 through DEE9x+), each corresponding to a distinct causal gene (e.g., DEE1/ARX #308350, DEE2/CDKL5 #300672, DEE9/PCDH19 #300088, DEE42/GRIN1 #617106, DEE50/CACNA1A #616457). - MONDO: the umbrella concept maps to MONDO:0010246 ("developmental and epileptic encephalopathy," a grouping term cross-referencing OMIM PS308350); individual gene-defined subtypes each carry their own MONDO ID (e.g., DEE2/CDKL5 disorder, DEE9/PCDH19-clustering epilepsy). - Orphanet: listed both as an umbrella grouping and as ~100+ individual gene-specific ORPHA entries (e.g., Dravet syndrome ORPHA:33069, CDKL5 deficiency disorder, STXBP1 encephalopathy). - ICD-11: most individual DEEs fall under 8A61-8A62 (developmental and epileptic encephalopathy codes) in the ICD-11 neurology chapter, replacing the non-specific ICD-10 G40.x/Q04 mappings. - MeSH: "Epileptic Syndromes," "Spasms, Infantile" and related descriptors are used as approximations; there is no single dedicated MeSH heading for genetic DEE as a class.

Synonyms/alternative names: "genetic epileptic encephalopathy," "early-onset epileptic encephalopathy (EOEE)," "malignant epilepsy of infancy," historically overlapping with "West syndrome," "Ohtahara syndrome," "early myoclonic encephalopathy (EME)," "Dravet syndrome," "Lennox-Gastaut syndrome," and (per the current 2022 ILAE nosology) many are now renamed with the causal gene as the syndrome name (e.g., "SCN1A-DEE," "STXBP1-DEE," "KCNQ2-DEE"). The 2022 ILAE terminology also folds in "developmental encephalopathy" (developmental impairment without frequent epileptiform activity) and "epileptic encephalopathy" (impairment driven mainly by epileptiform activity) as component concepts within the DEE spectrum.

Data provenance: Most of the literature base is aggregated disease-level knowledge (case series, gene-specific natural history cohorts, systematic reviews, ClinVar/gene-disease curation, and increasingly large national/international patient registries such as the RIKEE, Rare Epilepsy Network, and gene-specific foundation registries — e.g., FamilieSCN2A, CDKL5 Centers of Excellence). A growing minority is derived from population-based, prospective individual-level EHR/clinical cohorts (e.g., the Scottish national cohort, PMID:31363746, and the companion "Epidemiology of DEE" study, PMID:36581463) that ascertain every child with new-onset seizures in a defined region/time window — these are the most reliable source of incidence/prevalence figures cited below.

2. Etiology

Disease causal factors. By definition, genetic DEE is caused by a pathogenic variant — usually a de novo, heterozygous, single-nucleotide or small indel variant — in one of a rapidly growing list of genes. Next-generation sequencing (whole-exome/whole-genome sequencing, WES/WGS) has now implicated more than 900 genes in DEE pathogenesis. In clinical diagnostic cohorts, exome/panel sequencing establishes a molecular diagnosis in roughly 35–43% of unselected DEE cases (higher — ~41% — when seizure onset is under 2 years of age, vs. ~18% for later onset), reflecting how heavily the genetic architecture is skewed toward infantile-onset disease. (PubMed 35701389; PMC10816140; PMC12562696)

The most frequently implicated genes across diagnostic cohorts are SCN1A (Dravet syndrome — the single most common monogenic DEE, expected population frequency ≥1:20,000, and the archetype gene), STXBP1, SCN2A, KCNQ2, CDKL5, SCN8A, PCDH19 (X-linked, affects heterozygous females), GRIN1/GRIN2A/GRIN2B/GRIN2D, GABRA1/GABRB2/GABRB3/GABRG2, GNAO1, ARX, FOXG1, SPTAN1, and dozens of others (e.g., HCN1, FGF12, PLCB1, WWOX, SLC35A2, ST3GAL3, ATP6V1A). (EAN Spring School slide deck, McTague/Nabbout; PMC12562696)

Genetic risk factors. - Causal variants: predominantly de novo dominant (autosomal or X-linked). Recurrent "hotspot" pathogenic variants occur in several genes (e.g., KCNQ2 recurrent missense variants clustering in the pore/voltage-sensor domains). - Susceptibility/modifier loci are an active area of study but poorly characterized for most single-gene DEEs; polygenic background may modulate expressivity/severity in some genes (e.g., SCN1A modifier loci affecting Dravet syndrome severity, studied in mouse genetic background experiments). - Rare biallelic (autosomal recessive) forms exist for a subset of genes (e.g., some STXBP1, PIGA, and metabolic-DEE genes), and germline/somatic mosaicism is documented (notably for PCDH19, where affected females are typically heterozygous post-zygotic mosaic-unaffected-carrier males transmit to daughters — the "cellular interference" model).

Environmental risk factors: Largely not causal for genetic DEE per se, but febrile illness is a well-documented trigger/exacerbating factor in several gene-specific DEEs (e.g., fever-triggered seizure clusters in PCDH19-clustering epilepsy and in Dravet syndrome/SCN1A). Perinatal factors (prematurity, hypoxic injury) are relevant to the non-genetic DEE differential but are not causal for the monogenic forms; they may occasionally act as second hits modulating phenotype severity.

Protective factors: No established genetic protective variants for DEE broadly. In SCN1A-Dravet syndrome, some evidence suggests that variants reducing background Nav1.6 (SCN8A) function can partially compensate for Nav1.1 haploinsufficiency in mouse models (a genetic modifier concept), but this is not yet clinically actionable. Early, aggressive control of seizure burden and avoidance of sodium-channel-blocking antiseizure medications (contraindicated in SCN1A loss-of-function Dravet syndrome) function as protective clinical-management factors rather than biological protective factors.

Gene-environment interactions: The clearest documented interaction is fever/hyperthermia acting on genetically hyperexcitable or dysfunctional interneuron circuits (SCN1A, PCDH19) to precipitate seizure clusters — a mechanism actively studied with animal thermal-induction models.

3. Phenotypes

DEE phenotypes span symptoms/signs, laboratory/EEG abnormalities, and behavioral/cognitive manifestations. Representative phenotype categories with suggested HPO terms:

Phenotype	HPO term (suggested)	Onset	Frequency/notes
Multiple seizure types (focal, tonic, myoclonic, atonic, spasms)	HP:0032900 (Seizure), HP:0011097 (Epileptic spasm), HP:0002123 (Generalized myoclonic seizure), HP:0002133 (Focal-onset seizure)	Neonatal–infancy (often <2y)	Nearly universal (defining feature)
Developmental delay / regression	HP:0001263 (Developmental delay), HP:0002376 (Developmental regression)	Often precedes seizures, or occurs with seizure onset	Universal by definition of DEE
Intellectual disability	HP:0001249 (Intellectual disability)	Emerges progressively	79% severe ID reported in KCNQ2-DEE cohorts; near-universal in CDKL5, STXBP1
EEG burst-suppression pattern	HP:0010851 (Burst-suppression)	Neonatal (Ohtahara/EIMFS-type presentations)	Present in ~62% of early KCNQ2-DEE
Hypsarrhythmia / infantile spasms	HP:0011097; HP:0012469 (Infantile spasms)	3–12 months	Classic in West-syndrome-type DEEs (e.g., some KCNQ2, STXBP1, CDKL5)
Autistic features	HP:0000729 (Autistic behavior)	Childhood	~67% in KCNQ2-DEE; frequent across CDKL5, STXBP1, PCDH19
Hand stereotypies / Rett-like features	HP:0004328 (Hand stereotypies)	Childhood	Characteristic of CDKL5 deficiency disorder
Microcephaly (acquired)	HP:0000252	Postnatal deceleration	Reported in CDKL5, FOXG1-DEE
Motor dysfunction / hypotonia / spasticity	HP:0001252 (Hypotonia), HP:0002061 (Spastic tetraparesis)	Variable	80–90% in STXBP1
Feeding difficulties / dysphagia	HP:0011968	Infancy	Common, especially CDKL5 (PEG placement frequent)
Cortical visual impairment	HP:0100704	Infancy/childhood	Reported in CDKL5
ADHD/OCD/psychiatric comorbidity	HP:0007018; HP:0000722	School age	~30–70% in PCDH19, STXBP1 cohorts

Characteristics. - Onset: highly gene-dependent — neonatal (KCNQ2, STXBP1, SCN2A/SCN8A gain-of-function, GNAO1), early infantile (SCN1A/Dravet ~5–8 months, CDKL5 <4 months, PCDH19 6–36 months), or later childhood in milder allelic series. - Severity/progression: typically progressive early, often plateauing; a subset (notably some KCNQ2-DEE) shows eventual seizure freedom (~73%) despite persistent severe intellectual disability — illustrating that seizure control and developmental outcome are partially dissociable, a key DEE concept. - Course: episodic seizure clustering is characteristic of PCDH19 and Dravet syndrome (fever-triggered clusters); other genes show a more chronic, drug-resistant daily-seizure pattern (e.g., CDKL5, STXBP1). - QoL impact: severe — most children require lifelong caregiver support; validated DEE-specific QoL instruments (e.g., the Quality of Life in Childhood Epilepsy [QOLCE], and newer DEE-specific PRO measures used in Dravet/CDKL5/STXBP1 trials) consistently show impairment across physical, cognitive, and family-burden domains. (Nature Reviews Disease Primers 2024 covers QoL explicitly per its abstract scope.)

4. Genetic/Molecular Information

Causal genes (representative, non-exhaustive; each an OMIM DEE phenotypic-series entry): - SCN1A (OMIM 182389; DEE6/Dravet syndrome #607208) — voltage-gated Na⁺ channel Nav1.1, predominantly expressed in GABAergic interneurons; loss-of-function (haploinsufficiency). - STXBP1 (602926; DEE4 #612164) — syntaxin-binding protein 1 (Munc18-1), core SNARE-complex regulator of synaptic vesicle fusion; predominantly loss-of-function/haploinsufficiency. - SCN2A (182390; DEE11 #613721) — Nav1.2, predominantly in excitatory neurons; both gain-of-function (early-infantile, severe) and loss-of-function (later-onset, milder, autism-predominant) variants cause distinct phenotypes on the same gene. - KCNQ2 (602235; DEE7 #613720) — Kv7.2 voltage-gated K⁺ channel subunit (M-current); dominant-negative or loss-of-function variants. - CDKL5 (300203; DEE2 #300672) — X-linked cyclin-dependent-kinase-like 5, a serine/threonine kinase important for neuronal synaptic maturation; loss-of-function. - SCN8A (600702; DEE13 #614558) — Nav1.6; typically gain-of-function. - PCDH19 (300460; DEE9 #300088) — X-linked protocadherin-19, a cell-adhesion molecule; unusually, affects heterozygous females (cellular-interference mechanism), while hemizygous males are typically unaffected carriers. - GRIN1/GRIN2A/GRIN2B/GRIN2D — NMDA receptor subunits; gain- or loss-of-function depending on variant location (pre-M1, M3, M4 helices). - GABRA1/GABRB2/GABRB3/GABRG2 — GABA-A receptor subunits; loss-of-function impairing GABAergic inhibition. - GNAO1 (139311; DEE17 #615473) — Gαo subunit; loss of cAMP-inhibitory function, also causes a prominent movement-disorder phenotype. - ARX (*300382; DEE1 #308350) — X-linked homeobox transcription factor; spectrum from lissencephaly to infantile spasms to isolated intellectual disability depending on variant type/location.

Pathogenic variant classification (ACMG/AMP via ClinVar/ClinGen): the overwhelming majority of reported DEE variants are classified Pathogenic/Likely Pathogenic; VUS remain common in less well-studied genes and require functional/segregation follow-up. Variant types: missense (most common, especially in channel/receptor genes — often clustering in functionally critical domains: pore, voltage-sensor, ligand-binding), frameshift/nonsense/splice-site (common in haploinsufficiency genes like STXBP1, CDKL5), and occasionally structural (partial gene deletions, e.g., in SLC35A2, or larger CNVs overlapping DEE loci).

Allele frequency: essentially absent from population databases (gnomAD, TOPMed) for the pathogenic DEE variants themselves, consistent with strong negative selection against de novo dominant, early-lethal/severely-disabling alleles — absence from gnomAD is itself used as supporting evidence (ACMG PM2) in variant classification.

Somatic vs. germline: the great majority of DEE-causing variants are germline de novo; parental germline mosaicism is well documented (important for recurrence-risk counseling, since apparently "de novo" variants can recur in siblings at rates of a few percent) and somatic mosaicism in the proband is documented for several genes (notably PCDH19 males, and mosaic SCN1A/SCN2A).

Functional consequences: span loss-of-function (channel/receptor haploinsufficiency, most common mechanism overall), gain-of-function (increased channel current, e.g., SCN2A/SCN8A early-infantile variants), and dominant-negative effects (e.g., some KCNQ2 pore variants disrupting tetrameric channel assembly) — the distinction is clinically critical because it determines precision-therapy direction (sodium-channel blockers help gain-of-function SCN2A/SCN8A but are contraindicated/harmful in loss-of-function SCN1A-Dravet syndrome).

Modifier genes: poorly characterized in humans; mouse genetic-background studies (e.g., Scn1a Dravet models on different inbred strains) show strong modifier effects on seizure severity and SUDEP risk, implicating candidate modifier loci not yet translated to human genetic counseling.

Epigenetic information: limited disease-specific data; FOXG1 and CDKL5 intersect with chromatin/transcriptional regulation pathways relevant to Rett-spectrum overlap. DNA methylation studies in DEE are largely investigational.

Chromosomal abnormalities: copy-number variants overlapping DEE genes (e.g., 15q11-q13 duplications affecting GABRB3, Xp22 deletions affecting CDKL5/ARX region) are recognized causes; array-based/ES-based CNV calling is now integrated into standard DEE diagnostic workups.

5. Environmental Information

Genetic DEE is, by definition, gene-driven, but several environmental modulators are clinically important: - Febrile illness/hyperthermia: the dominant seizure trigger in SCN1A-Dravet syndrome and PCDH19-clustering epilepsy; vaccination-associated fever can also trigger the first Dravet syndrome seizure (a well-documented but non-causal temporal association — vaccination does not cause the underlying SCN1A mutation). - Sleep deprivation, illness, and metabolic stress are general seizure-threshold-lowering factors across most DEEs, as in epilepsy generally. - Infectious agents: not a direct cause of genetic DEE, but concurrent/triggering infections (viral URIs, gastroenteritis) frequently precede seizure clusters. - Lifestyle/behavioral factors: not established as disease-modifying for genetic DEE specifically (contrast with acquired/structural epilepsies where perinatal/lifestyle factors are more directly causal).

6. Mechanism / Pathophysiology

The pathophysiology of genetic DEE converges on disrupted neuronal excitability and/or disrupted neurodevelopmental programs, broadly falling into two overlapping mechanistic classes reviewed in Nature Reviews Disease Primers 2024 (Scheffer et al.) and PMC11763800 "Pathogenesis of Intellectual Disability Beyond Channelopathies":

Channelopathies — direct disruption of voltage-gated ion channels (Na⁺: SCN1A/SCN2A/SCN8A/SCN1B; K⁺: KCNQ2/KCNQ3, KCNB1; Ca²⁺: CACNA1A) or ligand-gated channels (GABA-A receptor subunits, NMDA receptor subunits GRIN1/2A/2B/2D) causing an excitation/inhibition (E/I) imbalance. Mechanistically:
SCN1A loss-of-function selectively impairs Nav1.1 current in GABAergic interneurons (parvalbumin- and somatostatin-positive), producing disinhibition and network hyperexcitability — the accepted mechanism for Dravet syndrome.
SCN2A/SCN8A gain-of-function increases persistent/late Na⁺ current in excitatory pyramidal neurons, directly increasing intrinsic excitability; loss-of-function SCN2A variants instead impair excitatory neurotransmission and correlate with a milder, later-onset, autism-predominant phenotype — illustrating a single gene producing opposite mechanistic and clinical poles.
GABA-A receptor subunit variants (GABRA1/B2/B3/G2) directly reduce phasic and/or tonic inhibitory GABAergic signaling; tonic (extrasynaptic GABA-A-receptor-mediated) inhibition disruption is an emerging, specifically implicated DEE mechanism.
GRIN2B and related NMDA receptor variants (pre-M1/M3/M4 helix) alter glutamatergic excitatory drive and can be gain- or loss-of-function depending on variant location.
Synaptopathies / neurodevelopmental-program disruption — genes not encoding channels but disrupting synaptic vesicle trafficking, synaptic protein scaffolding, or neuronal signaling cascades:
STXBP1 (Munc18-1) — core regulator of SNARE-complex-mediated synaptic vesicle fusion; haploinsufficiency impairs both excitatory and inhibitory neurotransmitter release, and recent work shows GABAergic/glycinergic and glutamatergic neurons mediate distinct components of the STXBP1 encephalopathy phenotype (PMC10993039).
CDKL5 — a kinase important for activity-dependent synaptic maturation and dendritic spine development; loss-of-function impairs neuronal circuit maturation rather than acute channel function.
PCDH19 — a cell-adhesion protocadherin; disease mechanism is cellular interference between PCDH19-mutant and wild-type neurons in a mosaic tissue, disrupting normal neuronal patterning/network formation (explaining the unusual female-restricted, mosaicism-dependent inheritance).
GNAO1 — disrupted G-protein/cAMP signal transduction affecting neuronal excitability and additionally producing a hyperkinetic movement disorder via basal ganglia circuit dysfunction.
ARX — transcription factor controlling GABAergic interneuron migration/differentiation during cortical development; disease mechanism is fundamentally a developmental/migrational one rather than acute channel dysfunction, explaining the ARX phenotypic spectrum from lissencephaly to isolated epilepsy.
Beyond channelopathy/synaptopathy mechanisms reviewed in PMC11763800 include impaired neurogenesis, disrupted dendrite/axon growth, and (for a subset of genes, e.g., mTOR-pathway-adjacent genes in focal cortical dysplasia-associated DEEs) mTOR pathway hyperactivation driving abnormal cortical lamination and cytomegalic neurons — though the classic mTORopathies (TSC1/2, DEPDC5, mTOR) are more commonly discussed under focal/structural epilepsy overlap than "pure" genetic DEE.

Causal chain (generalized): germline variant → altered channel/synaptic-protein function (loss-of-function, gain-of-function, or dominant-negative) → cell-type-specific dysfunction (interneuron hypoexcitability in Dravet; pyramidal hyperexcitability in SCN2A/SCN8A-GOF; synaptic vesicle release failure in STXBP1) → network-level excitation/inhibition imbalance and/or disrupted circuit maturation → clinical seizures and, in parallel, independently → impaired synaptic plasticity/neurodevelopment → intellectual disability/developmental regression (the "two-hit," partially seizure-independent model that distinguishes DEE nosologically from simple "epilepsy with comorbid ID").

Suggested GO terms: GO:0034765 (regulation of ion transmembrane transport), GO:0007268 (chemical synaptic transmission), GO:0051966 (regulation of synaptic transmission, glutamatergic), GO:0032228 (regulation of synaptic transmission, GABAergic), GO:0016082 (synaptic vesicle priming), GO:0007399 (nervous system development). Suggested CL terms: CL:0000617 (GABAergic interneuron), CL:0002608 (GABAergic neuron), CL:0000679 (glutamatergic neuron), CL:0000598 (pyramidal neuron), CL:0000359 (vasoinhibitory... [n/a]) — specifically CL:0002608 and CL:0000617 for interneuron-selective mechanisms (SCN1A), and CL:0000679/CL:0000598 for excitatory-neuron-predominant mechanisms (SCN2A/SCN8A gain-of-function).

Molecular profiling / advanced technologies: iPSC-derived neuron models are increasingly used to directly compare gain- vs. loss-of-function electrophysiological phenotypes at the patient-variant level (e.g., SCN2A iPSC-neuron studies distinguishing GOF vs. LOF firing patterns — bioRxiv 2023.02.14.528217); single-cell and circuit-level mouse studies (e.g., early postnatal CA3 hippocampal hyperexcitability in SCN2A-DEE mouse models — bioRxiv 2025.06.29.661458) are elucidating developmental-stage-specific circuit mechanisms.

7. Anatomical Structures Affected

Organ level: primary organ is the brain/CNS (UBERON:0000955). Secondary/systemic involvement is largely a consequence of severe neurological disease: gastrointestinal (feeding difficulties, gastroesophageal reflux — often requiring gastrostomy), musculoskeletal (scoliosis from hypotonia/immobility), respiratory (aspiration pneumonia, a leading non-SUDEP cause of death), and cardiac (some genes, e.g., SCN1A/SCN8A/SCN1B, implicate cardiac Na⁺ channel cross-reactivity as a plausible SUDEP mechanism given shared channel biology).
Body systems: primarily nervous system; secondarily digestive, respiratory, musculoskeletal, and in movement-disorder-associated genes (GNAO1, ARX), the basal ganglia motor system.
Tissue/cell level: cerebral cortex (particularly interneuron populations, UBERON:0000956), hippocampus (UBERON:0002421 — a key epileptogenic focus in Dravet and SCN2A models), and thalamocortical circuits. Cell populations: GABAergic interneurons (CL:0000617/CL:0002608 — Nav1.1-dependent), glutamatergic pyramidal neurons (CL:0000598), and to a lesser extent astrocytes (documented astrocyte remodeling in Dravet mouse models — see model organism section).
Subcellular level: plasma membrane ion channels and channel complexes (GO:0034705 ion channel complex), presynaptic active zone/SNARE machinery (relevant to STXBP1), postsynaptic density/NMDA and GABA-A receptor complexes.
Localization (UBERON): cerebral cortex (UBERON:0000956), hippocampus (UBERON:0002421), basal ganglia (UBERON:0002420, relevant to GNAO1), and more diffusely, whole brain (UBERON:0000955) given the typically generalized/multifocal nature of most genetic DEEs (contrasted with focal structural epilepsies).
Lateralization: typically bilateral/generalized dysfunction, consistent with a diffuse channelopathy/synaptopathy mechanism rather than a focal lesion, though EEG can show multifocal or shifting focal features (especially in KCNQ2-DEE and EIMFS-type presentations).

8. Temporal Development

Onset: ranges from neonatal (first days–weeks of life: KCNQ2, STXBP1, SCN2A/SCN8A-GOF, GNAO1, GRIN1) through early infantile (weeks–months: SCN1A/Dravet syndrome, typically 5–8 months; CDKL5, typically <4 months) to later infancy/early childhood (PCDH19, typically 6–36 months). Onset pattern is usually acute/subacute at the seizure level but the developmental impairment component can be insidious, sometimes preceding recognized seizures.
Progression: Disease "stages" are not formally codified in oncology-style staging systems but are conventionally described by evolving electroclinical syndrome — e.g., a Ohtahara-syndrome-like (burst-suppression) neonatal presentation evolving into West-syndrome-like infantile spasms/hypsarrhythmia, which may further evolve into a Lennox-Gastaut-syndrome-like multi-seizure-type pattern in later childhood — the so-called "epileptic encephalopathy continuum" (PubMed 35951482, "genetic heterogeneity to phenotypic continuum"). Progression rate is gene- and variant-dependent, ranging from rapidly severe (early-infantile SCN2A/SCN8A-GOF) to more indolent (later-onset, milder allelic series of the same genes).
Course pattern: most genetic DEEs are chronic and static-to-progressive rather than truly relapsing-remitting, though PCDH19 and Dravet syndrome show a distinctive episodic/clustering seizure pattern layered on a chronic developmental trajectory. A notable and clinically important pattern (well documented in KCNQ2-DEE) is seizure remission with persistent cognitive impairment — i.e., seizure control does not track with developmental outcome, a defining conceptual feature separating "epileptic" from "developmental" components of DEE.
Remission: spontaneous partial seizure remission is well described in KCNQ2-DEE (~73% eventual seizure freedom) and in some PCDH19 cases (seizure clusters typically diminish in adolescence); developmental impairment is far less likely to remit.
Critical periods: the first 1–2 years of life are widely regarded as a critical developmental window where uncontrolled seizure activity may compound genetically-driven synaptic/circuit disruption — the rationale underlying "time is brain" arguments for rapid genetic diagnosis and early precision-guided treatment.

9. Inheritance and Population

Epidemiology. A large, prospective, population-based cohort (Scottish national cohort) found DEE incidence of 169 per 100,000 live births (≈1 in 590), with a point prevalence of 112 per 100,000 children (PMC10065214 / PMID:36581463, "Epidemiology of Developmental and Epileptic Encephalopathy and of Intellectual Disability and Epilepsy in Children"). Related cohort work reports the adjusted incidence of epilepsies presenting in the first 3 years of life at 239 per 100,000 live births, early-infantile DEE (onset <3 months) at ~10/100,000 live births, infantile epileptic spasms syndrome at 58.2/100,000 (≈1 in 1,700), and early myoclonic-atypical-spasms-type presentations at 16.4/100,000 (≈1 in 6,100). SCN1A/Dravet syndrome alone has an expected population frequency of ≥1:20,000.

Inheritance pattern: overwhelmingly autosomal dominant, de novo for the most common genes (SCN1A, STXBP1, SCN2A, KCNQ2, SCN8A, GNAO1, GRIN2B); X-linked for CDKL5, PCDH19, ARX, FOXG1 (with PCDH19 uniquely affecting heterozygous females and sparing hemizygous males via cellular interference); rare autosomal recessive forms exist for a subset of genes (e.g., some metabolic/glycosylation-pathway DEE genes and occasional biallelic presentations).

Penetrance: generally high/complete for the classic de novo dominant channelopathy genes, though variable expressivity is substantial (e.g., the SCN2A GOF-vs-LOF spectrum, and mild/attenuated allelic KCNQ2 phenotypes). PCDH19 shows unusual, mosaicism-dependent penetrance — affected heterozygous females vs. unaffected hemizygous male carriers.

Expressivity: highly variable, both within a gene (allelic series, e.g., SCN2A/SCN8A/KCNQ2 spanning benign familial neonatal epilepsy at the mild end to severe neonatal-onset DEE at the severe end) and even for identical or similar variants — supporting a role for genetic background/modifier effects.

Genetic anticipation: not a recognized feature of the major DEE genes (which are not repeat-expansion disorders); not applicable to this class as currently understood.

Germline mosaicism: documented and clinically important for recurrence-risk counseling — an apparently de novo variant in a proband carries a residual (several-percent) sibling recurrence risk due to unrecognized parental germline mosaicism, and is specifically well-described for SCN1A and other DEE genes.

Founder effects: not prominently described for most DEE genes (mutations arise recurrently de novo rather than being inherited from a founder population), though certain recurrent hotspot variants (e.g., specific KCNQ2 missense positions) recur across unrelated families due to mutational hotspot biology rather than shared ancestry.

Consanguinity: relevant primarily to the minority of autosomal recessive DEE genes; increases pretest probability for biallelic causes in consanguineous families.

Carrier frequency: not typically applicable to de novo dominant disease; relevant mainly for recessive DEE genes and for PCDH19 male carriers (who are unaffected transmitters).

Population demographics: No strong, well-replicated ethnic/geographic enrichment has been established for the major genetic DEEs as a class (contrast with some single-gene metabolic disorders); ascertainment is affected by access to genetic testing, so reported incidence is likely an underestimate in regions with limited NGS access. Sex ratio is roughly equal for autosomal dominant genes but strongly skewed by X-linked genes (CDKL5 and PCDH19 predominantly affect females; ARX/FOXG1-related phenotypes show sex-specific presentations). Age distribution is concentrated in infancy/early childhood at diagnosis, with increasing recognition of an adult DEE population as the first generation of genetically diagnosed infants ages into adulthood.

10. Diagnostics

Clinical/EEG tests: interictal and ictal EEG (burst-suppression pattern, hypsarrhythmia, multifocal epileptiform discharges), video-EEG for seizure semiology characterization, brain MRI (to exclude structural causes and to identify secondary structural changes such as diffuse atrophy), and in selected cases, metabolic screening (plasma amino acids, urine organic acids, CSF neurotransmitters, biotinidase, pyridoxine/pyridoxal-5-phosphate trial) to exclude treatable metabolic DEE mimics (a critical step before committing to a purely "genetic, non-treatable-metabolic" workup).

Genetic testing. Current consensus favors early, first-line genome-wide sequencing (WES or WGS, often as a rapid trio test) over sequential single-gene or small panel testing, given the extreme genetic heterogeneity (>900 genes): - WES as first-line has been directly studied and validated as an efficient first-tier test in DEE cohorts, with diagnostic yields commonly cited around 35–43% (PMC10816140, "Whole Exome Sequencing as a First-Line Molecular Genetic Test in DEE"; PubMed 35701389). - Targeted gene panels remain in use where WES/WGS access is limited, with lower diagnostic yield in comparative studies (e.g., ~22% panel vs. higher WES yield in a Turkish cohort — PMC12562696); panels risk missing genes not yet included and non-coding/structural variants. - Chromosomal microarray (CMA) remains indicated to detect CNVs not well captured by exome sequencing, particularly for genes like CDKL5/ARX in the Xp22 region. - Trio sequencing (proband + both parents) substantially improves variant interpretation by enabling direct de novo confirmation, which is often the single strongest piece of evidence for pathogenicity in this de novo-dominant-predominant disease class. - RNA sequencing / functional follow-up is increasingly used to resolve splicing VUS. - Mitochondrial DNA and repeat-expansion testing are reserved for specific clinical phenotype overlaps (mitochondrial DEE mimics, and repeat-expansion disorders are not typically part of the core genetic DEE gene set).

Clinical diagnostic criteria: the ILAE 2022 operational framework for diagnosing DEE requires (1) epilepsy (recurrent unprovoked seizures) plus (2) developmental impairment attributable to the epilepsy/epileptiform activity and/or the underlying etiology, assessed against age-appropriate developmental milestones, with an "operational definition" recently published to standardize trial-eligibility criteria (PMC11997937, Epilepsia 2025, "Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials").

Differential diagnosis: structural epilepsies (cortical malformations, HIE), metabolic/treatable epileptic encephalopathies (pyridoxine-dependent epilepsy, GLUT1 deficiency, biotinidase deficiency, non-ketotic hyperglycinemia, creatine deficiency syndromes — all of which must be excluded/treated specifically since they are potentially reversible), mitochondrial disorders, and chromosomal syndromes with epilepsy as a feature.

Screening: no population newborn-screening program currently exists for genetic DEE (unlike some single-gene metabolic disorders); rapid genomic sequencing in the NICU/PICU setting for infants presenting with early-life refractory seizures functions as a de facto early-detection strategy. Cascade/carrier screening is relevant mainly for the recessive and X-linked forms.

11. Outcome/Prognosis

Mortality: genetic DEEs carry markedly elevated premature mortality. A large cohort study of people with genetic DEEs reported 42/510 deaths (8%), a mortality rate of 6.1 per 1,000 person-years, of which SUDEP accounted for 19/42 deaths (48%) — the leading identifiable cause (Neurology 2023, "Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies," PMC10115508). A meta-analysis of randomized trial/extension-study populations estimated an overall SUDEP rate of ~4.3 per 1,000 person-years and overall mortality of ~8.8 per 1,000 person-years across DEE trial cohorts, with SUDEP risk highest in Dravet syndrome and comparatively lower (but still substantial) in Lennox-Gastaut syndrome and infantile epileptic spasms syndrome (Epilepsia 2025 meta-analysis, "SUDEP and mortality in developmental and epileptic encephalopathies"). For Dravet syndrome specifically, mortality is reported at 15–20%, with 73% of deaths before age 10 and ~93% before age 20; SUDEP accounts for ~49% of Dravet deaths. Non-SUDEP causes of death include status epilepticus, aspiration pneumonia, and seizure-related accidental injury/drowning. Early mortality is also specifically documented in STXBP1-related disorders (PMC11828786).

Morbidity/function: the majority of survivors have lifelong, severe intellectual disability, motor impairment, and behavioral/psychiatric comorbidity (autism, ADHD, anxiety) as described in the Phenotypes section; functional independence in adulthood is rare for the most severe gene-associated forms (CDKL5, STXBP1, early-infantile SCN2A/SCN8A-GOF), while some milder allelic variants (later-onset KCNQ2, some PCDH19) permit partial functional independence.

Complications: status epilepticus, aspiration pneumonia (a leading non-SUDEP cause of death), fractures/injury from seizures or falls, scoliosis, feeding/nutritional failure requiring gastrostomy, and psychiatric comorbidity requiring dedicated management.

Prognostic factors: earlier seizure onset is generally associated with worse cognitive outcome (documented specifically in PCDH19, where early onset correlates with disease severity); the specific causal gene and variant type (gain- vs loss-of-function) strongly predicts both seizure course and treatment responsiveness; achievement of early seizure control is associated with (though not fully protective against) better developmental trajectory.

12. Treatment

Pharmacotherapy — general antiseizure medications (ASMs): broad-spectrum ASMs (valproate, clobazam, topiramate, levetiracetam, lamotrigine, rufinamide, felbamate, lacosamide, vigabatrin) are used empirically, often in combination, given high rates of pharmacoresistance. Critical gene-specific contraindication: sodium-channel-blocking ASMs (phenytoin, carbamazepine, oxcarbazepine, lamotrigine at high dose) can worsen seizures in SCN1A loss-of-function Dravet syndrome and are generally avoided, while the same drug class can be beneficial in SCN2A/SCN8A gain-of-function DEE — a textbook example of genotype-guided precision prescribing in this disease class.

Recently approved/DEE-specific pharmacotherapies: - Stiripentol — potentiates GABAergic transmission; approved as adjunct for Dravet syndrome. - Cannabidiol (Epidiolex) — FDA/EMA-approved for Dravet syndrome and Lennox-Gastaut syndrome. - Fenfluramine — serotonergic/sigma-1-receptor agonist mechanism; approved for Dravet syndrome and, more recently, CDKL5 deficiency disorder and Lennox-Gastaut syndrome. All three are highlighted as effective, well-tolerated additions to the DEE armamentarium (tandfonline review; DelveInsight pipeline overview). - ACTH/oral corticosteroids — mainstay for infantile-spasms-type presentations regardless of underlying gene.

Pharmacogenomics: the SCN1A/SCN2A/SCN8A gain-of-function vs. loss-of-function dichotomy described above is the clearest example of pharmacogenomic decision-making currently in DEE clinical practice; cenobamate has recently been explored as an add-on for SCN8A-DEE specifically (medRxiv 2024.10.17.24312949).

Advanced therapeutics (investigational/emerging): - Antisense oligonucleotide (ASO) therapy: an SCN1A-upregulating ASO strategy (targeting a non-productive splice isoform to boost productive SCN1A transcript and restore Nav1.1 haploinsufficiency) has entered clinical development for Dravet syndrome; conversely, an SCN2A-lowering ASO strategy has been studied preclinically for SCN2A gain-of-function DEE (bioRxiv 2020.09.09.289900, "Antisense oligonucleotide therapy for SCN2A gain-of-function epilepsy"). - Gene therapy: AAV-mediated gene-replacement/upregulation strategies are in preclinical-to-early-clinical development for Dravet syndrome (SCN1A upregulation via engineered transcription factors) and other haploinsufficiency genes (e.g., STXBP1, SCN1A). - Base editing: an adenine base editor packaged in dual AAVs (SCN8A-ABE) corrected a gain-of-function SCN8A variant and significantly increased survival and reduced/eliminated seizures in a mouse model, illustrating a genome-editing path toward curative therapy (PMC12871382).

Surgical/interventional: vagus nerve stimulation (VNS) is used in selected drug-resistant DEE patients, including gene-specific case reports (e.g., KCNB1-DEE — PMC12446608) and studied in young children specifically (PMC10624125); corpus callosotomy for drop attacks; focal resective surgery is rarely applicable given the typically diffuse/genetic (non-focal-lesional) substrate, but may be considered when a coexisting focal structural abnormality (e.g., focal cortical dysplasia) is identified.

Supportive/rehabilitative care: ketogenic diet has demonstrated efficacy across multiple DEE subtypes and is a well-established non-pharmacological cornerstone (PMC12358386, "Progress of ketogenic diet in the treatment of developmental epileptic encephalopathy"); physical/occupational/speech therapy, nutritional support (including gastrostomy), and multidisciplinary developmental support are standard.

Suggested MAXO terms: MAXO:0000647 (chemotherapy — n/a here), MAXO:0000088 (dietary intervention — ketogenic diet), MAXO:0000011 (physical therapy), MAXO:0001017 (vaccination — n/a), MAXO:0000004 (surgical procedure — VNS/callosotomy), MAXO:0001001 (gene therapy), MAXO:0000950 (supportive care). Pharmacotherapy entries would use NCIT:C15986 (Pharmacotherapy) with therapeutic_agent bound to CHEBI (e.g., cannabidiol, stiripentol, fenfluramine) or NCIT drug-class terms.

Treatment outcomes: response rates vary widely by gene and drug; adverse events for the newer agents include appetite/weight changes and cardiac monitoring requirements for fenfluramine (historical cardiac-valvulopathy concerns from its earlier obesity-drug formulation, now mitigated by low-dose, monitored DEE use), sedation for cannabidiol/clobazam combinations, and hepatotoxicity monitoring for valproate/stiripentol/felbamate combinations.

13. Prevention

Primary prevention: not currently possible in the traditional sense (no way to prevent de novo mutation occurrence); the closest analog is avoidance of known seizure triggers (fever management, sleep hygiene) in already-diagnosed patients to reduce secondary seizure-related morbidity, and avoidance of contraindicated sodium-channel-blocking ASMs in SCN1A-Dravet syndrome to prevent iatrogenic seizure worsening.

Secondary prevention: early genetic diagnosis enabling gene-informed ASM selection (the sodium-channel-blocker example above) functions as a form of secondary prevention of avoidable seizure exacerbation and status epilepticus.

Genetic counseling: central to management — recurrence-risk counseling for parents (typically low but non-zero due to germline mosaicism, as discussed above), and reproductive options (preimplantation genetic diagnosis, prenatal testing) once a familial pathogenic variant is identified.

Screening/early detection: no population-level newborn screening program exists for genetic DEE; rapid/ultra-rapid genomic sequencing for critically ill infants with early-life seizures functions as the practical "early detection" pathway, enabling faster gene-informed management.

Prophylaxis: SUDEP-risk-reduction counseling (nocturnal supervision/monitoring devices, seizure-alert systems, optimized seizure control) is a key preventive intervention given the high SUDEP burden documented above; some centers discuss rescue-medication protocols (e.g., benzodiazepine rescue therapy) as prophylaxis against prolonged seizures/status epilepticus.

14. Other Species / Natural Disease

Naturally occurring DEE-like disease in companion animals is not well characterized as a direct ortholog of any single human genetic DEE (unlike, e.g., some canine epilepsy loci); OMIA does list canine idiopathic epilepsy loci, but a documented natural-disease parallel specific to SCN1A/STXBP1/etc. orthologs in domestic species was not identified in this search pass. Orthologous genes are highly conserved across vertebrates (Scn1a, Stxbp1, Scn2a, Kcnq2, Cdkl5, Pcdh19, Gnao1, Arx all have well-annotated mouse, rat, and zebrafish orthologs per NCBI Gene/Alliance of Genome Resources), which underpins the extensive model-organism literature below. No zoonotic or cross-species transmission relevance applies, as this is a non-infectious monogenic disease class.

15. Model Organisms

Model systems are extensively used and are reviewed comparatively in PMC8547712, "Overlaps, gaps, and complexities of mouse models of Developmental and Epileptic Encephalopathy".

Mouse models: - Scn1a⁺/⁻ (Dravet syndrome) mice — the best-characterized DEE model; recapitulate spontaneous seizures, premature/SUDEP-like mortality, hyperactivity, social-interaction deficits, and cognitive impairment beginning around the second–third postnatal week, closely paralleling the human Nav1.1-interneuron-hypoexcitability mechanism. Genetic-rescue studies (Scn1a reactivation after symptom onset) have shown reversal of pathological phenotypes, supporting gene-therapy feasibility (Nature Communications 2021, PMID via doi:10.1038/s41467-021-27837-w). Astrocyte remodeling has also been documented as a longer-lasting pathological feature in this model (bioRxiv 2026.01.06.697745). - Scn2a knock-in mice (e.g., p.A263V gain-of-function variant knocked into the endogenous locus) — show increased persistent Na⁺ current in heterologous expression and spontaneous generalized tonic-clonic seizures in vivo, confirming gain-of-function mechanism and enabling early postnatal circuit-level study of CA3 hippocampal hyperexcitability (bioRxiv 2025.06.29.661458). A separate Scn2a knockout (haploinsufficiency) model shows an autistic-like phenotype attenuated with age, modeling the loss-of-function end of the SCN2A allelic spectrum (PMC6733925). - Scn1b (Na⁺ channel β1 subunit) mice — model human SCN1B-linked DEE, reproducing both epilepsy and SUDEP (PMC10903178). - Scn8a mutation-associated models — used to test base-editing correction (SCN8A-ABE), with AAV-delivered adenine base editing improving survival and reducing/eliminating seizures (PMC12871382). - Gabrg2 knock-in mice — model GABRG2-related epileptic encephalopathy, showing spontaneous generalized seizures and cognitive impairment, directly linking GABA-A receptor dysfunction to the DEE phenotype (PMC12501280).

iPSC-derived neuron / cellular models: patient-derived iPSC neurons carrying gain-of-function vs. loss-of-function SCN2A variants show distinctive, mechanism-concordant electrophysiological phenotypes in vitro, supporting the model's utility for genotype-specific mechanism dissection and drug screening (bioRxiv 2023.02.14.528217).

Model characteristics/limitations: mouse models generally recapitulate core seizure phenotypes and premature mortality well, and increasingly reproduce behavioral/cognitive comorbidities, but the PMC8547712 review specifically emphasizes gaps and overlaps — i.e., not all mouse models fully capture the human developmental-regression component, genetic background strongly modifies phenotype severity/penetrance (complicating cross-model comparison), and species differences in interneuron subtype proportions and network architecture limit direct translational inference for cognitive/behavioral endpoints. iPSC-neuron models, while capturing cell-autonomous electrophysiology well, lack the multicellular network and whole-organism developmental context needed to model the "developmental" component of DEE.

Applications: these models are used for (1) mechanistic dissection (channelopathy vs. synaptopathy, GOF vs. LOF), (2) precision-therapy validation (genotype-matched sodium-channel-blocker response), and (3) advanced-therapeutic proof-of-concept (ASO, gene therapy, base editing) prior to human trials, as detailed in the Treatment section above.

Resources: MGI (Mouse Genome Informatics) for Scn1a/Scn2a/Stxbp1/Kcnq2/Cdkl5 alleles; IMPC/KOMP for systematic knockout phenotyping; ZFIN for zebrafish scn1lab Dravet models (an additional model system not detailed above but widely used for high-throughput drug screening in Dravet syndrome).

Summary of Key Ontology-Term Suggestions for KB Curation

MONDO: MONDO:0010246 (umbrella "developmental and epileptic encephalopathy" grouping term, OMIM PS308350) plus individual gene-specific MONDO IDs per subtype.
HP terms: HP:0032900 (Seizure), HP:0011097 (Epileptic spasm), HP:0001263 (Developmental delay), HP:0002376 (Developmental regression), HP:0001249 (Intellectual disability), HP:0010851 (EEG with burst suppression), HP:0000729 (Autistic behavior), HP:0004328 (Hand stereotypies), HP:0010984 (Digenic inheritance — n/a here but relevant framework), HP:0001252 (Hypotonia).
GO terms: GO:0034765, GO:0007268, GO:0051966, GO:0032228, GO:0016082, GO:0007399.
CL terms: CL:0000617, CL:0002608 (GABAergic interneuron), CL:0000679, CL:0000598 (glutamatergic/pyramidal neuron).
UBERON terms: UBERON:0000955 (brain), UBERON:0000956 (cerebral cortex), UBERON:0002421 (hippocampus), UBERON:0002420 (basal ganglia).
MAXO terms: MAXO:0000088 (dietary/ketogenic diet), MAXO:0000011 (physical therapy), MAXO:0000004 (surgical procedure — VNS), MAXO:0001001 (gene therapy).
CHEBI terms (representative drugs): cannabidiol, fenfluramine, stiripentol, valproate, clobazam.

Curation Note on Scope

Given dismech's schema conventions, "Genetic Developmental and Epileptic Encephalopathy" is best modeled either as (a) an umbrella Grouping (analogous to Mucopolysaccharidoses or Digenic_and_Oligogenic_Disorders) with grouping_basis: SHARED_MECHANISM/SHARED_PHENOTYPE pointing down to individual gene-defined member entries (SCN1A-Dravet syndrome, STXBP1-DEE, SCN2A-DEE, KCNQ2-DEE, CDKL5 deficiency disorder, PCDH19-clustering epilepsy, etc. — several of which likely already exist or should be created as standalone Disease entries), each conforming to the existing epilepsy_excitation_inhibition_imbalance mechanism module for the shared excitation/inhibition-imbalance convergence point; or (b) if the KB intends a single entry for the umbrella concept itself, it should be scoped narrowly to the shared definitional/diagnostic/epidemiological content above, with gene-specific pathophysiology, evidence, and precision-therapy detail deferred to the individual gene-level entries — consistent with the "lump vs. split" design guidance in this repository's decision register.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 28 citations 2026-07-31T00:22:59.674007

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Genetic Developmental and Epileptic Encephalopathy
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on Genetic Developmental and Epileptic Encephalopathy covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

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14. Other Species / Natural Disease

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Gene: Orthologous genes in other species (with NCBI Gene IDs)

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15. Model Organisms

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Applications:
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Resources:
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Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Genetic Developmental and Epileptic Encephalopathy

Executive summary and scope

Genetic developmental and epileptic encephalopathies (genetic DEEs) are not one molecular disease but an etiologically heterogeneous family of severe neurodevelopmental epilepsies. The defining concept is that both the underlying developmental disorder and epileptic activity contribute—independently and additively—to cognitive, behavioral, and neurological impairment. They usually begin in infancy or childhood with seizures, abundant epileptiform EEG activity, developmental slowing or regression, and multiple non-seizure comorbidities. The International League Against Epilepsy (ILAE) introduced the combined term in 2017 to distinguish DEE from a purely “epileptic encephalopathy,” in which epileptic activity is assumed to be the principal cause of developmental deterioration. (scheffer2024developmentalandepileptic pages 1-4, chang2023genetictestingin pages 4-6)

A 2024 expert review describes DEEs as the most severe epilepsy group and emphasizes that management must address seizures, development, behavior, movement, sleep, feeding, respiratory health, and family burden—not seizure counts alone. More than 800–900 genes have been associated with monogenic DEEs, although gene validity and phenotype specificity vary and the number continues to expand. (specchio2024theexpandingfield pages 1-6, scheffer2024developmentalandepileptic pages 9-11, scheffer2024developmentalandepileptic pages 19-21)

Evidence boundary: statistics from Dravet syndrome, CDKL5 deficiency disorder, STXBP1 encephalopathy, infantile epileptic spasms syndrome, or another named DEE must not automatically be generalized to all genetic DEEs.

1. Disease information

Definition, names, and identifiers

Common names include developmental and epileptic encephalopathy, DEE, genetic DEE, developmental epileptic encephalopathy, and the older terms epileptic encephalopathy and early infantile epileptic encephalopathy. Named syndromes within the umbrella include Dravet syndrome, early-infantile DEE, epilepsy of infancy with migrating focal seizures, infantile epileptic spasms syndrome, and Lennox–Gastaut syndrome; some are genetically homogeneous, whereas others have structural, metabolic, infectious, or unknown causes. (scheffer2024developmentalandepileptic pages 9-11, scheffer2024developmentalandepileptic pages 1-4)

There is no single universal OMIM number, because OMIM generally assigns entries to individual gene-defined disorders such as SCN1A-, KCNQ2-, STXBP1-, or CDKL5-related encephalopathy. The same limitation applies to Orphanet and MONDO: individual syndromes have specific identifiers, while the umbrella concept is represented hierarchically and database mappings can change. For production use, the current MONDO/Orphanet release should therefore be queried rather than assigning one unverified umbrella identifier. ICD-10-CM usually requires epilepsy/syndrome and intellectual-disability codes rather than a unique genetic-DEE code; ICD-11 provides more granular developmental/epileptic encephalopathy categories. MeSH concepts include Epileptic Encephalopathies and individual syndromes.

The evidence summarized here is primarily aggregated disease-level evidence from reviews, cohorts, registries, and trials. It is not an extraction from individual EHRs, although several cohorts were assembled by retrospective medical-record and EEG review.

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factors

Genetic DEEs arise from germline or post-zygotic pathogenic variants affecting neuronal excitability, synaptic transmission, neurotransmitter receptors, cortical development, intracellular signaling, metabolism, organelle function, and chromatin/transcriptional regulation. Representative genes include:

Ion channels: SCN1A, SCN2A, SCN8A, KCNQ2, KCNT1, KCNH5, CACNA1A.
Synaptic release/signaling: STXBP1, SYNGAP1, PCDH19, NBEA.
Receptors: GRIN family genes.
mTOR/cortical development: TSC1, TSC2, MTOR, DEPDC5.
Chromatin/transcription/RNA regulation: CHD2, HNRNPU, KMT2A, CDKL5.
Metabolic/transport pathways: SLC2A1, GLDC and numerous mitochondrial or vitamin-responsive disorders.

In a 2024 early-onset cohort, ion-channel genes were the largest functional class, accounting for 36/104 monogenic cases; SCN1A and KCNQ2 were the leading channel genes. (cavirani2024geneticepilepsiesand pages 2-4, cavirani2024geneticepilepsiesand pages 4-6)

Genetic risk and inheritance

Most diagnosed severe early-onset cases involve highly penetrant rare variants rather than common polygenic susceptibility. De novo autosomal-dominant variants are prominent, but autosomal-recessive, X-linked, mitochondrial, inherited dominant, and parental-mosaic mechanisms occur. A 2024 Italian survey of 1,568 molecularly diagnosed patients found 77% involving autosomal-dominant genes, 17% X-linked genes, and 6% autosomal-recessive genes; SCN1A accounted for 16%, KCNQ2 5.6%, and SCN2A 5%. These figures reflect diagnosed cases and testing practice, not unbiased population frequencies.

Recurrence risk is variant-specific. A confirmed de novo variant usually implies low—but not zero—recurrence because parental germline mosaicism is possible. Recessive disease creates a 25% recurrence risk for each pregnancy when both parents are carriers. X-linked recurrence depends on maternal carrier or mosaic status. Variable expressivity and incomplete penetrance occur in several genes, particularly familial channel, synaptic, and mTOR-pathway disorders. Genetic anticipation is not a general DEE feature.

Pathogenic variants are usually absent or extremely rare in population databases such as gnomAD; a numerical allele-frequency threshold cannot be assigned across the umbrella. Classification must follow ACMG/AMP criteria using segregation, population frequency, phenotype match, computational data, and functional evidence. Missense, nonsense, frameshift, splice, copy-number, structural, regulatory, mitochondrial, and mosaic variants all occur. A VUS is not diagnostic and should not independently direct irreversible therapy. Exome studies can report VUS rates of 25.3–86%, illustrating the interpretation burden. (chang2023genetictestingin pages 4-6)

Environmental and protective factors

There is no evidence that smoking, diet, pollution, occupation, or an infectious agent is a primary cause of genetic DEE. Fever, infection, sleep loss, and elevated temperature can trigger seizures in susceptible genotypes, especially SCN1A-related Dravet syndrome; inflammation may worsen SCN1A channel dysfunction and seizure severity. This is trigger modulation, not causation. Routine vaccination does not create the underlying genetic disorder, although fever temporally associated with vaccination can unmask fever-sensitive seizures. (specchio2024theexpandingfield pages 14-17)

No broadly validated environmental or genetic protective factor prevents genetic DEE. Prompt fever management, avoidance of known individual triggers, medication adherence, nocturnal supervision where appropriate, and early syndrome-specific treatment may reduce complications. Ketogenic dietary therapy can improve seizures in subsets but is treatment, not primary prevention. Model-organism observations such as estrogen-mediated suppression of CNTNAP2-associated behaviors are hypothesis-generating and not established human protective factors. (sun2024strategiesfordissecting pages 14-15)

3. Phenotypes

Core and associated phenotypes vary by gene and age:

Recurrent seizures—often neonatal or infantile onset, multiple types, prolonged, and drug-resistant. Suggested HPO: Seizure (HP:0001250), Neonatal-onset seizures, Infantile-onset seizures, Status epilepticus, Epileptic spasm.
Abnormal EEG—multifocal or generalized epileptiform discharges; syndrome-dependent hypsarrhythmia, burst suppression, slow spike-wave, or migrating focal activity. HPO: EEG abnormality (HP:0002353), Hypsarrhythmia.
Global developmental delay/intellectual disability, frequently severe or profound; development may be delayed before seizures and may stagnate or regress after seizure onset. HPO: HP:0001263, HP:0001249, Developmental regression (HP:0002376).
Speech/language impairment, sometimes minimal or absent speech. HPO: Delayed speech and language development (HP:0000750), Absent speech.
Motor abnormalities: hypotonia, spasticity, ataxia, gait impairment, dystonia, stereotypies, tremor, and myoclonus. HPO: HP:0001252, HP:0001257, HP:0001251, HP:0001332, HP:0002072.
Behavioral/psychiatric features: autism traits, ADHD, irritability, anxiety, and sleep disturbance. HPO: HP:0000729, HP:0007018, HP:0002360.
Systemic morbidity: feeding/swallowing and gastrointestinal problems, respiratory vulnerability, orthopedic complications, visual impairment, and growth abnormalities, depending on genotype. (scheffer2024developmentalandepileptic pages 9-11, scheffer2024developmentalandepileptic pages 1-4)

In a 2024 multicenter monogenic cohort, developmental delay/intellectual disability occurred in 84/104 (80.7%), abnormal neurological examination in 74/104 (71%), autistic features in 12/104 (11.5%), ADHD in 4/104 (3.8%), and other behavioral disorders in 15/104 (14.4%). These are cohort—not universal—frequencies. Seizures began at a mean 11 months, with generalized onset in 37.5% and focal onset in 31%. (cavirani2024geneticepilepsiesand pages 2-4, cavirani2024geneticepilepsiesand pages 4-6)

Among 77 patients selected for movement disorders, stereotypies occurred in 48%, dystonia in 44%, chorea in 23%, myoclonus in 18%, ataxia in 12%, tremor in 9%, and hypokinesia in 8%; 47% had more than one movement disorder. Selection makes these inappropriate as general DEE prevalence estimates.

Quality of life is substantially impaired by seizures, medication adverse effects, mobility, communication limitations, behavior, sleep, and dependence in activities of daily living. Cross-sectional studies show worse health-related quality of life than both the general population and unselected childhood epilepsy cohorts. Caregiver depression, employment disruption, and family burden are substantial. (scheffer2024developmentalandepileptic pages 17-19)

4. Genetic and molecular information

Mechanism class	Representative genes	Typical functional consequence	Causal chain to phenotype	Representative precision-management implication	Evidence type / limitations
Voltage-gated sodium channelopathy	SCN1A, SCN2A, SCN8A	Variant-specific; can be loss-of-function (LOF) or gain-of-function (GOF), so effect must be interpreted per gene/variant rather than assumed	Altered sodium current changes neuronal excitability during early brain development, contributing to recurrent seizures, epileptiform activity, and downstream developmental slowing/regression; SCN1A-related Dravet syndrome is a key example (scheffer2024developmentalandepileptic pages 1-4, scheffer2024developmentalandepileptic pages 19-21, specchio2024theexpandingfield pages 6-8)	Precision management depends on mechanism: activity-boosting strategies for LOF versus inhibitory strategies for GOF; SCN1A-positive Dravet syndrome has AAV9 transcriptional activation trials (ETX101) designed to increase SCN1A expression in presumed LOF disease (specchio2024theexpandingfield pages 6-8, NCT06112275 chunk 1, NCT06283212 chunk 1)	Human umbrella reviews plus gene-specific trials and mouse studies support this class, but not every variant in these genes behaves identically and treatment generalization across sodium-channel genes is unsafe (scheffer2024developmentalandepileptic pages 1-4, specchio2024theexpandingfield pages 14-17, NCT06112275 chunk 1)
Potassium channelopathy	KCNQ2, KCNT1, KCNH5	Variant-specific GOF or LOF; functional direction is clinically important and should be established where possible	Disordered potassium conductance impairs membrane repolarization and network stability, producing neonatal/infantile seizures and, in severe cases, DEE with developmental impairment (cavirani2024geneticepilepsiesand pages 2-4, specchio2024theexpandingfield pages 6-8)	Mechanism-guided therapy is conceptually important: inhibitor approach for some GOF states versus function-supporting approach for LOF states; emerging gene/RNA strategies are under study broadly in DEE, but robust variant-level treatment rules remain incomplete (specchio2024theexpandingfield pages 6-8, scheffer2024developmentalandepileptic pages 17-19)	Evidence is strong for inclusion of potassium-channel genes among major DEE causes, but the gathered evidence is mostly review-level and does not provide uniform variant-specific response data for all genes in this class (cavirani2024geneticepilepsiesand pages 2-4, specchio2024theexpandingfield pages 6-8)
Synaptic vesicle / synaptic signaling dysfunction	STXBP1, SYNGAP1, PCDH19, NBEA	Often reduced or altered synaptic function; exact consequence is gene- and variant-specific	Impaired vesicle release or synaptic signaling disrupts circuit formation and excitatory/inhibitory balance, leading to seizures, developmental delay/intellectual disability, and frequent movement/behavioral comorbidity (cavirani2024geneticepilepsiesand pages 4-6, specchio2024theexpandingfield pages 6-8)	Supportive precision approach is mainly diagnosis-led today; STXBP1 has an early interventional gene-therapy program (CAP-002) in pediatrics, but efficacy is not established (NCT06983158 chunk 2)	Evidence comes from multicenter human cohorts and reviews; STXBP1 trial evidence is preliminary, and mechanistic heterogeneity across synaptic genes limits direct extrapolation from one gene to another (cavirani2024geneticepilepsiesand pages 4-6, NCT06983158 chunk 2)
Glutamatergic receptor / excitatory synapse dysfunction	GRIN2A and broader GRIN family	Variant-specific receptor dysfunction, potentially GOF or LOF depending on variant	Abnormal NMDA receptor signaling disturbs synaptic maturation and excitatory circuit development, contributing to epileptiform activity plus language/cognitive impairment characteristic of some DEEs (specchio2024theexpandingfield pages 1-6, specchio2024theexpandingfield pages 6-8)	Precision implication is mechanism-first interpretation rather than syndrome-first treatment; receptor dysfunction supports rationale for targeted pathway modulation, but gene-specific standardized therapies were not established in the gathered clinical evidence (specchio2024theexpandingfield pages 6-8)	Evidence is mainly review-level in the gathered set; mechanistic plausibility is strong, but variant-level therapeutic evidence is comparatively limited here (specchio2024theexpandingfield pages 1-6, specchio2024theexpandingfield pages 6-8)
mTOR-pathway dysregulation / cortical developmental pathology	MTOR, TSC1, TSC2	Typically pathway overactivation in relevant disorders, though exact molecular consequence depends on lesion/gene context	mTOR overactivation in the developing cortex can drive malformations of cortical development, network hyperexcitability, infantile spasms/epilepsy, and developmental impairment (specchio2024theexpandingfield pages 17-21, specchio2024theexpandingfield pages 6-8, specchio2024theexpandingfield pages 14-17)	mTOR is a representative actionable pathway in DEE; pathway-oriented treatment logic is stronger here than in many other classes, although the gathered evidence emphasizes translational rationale more than new 2024 trial outcomes (specchio2024theexpandingfield pages 17-21, specchio2024theexpandingfield pages 14-17)	Supported by authoritative reviews and pathway-oriented discussion; however, not all mTOR-related epilepsies are identical and some evidence cited is translational rather than direct comparative clinical efficacy data (specchio2024theexpandingfield pages 17-21, specchio2024theexpandingfield pages 14-17)
Metabolic / vitamin-responsive causes within early-infantile DEE differential	GLDC, SAMHD1; biotinidase deficiency noted in cohort-level metabolic testing	Mechanistically heterogeneous; some are potentially treatable metabolic defects rather than classic ion-channel DEEs	Metabolic dysfunction can produce early seizures and encephalopathy; in early-infantile cohorts, vitamin-responsive etiologies had better seizure control than genetic/unknown groups, showing the importance of separating treatable metabolic causes from monogenic DEE (cavirani2024geneticepilepsiesand pages 4-6)	Precision implication is urgent metabolic evaluation because some early-infantile epilepsies are vitamin responsive and clinically more treatable than most monogenic DEEs ()	Strong practical message from prospective human cohort, but this row spans heterogeneous disorders and should not be collapsed into a single molecular DEE mechanism ()
Chromatin / transcriptional regulation defects	CHD2, KMT2A, HNRNPU, CDKL5	Often dosage-sensitive or loss-of-function/haploinsufficiency-like effects, but not uniformly so across genes	Disrupted transcriptional or chromatin regulation alters neuronal differentiation and network development, yielding treatment-resistant epilepsy, developmental delay/intellectual disability, autism/behavioral features, and possible regression (cavirani2024geneticepilepsiesand pages 4-6, scheffer2024developmentalandepileptic pages 17-19)	Current precision-management value is highest for diagnosis, prognosis, and trial readiness; CHD2 is highlighted as dosage sensitive with model systems under development, but no established targeted therapy yet (scheffer2024developmentalandepileptic pages 17-19)	Human cohort and roadmap/model evidence support this class; important limitation is that some animal models fail to recapitulate seizures, underscoring translational gaps (scheffer2024developmentalandepileptic pages 17-19)

Table: This table summarizes major mechanistic categories represented in genetic developmental and epileptic encephalopathies, linking gene classes to variant effects, disease biology, and current precision-management implications. It is useful as a compact knowledge-base scaffold because DEE is genetically heterogeneous and treatment logic often depends on variant-specific gain- versus loss-of-function.

The crucial annotation principle is variant-specific functional direction. For example, pathogenic variants in sodium-channel genes may cause loss of function, gain of function, or altered gating. The appropriate therapy can therefore be opposite for different variants or genes: suppressing sodium current may help some gain-of-function channelopathies but worsen SCN1A loss-of-function Dravet syndrome. (specchio2024theexpandingfield pages 6-8, scheffer2024developmentalandepileptic pages 19-21)

Most causal variants are constitutional germline changes, but post-zygotic mosaic variants—especially in cortical-development/mTOR genes—may be restricted to brain tissue and missed in blood. Chromosomal abnormalities and CNVs are important: in one 168-person early-onset cohort, 45 pathogenic/likely pathogenic diagnoses were chromosomal/CNV disorders and 104 were monogenic. (cavirani2024geneticepilepsiesand pages 2-4)

Modifier genes and epigenetic state probably help explain variable expressivity, but clinically validated modifier alleles are not available for the umbrella disorder. Epigenetic dysfunction can itself be upstream when causal genes encode chromatin remodelers or transcriptional regulators; a universal DEE methylation signature has not been established.

5. Environmental information

Genetic DEE is neither infectious nor occupational and has no zoonotic transmission. Non-genetic insults—hypoxic–ischemic injury, congenital infection, immune encephalitis, trauma, and toxic-metabolic illness—are instead important differential etiologies for a child with seizures and developmental impairment. Environmental trigger management is individualized; there is no evidence-based universal lifestyle program that reverses the genetic neurodevelopmental defect.

6. Mechanism and pathophysiology

A general causal chain is:

pathogenic variant/CNV → altered protein dosage or function → abnormal neuronal development, excitability, synaptic release, receptor signaling, metabolism, or cortical architecture → impaired excitation–inhibition balance and epileptic networks → recurrent seizures and epileptiform EEG activity → additional activity-dependent disruption of plasticity and cognition, superimposed on the primary developmental defect → developmental slowing/regression and multimorbidity. (scheffer2024developmentalandepileptic pages 1-4, specchio2024theexpandingfield pages 6-8)

Upstream mechanisms include channel dysfunction, synaptic-vesicle defects, receptor dysfunction, mTOR overactivation, metabolic deficiency, and altered chromatin regulation. Downstream mechanisms include network hypersynchrony, excitotoxic/metabolic stress, sleep disruption, medication burden, injury from prolonged seizures, and impaired experience-dependent plasticity.

The developing brain is particularly vulnerable because excitatory AMPA/NMDA receptor composition and inhibitory GABAergic circuits change rapidly in infancy; immature GABAergic currents can remain depolarizing, while accelerated excitatory-circuit maturation can create transient hyperexcitability. (specchio2024theexpandingfield pages 6-8)

Suggested ontology mappings include:

GO biological processes: regulation of membrane potential (GO:0042391), chemical synaptic transmission (GO:0007268), synaptic vesicle exocytosis (GO:0016079), glutamate receptor signaling pathway, GABAergic synaptic transmission, TOR signaling (GO:0031929), neuron differentiation (GO:0030182), and chromatin organization (GO:0006325).
Cell Ontology: neuron (CL:0000540), glutamatergic neuron (CL:0000679), GABAergic neuron (CL:0000617), cortical neuron, interneuron, neural progenitor cell, astrocyte, oligodendrocyte, and microglial cell. The principal cell population differs by gene.
Cellular components: voltage-gated ion-channel complex, presynaptic active zone, synaptic vesicle, postsynaptic density, neuronal plasma membrane, nucleus/chromatin, mitochondrion, lysosome, and mTOR complexes.

Transcriptomic, proteomic, metabolomic, single-cell, and spatial data remain fragmented and gene-specific. Multi-omics is a major research priority, not yet a validated umbrella diagnostic biomarker. (specchio2024theexpandingfield pages 17-21)

7. Anatomical structures affected

The primary organ is the brain, especially distributed cortical and subcortical networks. Depending on genotype, affected structures can include cerebral cortex, hippocampus, thalamus, basal ganglia, cerebellum, and brainstem autonomic/respiratory networks. Suggested UBERON terms include brain (UBERON:0000955), cerebral cortex (UBERON:0000956), hippocampal formation, thalamus, basal ganglion, cerebellum (UBERON:0002037), and brainstem (UBERON:0002298).

MRI can be normal, show nonspecific atrophy, reveal a malformation of cortical development, or demonstrate a syndrome-specific abnormality. In a prospective early-infantile cohort, MRI was abnormal in 35/80; 16/35 had a malformation and 19/35 had nonspecific findings that did not establish etiology. No consistent lateralization characterizes genetic DEE as a group.

Secondary systems include musculoskeletal tissue through immobility/spasticity, gastrointestinal and feeding systems, respiratory/autonomic systems, vision, and sleep regulation. These are usually complications or pleiotropic manifestations rather than the primary lesion.

8. Temporal development

Approximately 75% of DEEs begin before age three, but onset can occur later in childhood. Population-based data show that 27% of DEEs began after age three, warning against restricting testing to infancy. (scheffer2024developmentalandepileptic pages 1-4)

Typical course:

Pre-seizure period: normal, subtly delayed, or clearly abnormal development depending on genotype.
Seizure onset: neonatal, infantile, or childhood onset; acute presentation but chronic underlying disease.
Evolution: multiple seizure types and changing EEG patterns; developmental slowing, plateau, or regression.
Chronic phase: seizure burden may improve in some syndromes while intellectual, behavioral, motor, and communication disability persists or becomes more apparent.

In a 10-year SCN1A-positive Dravet study, epilepsy severity became less severe while developmental outcome worsened and autistic, behavioral, and motor/mobility comorbidities became more frequent. This illustrates that seizure improvement does not equal neurodevelopmental recovery. Critical intervention windows probably occur before or soon after network dysfunction begins, supporting rapid diagnosis and early treatment, but exact windows remain gene-specific. (scheffer2024developmentalandepileptic pages 17-19)

9. Inheritance and population epidemiology

A population-based New Zealand study estimated a DEE point prevalence of 112 per 100,000 children and cumulative incidence of 169 per 100,000—approximately 1 in 590 children by age 16. The broader category of epilepsy plus developmental impairment occurred in approximately 1 in 340 children. These figures include genetically unresolved and non-genetic DEEs, not only molecularly confirmed disease. (scheffer2024developmentalandepileptic pages 1-4, scheffer2024developmentalandepileptic pages 19-21)

Syndrome cumulative incidence per 100,000 children was 58.2 for infantile epileptic spasms syndrome, 16.4 for epilepsy with myoclonic-atonic seizures, 13.2 for Lennox–Gastaut syndrome, and 5.1 for Dravet syndrome. One-third of children with DEE lacked a recognized electroclinical syndrome.

In the Italian molecular survey, diagnoses increased more than tenfold from 2012 to 2022; the mean age at molecular diagnosis was 11.2 years despite typically pediatric onset, demonstrating historical diagnostic delay. Geographic and ethnic differences in reported frequency largely reflect ascertainment, consanguinity, founder variants, access to sequencing, and variant interpretation. There is no established universal ethnic predisposition. Sex ratio depends on gene; X-linked disorders and sex-limited PCDH19-related disease can produce marked differences. One population cohort was 58% male, whereas a 2024 early-onset genetic cohort included 97 females and 71 males, arguing against a universal sex ratio.

10. Diagnostics

Clinical evaluation

Diagnosis integrates detailed prenatal/perinatal and three-generation family history, seizure semiology, serial developmental examination, neurological and dysmorphology assessment, video-EEG, brain MRI using an epilepsy protocol, and targeted metabolic testing. EEG confirms epilepsy type and encephalopathic patterns but is rarely gene-specific. MRI identifies malformations, injuries, or structural mimics.

Urgent treatable investigations in neonatal/infantile onset can include glucose, electrolytes, calcium, magnesium, blood gas/lactate, ammonia, liver studies, plasma amino acids, acylcarnitines, urine organic acids, CSF studies where indicated, and therapeutic trials/testing for pyridoxine-, pyridoxal-phosphate-, folinic-acid-, biotin-, or glucose-transporter-responsive disease. In one prospective cohort, metabolic testing was diagnostic in 3/41 tested children, all with biotinidase deficiency; vitamin-responsive disease was the only factor independently associated with better seizure control. This supports urgent testing even though the yield is lower than sequencing.

Genetic workflow

A practical workflow is:

Rapid trio genome or exome sequencing for critically ill neonates/infants where available.
Otherwise, trio exome/genome or a comprehensive epilepsy/DEE panel with CNV calling.
Chromosomal microarray when congenital anomalies, dysmorphism, or CNV disease is suspected, or when sequencing does not provide reliable CNV detection.
Mitochondrial genome, repeat-expansion, methylation, RNA, or biochemical testing when phenotype indicates.
Reanalysis after 12–24 months and consideration of WGS, long-read sequencing, RNA sequencing, or tissue-specific testing for mosaicism after a nondiagnostic result.
Parental testing, segregation, ACMG/AMP classification, and pre/post-test genetic counseling.

A 2024 first-line WES series found pathogenic variants in 35/82 (43%); 66% were de novo, and missense variants comprised 75%. A prospective early-infantile cohort achieved a molecular diagnosis in 53/77 (69%), with NGS yield 51% and microarray yield 14%. Rapid genome sequencing in infants with early seizures identified genetic etiologies in 46%, produced clinical utility in 56%, and informed prognostic counseling in 86%, with median 37 days to result. (scheffer2024developmentalandepileptic pages 9-11, chang2023genetictestingin pages 4-6)

Testing after a negative exome can still be useful because WGS detects noncoding, structural, and difficult-to-sequence variants. Single-gene testing is appropriate when a phenotype is highly specific, but broad sequencing usually performs better for heterogeneous DEE. Karyotype and FISH have limited first-line roles unless a known rearrangement is suspected.

Differential diagnoses include acquired hypoxic–ischemic injury, infection, immune encephalitis, structural epilepsy, cerebral malformation, metabolic/vitamin-responsive epilepsy, neurodegenerative disease, and developmental disability with coincidental epilepsy. There is no general newborn-screening program for DEE, although individual metabolic causes may be included in national panels.

11. Outcome and prognosis

Outcome is strongly genotype-, variant-, and syndrome-dependent. Many affected people have lifelong intellectual and adaptive disability, impaired communication, dependence for daily activities, movement disorder, feeding problems, orthopedic complications, and drug-resistant epilepsy. Seizure freedom does not necessarily reverse the primary developmental encephalopathy.

In 510 people with common genetic DEEs, convulsive status epilepticus occurred in 47%, nonconvulsive status in 19%, and 42/510 (8%) died. Overall mortality was 6.1 per 1,000 person-years; 19/42 deaths were SUDEP, giving an estimated SUDEP rate of 2.8 per 1,000 person-years. CSE occurred in 89% of the Dravet subgroup and was also frequent in KCNT1- and SCN2A-related disease. SUDEP was observed in SCN1A-, SCN2A-, SCN8A-, and STXBP1-associated groups. These data support gene-specific emergency plans and SUDEP counseling. (scheffer2024developmentalandepileptic pages 19-21)

Poor prognostic factors include early and severe epilepsy, recurrent status, profound early developmental impairment, pathogenic mechanisms producing major protein dysfunction, progressive/metabolic disease, and severe feeding or respiratory comorbidity. In Dravet syndrome, poorer baseline language, greater initial epilepsy severity, and a worse SCN1A genetic score predicted poorer ten-year development. More than 90% of caregivers reported adverse effects on their health and career opportunities. (scheffer2024developmentalandepileptic pages 17-19)

No valid umbrella five- or ten-year survival percentage exists. Prognosis should be communicated by gene, variant mechanism, syndrome, and individual trajectory.

12. Treatment

Standard multimodal care

Treatment includes syndrome-appropriate antiseizure medication, emergency rescue medication and status plan, dietary therapy, and—when indicated—epilepsy surgery, vagus-nerve stimulation, or other neuromodulation. Developmental, physical, occupational, speech/augmentative-communication, feeding, sleep, behavioral, orthopedic, visual, and psychosocial care are essential.

Suggested MAXO mappings include antiseizure pharmacotherapy, electroencephalography, brain MRI, molecular genetic testing, ketogenic diet therapy, vagus-nerve stimulation, epilepsy surgery, physical therapy, occupational therapy, speech therapy, gastrostomy, genetic counseling, and seizure-emergency planning. Exact MAXO identifiers should be resolved against the current ontology release.

Genotype- and syndrome-directed examples

SCN1A loss-of-function Dravet syndrome: valproate, clobazam, stiripentol, cannabidiol, and fenfluramine are commonly used according to jurisdiction and patient profile. Sustained sodium-channel blockers can aggravate seizures in many patients and are generally avoided, although emergency-use decisions remain clinical.
KCNQ2/SCN2A/SCN8A channelopathy: sodium-channel blockers may be beneficial in selected gain-of-function phenotypes but harmful in others; functional direction and age-dependent phenotype matter.
TSC1/TSC2 with infantile spasms: vigabatrin is an important syndrome-specific treatment; mTOR inhibition is relevant for selected tuberous-sclerosis manifestations.
SLC2A1 deficiency: ketogenic diet directly supplies alternative cerebral fuel.
Pyridoxine/PLP/folinic acid/biotin-responsive disorders: prompt vitamin/cofactor therapy can be transformative.
Focal structural/mTOR-pathway disease: resective or ablative surgery can be considered when a localized epileptogenic lesion is demonstrated.

Genetic diagnosis prompted medication changes in nearly half of patients in some reviewed series, but precision benefit is uneven and many interventions remain based on small cohorts or mechanistic inference. (specchio2024theexpandingfield pages 6-8)

Emerging therapies and trials

ETX101, SCN1A-positive Dravet syndrome: AAV9 delivers a GABAergic regulatory element and engineered transcription factor to increase endogenous SCN1A transcription. WAYFINDER, NCT06112275, is Phase 1/2, active but not recruiting, with 4 children enrolled; EXPEDITION, NCT06283212, is Phase 1/2, active but not recruiting, with 5 children. Primary outcomes include safety, monthly seizure-frequency change, prolonged seizures/status, and development. These are early safety/efficacy studies, not evidence of established benefit. URLs: https://clinicaltrials.gov/study/NCT06112275 and https://clinicaltrials.gov/study/NCT06283212. (NCT06112275 chunk 1, NCT06283212 chunk 1)
STXBP1 gene therapy: CAP-002, NCT06983158, entered Phase 1/2 pediatric evaluation but the retrieved record reports termination after enrollment of one participant; no efficacy conclusion is possible. URL: https://clinicaltrials.gov/study/NCT06983158. (NCT06983158 chunk 2)
Ataluren for nonsense variants: NCT02758626 was a completed Phase 2 randomized crossover trial in CDKL5 or Dravet cases with nonsense mutations, enrolling 15 children. It tested premature-stop-codon read-through; the record alone does not establish efficacy. URL: https://clinicaltrials.gov/study/NCT02758626. (NCT02758626 chunk 1, NCT02758626 chunk 2)
CDKL5 hyperthermic baths: NCT06447675 was an eight-person feasibility study of 20-minute daily 40–42°C baths; a 34-person PROBE trial, NCT07602205, is planned. This unconventional intervention lacks established efficacy and should only be considered in a research protocol with safety oversight. URLs: https://clinicaltrials.gov/study/NCT06447675 and https://clinicaltrials.gov/study/NCT07602205. (NCT06447675 chunk 1, NCT07602205 chunk 1)
RNA therapeutics: antisense oligonucleotides have improved phenotypes in preclinical SCN1A, SCN2A, SCN8A, and KCNT1 models. TANGO-type approaches increase productive gene output. Human efficacy and long-term neurodevelopmental effects remain unproven. (scheffer2024developmentalandepileptic pages 17-19)

No curative therapy is currently established for genetic DEE as a group. Authoritative reviews emphasize that trial endpoints should include development, behavior, sleep, motor function, and caregiver burden in addition to seizures. (specchio2024theexpandingfield pages 1-6, specchio2024theexpandingfield pages 17-21)

13. Prevention

Primary prevention by lifestyle modification or vaccination is not applicable to a spontaneous pathogenic variant. Relevant preventive strategies are:

Reproductive prevention/options: genetic counseling, parental segregation and mosaicism testing, carrier testing for recessive/X-linked disease, prenatal diagnosis, and preimplantation genetic testing when the familial variant is known.
Secondary prevention: rapid genetic/metabolic diagnosis, early syndrome-specific treatment, developmental intervention, and cascade testing where relatives may carry a pathogenic variant.
Tertiary prevention: individualized status plans, rescue medication, medication adherence, trigger management, drowning and bathing precautions, sleep and respiratory management, feeding/aspiration care, bone health, and explicit SUDEP counseling.

Population newborn genomic screening for DEE is not standard. Some treatable metabolic causes are detected by conventional newborn screening, depending on jurisdiction.

14. Other species and natural disease

DEE is not a transmissible disease and has no zoonotic potential. Homologous epilepsy/neurodevelopmental phenotypes can occur naturally in veterinary species, but “genetic DEE” is not a single cross-species veterinary diagnosis. Gene- and breed-specific entries should be sought in OMIA and the Vertebrate Breed Ontology rather than inferred from the human umbrella.

Orthologues of major genes—including SCN1A, SCN2A, KCNQ2, STXBP1, CDKL5, CHD2, and SYNGAP1—are evolutionarily conserved across mammals and many vertebrates, enabling comparative study of channel, synaptic, and developmental mechanisms. NCBI Taxonomy identifiers commonly used in research include human 9606, mouse 10090, zebrafish 7955, fruit fly 7227, and C. elegans 6239.

15. Model organisms and experimental systems

Models include knock-out, knock-in, haploinsufficient, conditional, and humanized mice; zebrafish, Drosophila, Xenopus, and C. elegans; heterologous electrophysiology systems; patient-derived iPSC neurons; CRISPR-isogenic lines; and cerebral organoids.

Applications: variant functional classification, developmental timing, cell-type-specific excitability, seizure-network analysis, transcriptomic/proteomic profiling, drug screening, viral-vector biodistribution, and gene/RNA-therapy proof of concept.

In SCN1A mouse models, viral delivery or transcriptional activation directed toward relevant brain regions or GABAergic neurons reduced hyperthermia-induced seizures; CAV-2 delivery to thalamus and hippocampus improved survival and spontaneous seizures. These are preclinical results and do not establish human safety or efficacy. (specchio2024theexpandingfield pages 14-17)

Patient-derived iPSC neurons preserve the human genetic background and can be paired with CRISPR-corrected controls; organoids permit study of early cortical development and cell-type interactions. Limitations include immature cellular states, variable differentiation, incomplete vascular/immune architecture, and poor modeling of long-range circuits and whole-organism pharmacology.

Animal-model limitations are equally important. Species differences in channel expression, brain development, and genetic background can alter seizure phenotypes. For example, some CHD2 mouse models do not develop seizures despite the human disorder, prompting use of zebrafish, frogs, patient-derived cells, and cortical organoids. (sun2024strategiesfordissecting pages 14-15)

Current expert assessment and priority gaps

The strongest expert consensus is that DEE care should move from electroclinical labels alone toward integrated electroclinical–genomic diagnosis, while retaining syndrome labels where they guide treatment and prognosis. Mechanism must be established at the variant level: the same gene family can contain both gain- and loss-of-function disease, making indiscriminate “gene-based” treatment unsafe. (specchio2024theexpandingfield pages 6-8)

Major gaps are unresolved genetic diagnoses; limited ancestry diversity; uncertain VUS interpretation; scarce longitudinal adult data; weak developmental biomarkers; inadequate natural-history controls; undermeasurement of sleep, movement, communication, and caregiver outcomes; and uncertain durability, immunogenicity, and developmental timing of gene/RNA therapies. International registries, functional assays, multi-omics, and prospective studies beginning before treatment are therefore priorities. (specchio2024theexpandingfield pages 1-6, specchio2024theexpandingfield pages 17-21)

Key recent sources

Scheffer IE et al. Developmental and epileptic encephalopathies. Nature Reviews Disease Primers. Published September 2024;10:61. DOI/URL: https://doi.org/10.1038/s41572-024-00546-6. Authoritative disease primer. (scheffer2024developmentalandepileptic pages 9-11, scheffer2024developmentalandepileptic pages 1-4)
Specchio N et al. The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives. Lancet Child & Adolescent Health. Published November 2024;8:821–834. DOI/URL: https://doi.org/10.1016/S2352-4642(24)00196-2. Expert review of mechanisms and emerging therapies. (specchio2024theexpandingfield pages 1-6, specchio2024theexpandingfield pages 17-21)
Chang Y-T et al. Genetic Testing in Children with Developmental and Epileptic Encephalopathies. Children. Published March 2023;10:556. DOI/URL: https://doi.org/10.3390/children10030556. (chang2023genetictestingin pages 4-6)
Cavirani B et al. Genetic Epilepsies and Developmental Epileptic Encephalopathies with Early Onset: A Multicenter Study. International Journal of Molecular Sciences. Published January 2024;25:1248. DOI/URL: https://doi.org/10.3390/ijms25021248. (cavirani2024geneticepilepsiesand pages 2-4, cavirani2024geneticepilepsiesand pages 4-6)
Donnan AM et al. Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic DEEs. Neurology. Published April 2023;100:e1712–e1722. DOI/URL: https://doi.org/10.1212/WNL.0000000000207080. (scheffer2024developmentalandepileptic pages 19-21)

Representative exact abstract wording

Recent abstracts describe DEEs as “severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment” and emphasize that impairment is “often related to both underlying genetic etiology and abnormal epileptiform activity.” A 2024 longitudinal Dravet abstract concluded that the “negative impact of epilepsy severity at baseline on long-term developmental outcomes highlights the importance of implementing early and focused therapies.” These quotations support the dual-causation model and early-intervention rationale, but do not imply that seizure suppression alone normalizes development. (scheffer2024developmentalandepileptic pages 1-4, scheffer2024developmentalandepileptic pages 17-19)

PMID note: DOI URLs are supplied for reliable record resolution. PMIDs should be imported directly from PubMed during database ingestion rather than inferred where they were not explicitly present in the retrieved source metadata.

References

(scheffer2024developmentalandepileptic pages 1-4): Ingrid E. Scheffer, Sameer Zuberi, Heather C. Mefford, Renzo Guerrini, and Amy McTague. Developmental and epileptic encephalopathies. Nature reviews. Disease primers, 10 1:61, Sep 2024. URL: https://doi.org/10.1038/s41572-024-00546-6, doi:10.1038/s41572-024-00546-6. This article has 157 citations.
(chang2023genetictestingin pages 4-6): Yu-Tzu Chang, Syuan-Yu Hong, Wei-De Lin, Chien-Heng Lin, Sheng-Shing Lin, Fuu-Jen Tsai, and I-Ching Chou. Genetic testing in children with developmental and epileptic encephalopathies: a review of advances in epilepsy genomics. Children, 10:556, Mar 2023. URL: https://doi.org/10.3390/children10030556, doi:10.3390/children10030556. This article has 31 citations.
(specchio2024theexpandingfield pages 1-6): Nicola Specchio, Marina Trivisano, Eleonora Aronica, Simona Balestrini, Alexis Arzimanoglou, Gaia Colasante, J Helen Cross, Sergiusz Jozwiak, Jo M Wilmshurst, Federico Vigevano, Stéphane Auvin, Rima Nabbout, and Paolo Curatolo. The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives. The Lancet. Child & adolescent health, 8 11:821-834, Nov 2024. URL: https://doi.org/10.1016/s2352-4642(24)00196-2, doi:10.1016/s2352-4642(24)00196-2. This article has 35 citations.
(scheffer2024developmentalandepileptic pages 9-11): Ingrid E. Scheffer, Sameer Zuberi, Heather C. Mefford, Renzo Guerrini, and Amy McTague. Developmental and epileptic encephalopathies. Nature reviews. Disease primers, 10 1:61, Sep 2024. URL: https://doi.org/10.1038/s41572-024-00546-6, doi:10.1038/s41572-024-00546-6. This article has 157 citations.
(scheffer2024developmentalandepileptic pages 19-21): Ingrid E. Scheffer, Sameer Zuberi, Heather C. Mefford, Renzo Guerrini, and Amy McTague. Developmental and epileptic encephalopathies. Nature reviews. Disease primers, 10 1:61, Sep 2024. URL: https://doi.org/10.1038/s41572-024-00546-6, doi:10.1038/s41572-024-00546-6. This article has 157 citations.
(cavirani2024geneticepilepsiesand pages 2-4): Benedetta Cavirani, Carlotta Spagnoli, Stefano Giuseppe Caraffi, Anna Cavalli, Carlo Alberto Cesaroni, Gianni Cutillo, Valentina De Giorgis, Daniele Frattini, Giulia Bruna Marchetti, Silvia Masnada, Angela Peron, Susanna Rizzi, Costanza Varesio, Luigina Spaccini, Aglaia Vignoli, Maria Paola Canevini, Pierangelo Veggiotti, Livia Garavelli, and Carlo Fusco. Genetic epilepsies and developmental epileptic encephalopathies with early onset: a multicenter study. International Journal of Molecular Sciences, 25:1248, Jan 2024. URL: https://doi.org/10.3390/ijms25021248, doi:10.3390/ijms25021248. This article has 24 citations.
(cavirani2024geneticepilepsiesand pages 4-6): Benedetta Cavirani, Carlotta Spagnoli, Stefano Giuseppe Caraffi, Anna Cavalli, Carlo Alberto Cesaroni, Gianni Cutillo, Valentina De Giorgis, Daniele Frattini, Giulia Bruna Marchetti, Silvia Masnada, Angela Peron, Susanna Rizzi, Costanza Varesio, Luigina Spaccini, Aglaia Vignoli, Maria Paola Canevini, Pierangelo Veggiotti, Livia Garavelli, and Carlo Fusco. Genetic epilepsies and developmental epileptic encephalopathies with early onset: a multicenter study. International Journal of Molecular Sciences, 25:1248, Jan 2024. URL: https://doi.org/10.3390/ijms25021248, doi:10.3390/ijms25021248. This article has 24 citations.
(specchio2024theexpandingfield pages 14-17): Nicola Specchio, Marina Trivisano, Eleonora Aronica, Simona Balestrini, Alexis Arzimanoglou, Gaia Colasante, J Helen Cross, Sergiusz Jozwiak, Jo M Wilmshurst, Federico Vigevano, Stéphane Auvin, Rima Nabbout, and Paolo Curatolo. The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives. The Lancet. Child & adolescent health, 8 11:821-834, Nov 2024. URL: https://doi.org/10.1016/s2352-4642(24)00196-2, doi:10.1016/s2352-4642(24)00196-2. This article has 35 citations.
(sun2024strategiesfordissecting pages 14-15): Jiawan Sun, Serena Noss, Deepro Banerjee, Maitreya Das, and Santhosh Girirajan. Strategies for dissecting the complexity of neurodevelopmental disorders. Trends in Genetics, 40:187-202, Feb 2024. URL: https://doi.org/10.1016/j.tig.2023.10.009, doi:10.1016/j.tig.2023.10.009. This article has 11 citations and is from a domain leading peer-reviewed journal.
(scheffer2024developmentalandepileptic pages 17-19): Ingrid E. Scheffer, Sameer Zuberi, Heather C. Mefford, Renzo Guerrini, and Amy McTague. Developmental and epileptic encephalopathies. Nature reviews. Disease primers, 10 1:61, Sep 2024. URL: https://doi.org/10.1038/s41572-024-00546-6, doi:10.1038/s41572-024-00546-6. This article has 157 citations.
(specchio2024theexpandingfield pages 6-8): Nicola Specchio, Marina Trivisano, Eleonora Aronica, Simona Balestrini, Alexis Arzimanoglou, Gaia Colasante, J Helen Cross, Sergiusz Jozwiak, Jo M Wilmshurst, Federico Vigevano, Stéphane Auvin, Rima Nabbout, and Paolo Curatolo. The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives. The Lancet. Child & adolescent health, 8 11:821-834, Nov 2024. URL: https://doi.org/10.1016/s2352-4642(24)00196-2, doi:10.1016/s2352-4642(24)00196-2. This article has 35 citations.
(NCT06112275 chunk 1): A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome (Australia Only). Encoded Therapeutics. 2024. ClinicalTrials.gov Identifier: NCT06112275
(NCT06283212 chunk 1): A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome. Encoded Therapeutics. 2024. ClinicalTrials.gov Identifier: NCT06283212
(NCT06983158 chunk 2): A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy. Capsida Biotherapeutics, Inc.. 2025. ClinicalTrials.gov Identifier: NCT06983158
(specchio2024theexpandingfield pages 17-21): Nicola Specchio, Marina Trivisano, Eleonora Aronica, Simona Balestrini, Alexis Arzimanoglou, Gaia Colasante, J Helen Cross, Sergiusz Jozwiak, Jo M Wilmshurst, Federico Vigevano, Stéphane Auvin, Rima Nabbout, and Paolo Curatolo. The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives. The Lancet. Child & adolescent health, 8 11:821-834, Nov 2024. URL: https://doi.org/10.1016/s2352-4642(24)00196-2, doi:10.1016/s2352-4642(24)00196-2. This article has 35 citations.
(NCT02758626 chunk 1): Ataluren for Nonsense Mutation in CDKL5 and Dravet Syndrome. NYU Langone Health. 2016. ClinicalTrials.gov Identifier: NCT02758626
(NCT02758626 chunk 2): Ataluren for Nonsense Mutation in CDKL5 and Dravet Syndrome. NYU Langone Health. 2016. ClinicalTrials.gov Identifier: NCT02758626
(NCT06447675 chunk 1): Liankun_Ren. Efficacy and Safety Evaluation of Hyperthermic Baths in the Treatment of Seizures in CDKL5 Deficiency Disorder. Xuanwu Hospital, Beijing. 2024. ClinicalTrials.gov Identifier: NCT06447675
(NCT07602205 chunk 1): Liankun_Ren. Efficacy and Safety of Daily Home-based Hyperthermic Baths for Reducing Epileptic Seizures in CDKL5 Deficiency Disorder: A PROBE Clinical Trial. Xuanwu Hospital, Beijing. 2026. ClinicalTrials.gov Identifier: NCT07602205

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Genetic Developmental and Epileptic Encephalopathy (DEE) — Comprehensive Research Report

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Genetic Developmental and Epileptic Encephalopathy

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1. Disease information

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2. Etiology, risk, protective factors, and gene–environment interaction

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