Autosomal Dominant Non-Syndromic Intellectual Disability

Genetic MONDO:0015802 Pathograph 32 Show in embeddings browser Non-Syndromic Intellectual Disability Intellectual Disability, Autosomal Dominant

Autosomal dominant non-syndromic intellectual disability is a genetically heterogeneous category in which intellectual and adaptive impairment initially lacks a recognizable syndromic pattern. Historical MRD-series diagnoses overlap with subsequently delineated neurodevelopmental syndromes, including disorders with epilepsy, behavioral differences and extra-neurological features. De novo variants are common in severe sporadic cohorts, but inherited variants and parental mosaicism also occur. Haploinsufficiency, gain of function and other altered-function mechanisms depend on the gene and allele; neither complete penetrance nor a uniform reduction of protein abundance defines this category. Candidate-gene sequencing identified SYNGAP1-related disease in 2009, followed by wider discovery through trio exome sequencing. Representative mechanisms affect synaptic function, gene regulation, cytoskeletal dynamics and neuronal development. Their inclusion here does not imply that every subtype follows one causal sequence. This entry retains its existing class-level scope and subtype identities while distinguishing that scope from individual clinical syndromes.

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Inheritance

Autosomal dominant inheritance HP:0000006

A heterozygous pathogenic variant can cause disease through a gene- and allele-specific mechanism. De novo variants are frequent in selected severe sporadic cohorts, while vertical transmission and parental mosaicism are documented. Penetrance and expressivity vary; a negative family history does not exclude a genetic diagnosis.

Autosomal dominant inheritance Expressivity: VARIABLE

Show evidence (3 references)

PMID:19196676 SUPPORT Human Clinical

"These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation."

First demonstration that de novo truncating variants in a single autosomal gene cause non-syndromic ID by an autosomal dominant mechanism.

PMID:29861108 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In two individuals, variants were inherited from a similarly affected parent, while all other variants (n = 34) occurred de novo."

The TLK2 series includes inherited and de novo variants; two additional probands had unknown inheritance. One affected mother had low-normal IQ, so dominant inheritance does not imply complete penetrance for ID.

PMID:28288114 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"one individual with an inherited nonsense variant from a father who is low-grade mosaic"

The CIC full text distinguishes transmission from a mosaic father from the other de novo or presumed germline-mosaic cases.

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Subtypes

Intellectual disability, autosomal dominant 22 (ZBTB18-related) MONDO:0012869

ZBTB18 hgnc:13030 Autosomal dominant inheritance

MONDO defines this concept as any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the ZBTB18 gene. ZBTB18 is already curated in this entry's `genetic:` block with its own primary-literature evidence and is assigned there to the chromatin and transcription module; this row adds the MONDO subtype identity that the gene record did not carry. ClinGen classifies the gene-disease relationship as Definitive, against `complex neurodevelopmental disorder`. Truncating alleles occur in the last exon and are not expected to undergo nonsense-mediated decay; selected missense alleles alter transcriptional repression in different ways.

Show evidence (2 references)

CGGV:assertion_d8ea518c-64da-4d4f-8551-66a005307e94-2026-05-22T100000.000Z SUPPORT Other

ClinGen's expert-panel gene-disease validity classification for this gene. The row also records which disease concept the panel curated against, which for this series is generally not the MRD-series term the subtype binds; the adnsid_clingen_disease_concept discussion on this entry collects that observation across all the subtypes.

CGGV:assertion_d8ea518c-64da-4d4f-8551-66a005307e94-2026-05-22T100000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other

"Nonsense and frameshift variants lead to a premature termination codon in the last (second) exon and are not expected to result in nonsense-mediated decay."

Expert synthesis: predicted decay escape means truncation must not be equated with transcript loss; altered transcriptional repression remains variant-dependent.

Intellectual disability, autosomal dominant 41 (TBL1XR1-related) MONDO:0014842

TBL1XR1 hgnc:29529 Autosomal dominant inheritance

MONDO defines this concept as any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the TBL1XR1 gene. TBL1XR1 encodes an F-box-like/WD40 repeat-containing protein acting in nuclear-receptor-mediated transcription, which places the subtype in this entry's chromatin and transcription module. ClinGen classifies the relationship as Definitive, against `complex neurodevelopmental disorder`. A caregiver-reported survey of 41 individuals described marked language impairment and regression in a subset. Recruitment, recall and incomplete molecular verification limit generalization; regression does not itself prove neurodegeneration.

Show evidence (4 references)

CGGV:assertion_8352a921-43c0-4097-9147-2618a4165b57-2020-07-07T170000.000Z SUPPORT Other

PMID:38378692 SUPPORT INDIRECT BACKGROUND Human Clinical

"TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood"

States the gene's molecular role and its established status as a neurodevelopmental disease gene. Quoted from the survey study's background rather than from its own results.

PMID:38378692 SUPPORT Human Clinical

"Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain."

The survey result behind the statement that language is the most severely affected domain.

+ 1 more reference

Intellectual disability, autosomal dominant 43 (HIVEP2-related) MONDO:0014858

HIVEP2 hgnc:4921 Autosomal dominant inheritance

MONDO defines this concept as any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the HIVEP2 gene. HIVEP2 encodes a large transcription factor regulating neurodevelopmental pathways, placing the subtype in this entry's chromatin and transcription module. No ClinGen Gene-Disease Validity curation was found for HIVEP2 in the gene-validity release read for this pass, searched by gene symbol across the full download. The subtype therefore rests on primary-literature series alone. Those series report dysmorphic features alongside the developmental delay, which is the same non-syndromic boundary problem this entry already documents for SYNGAP1, TRIO, MED13L and KMT5B.

Show evidence (2 references)

PMID:27003583 SUPPORT Human Clinical

"Here, we describe six patients with developmental delay, intellectual disability, and dysmorphic features with de novo likely gene-damaging variants in HIVEP2 identified by whole-exome sequencing (WES)."

Six further probands with de novo likely gene-damaging HIVEP2 variants, and the source of the dysmorphism caveat recorded above.

PMID:27003583 SUPPORT INDIRECT BACKGROUND Human Clinical

"HIVEP2 encodes a large transcription factor that regulates various neurodevelopmental pathways."

Places HIVEP2 in this entry's chromatin and transcriptional regulation module.

Intellectual disability, autosomal dominant 45 (CIC-related) MONDO:0030910

CIC hgnc:14214 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records CIC as its causal gene by RO:0004003. CIC encodes the transcriptional repressor capicua, which forms a repressor complex with ataxin 1, so the subtype is a chromatin and transcription module lesion. ClinGen classifies the relationship as Definitive, against `complex neurodevelopmental disorder`. The human probands were ascertained by reverse phenotyping from conditional mouse mutants rather than from a human non-syndromic intellectual disability cohort, which is worth recording because the ascertainment route shapes which features get reported.

Show evidence (2 references)

CGGV:assertion_a0f9a222-8872-4054-b767-25f8fb4e404a-2023-01-18T110000.000Z SUPPORT Other

PMID:28288114 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"one individual with an inherited nonsense variant from a father who is low-grade mosaic"

The full text identifies four de novo variants and one variant inherited from a mosaic father among the five initial individuals; two additional siblings suggest parental germline mosaicism. This corrects the abstract shorthand describing all five as de novo.

Intellectual disability, autosomal dominant 46 (KCNQ5-related) MONDO:0030911

KCNQ5 hgnc:6299 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records KCNQ5 as its causal gene by RO:0004003. KCNQ5 is widely expressed in the brain and generates the neuronal M-type potassium current. Frog-oocyte assays found both reduced and increased channel function for disease-associated variants. This subtype follows the altered-protein-activity branch; the assays do not directly establish an identical excitability change in patients for both directions. No ClinGen Gene-Disease Validity curation was found for KCNQ5 in the gene-validity release read for this pass, searched by gene symbol across the full download.

Show evidence (3 references)

PMID:28669405 SUPPORT Human Clinical

"Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four)."

The four-proband series establishing de novo KCNQ5 missense variants as a cause of intellectual disability.

PMID:28669405 SUPPORT INDIRECT BACKGROUND Human Clinical

"KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current."

Channel-function background; this is not a direct measurement of patient neuronal excitability.

PMID:28669405 SUPPORT In Vitro

"Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology."

Oocyte electrophysiology demonstrates bidirectional changes in channel function. The proposed neuronal consequences are not a direct measurement in patient neurons.

Intellectual disability, autosomal dominant 47 (STAG1-related) MONDO:0030912

STAG1 hgnc:11354 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records STAG1 as its causal gene by RO:0004003. STAG1 belongs to the STAG subunit of the core cohesin complex, making this subtype a cohesinopathy. ClinGen classifies the relationship as Definitive, against `complex neurodevelopmental disorder`. Its non-syndromic placement conflicts with its clinical description: MONDO itself also asserts MONDO:0030912 as a subclass of `multiple congenital anomalies/dysmorphic syndrome-intellectual disability`, so the two placements contradict each other within one ontology, and the defining case series reports shared facial features and calls the phenotype syndromic.

Show evidence (4 references)

CGGV:assertion_30cc66e4-e3cf-428d-9f27-58e8427c94f1-2022-09-20T060000.000Z SUPPORT Other

PMID:28119487 SUPPORT Human Clinical

"We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation."

The defining series, and the source of the observation that the authors themselves describe the phenotype as syndromic.

PMID:28119487 SUPPORT Human Clinical

"The 17 patients shared common facial features, with wide mouth and deep-set eyes."

The specific shared dysmorphic findings behind the syndromic characterisation.

+ 1 more reference

Clark-Baraitser syndrome (TRIP12-related, MRD49) MONDO:0030914

TRIP12 hgnc:12306 Autosomal dominant inheritance

The one member of this series MONDO labels with an eponym rather than an MRD number; `MRD49` and `intellectual disability, autosomal dominant 49` are both MONDO synonyms of the same class, and MONDO asserts it as a direct subclass of this entry's own term with TRIP12 as its causal gene by RO:0004003. TRIP12 encodes a HECT-domain E3 ubiquitin ligase on chromosome 2q36.3 and acts through haploinsufficiency, with variant-level support from reduced transcript abundance for one splice allele. Its proposed ubiquitin-proteasome consequences are distinct from the synaptic, chromatin and cytoskeletal examples in the graph. MONDO cross-references the class to both OMIM:617752 and OMIM:300602. ClinGen classifies the gene-disease relationship as Definitive, against `complex neurodevelopmental disorder`, and a peripheral-blood DNA methylation episignature has been reported. This is an adjunct to variant interpretation; two affected discovery samples were excluded as outliers, so the study does not establish perfect sensitivity for all alleles.

Show evidence (5 references)

CGGV:assertion_011b99b3-0d17-4615-800e-36f4bacd8117-2022-04-05T060000.000Z SUPPORT Other

PMID:36430143 SUPPORT BACKGROUND Human Clinical

"Clark-Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene."

Establishes that the eponymous syndrome is TRIP12-related and autosomal dominant.

PMID:36430143 SUPPORT Human Clinical

"We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 variants, establishing its utility as a clinical biomarker for Clark-Baraitser syndrome."

Peripheral-blood classifier development and validation. Two discovery outliers were excluded; this supports a potential diagnostic adjunct, not universal sensitivity or a brain mechanism.

+ 2 more references

Intellectual disability, autosomal dominant 50 (NAA15-related) MONDO:0030916

NAA15 hgnc:30782 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records NAA15 as its causal gene by RO:0004003. NAA15 is the auxiliary subunit of the NatA N-terminal acetyltransferase complex, and haploinsufficiency is supported by both transcript degradation and copy-number deletions. ClinGen classifies the relationship as Definitive but curates it explicitly against `syndromic intellectual disability`, and the defining 38-individual cohort reports craniofacial dysmorphology, congenital cardiac anomalies and seizures in some subjects - so both the expert panel and the primary cohort contradict a non-syndromic placement.

Show evidence (4 references)

CGGV:assertion_f9732e0c-1306-4fb5-b1b3-873258903e75-2022-01-05T170000.000Z SUPPORT Other

PMID:29656860 SUPPORT Human Clinical

"Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder."

The 38-individual cohort establishing NAA15 as a dominant neurodevelopmental gene.

PMID:29656860 SUPPORT Human Clinical

"Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects."

The extra-cognitive features behind the syndromic caveat recorded above.

+ 1 more reference

Intellectual disability, autosomal dominant 51 (KMT5B-related) MONDO:0030917

KMT5B hgnc:24283 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records KMT5B as its causal gene by RO:0004003. KMT5B is already curated in this entry's `genetic:` block with its own primary-literature evidence, including the caveat that the recurring macrocephaly and overgrowth constitute an emerging recognisable gestalt; this row adds the MONDO subtype identity that the gene record did not carry. ClinGen classifies the relationship as Definitive, against `complex neurodevelopmental disorder`. A `stubs/Intellectual_Disability_Autosomal_Dominant_51.yaml` entry proposes this same MONDO class as a standalone Disease; that stub is deliberately left in place rather than resolved here, because promoting it is a lump/split decision about the whole series and not about one member of it.

Show evidence (1 reference)

CGGV:assertion_885d56b0-a2b0-4a3d-9f11-4034298e074e-2022-04-08T072351.945Z SUPPORT Other

Intellectual disability, autosomal dominant 53 (CAMK2A-related) MONDO:0030919

CAMK2A hgnc:1460 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records CAMK2A as its causal gene by RO:0004003. CAMK2A is already curated in this entry's `genetic:` block with its own primary-literature and functional evidence, and is assigned there to the synaptic transmission and plasticity module; this row adds the MONDO subtype identity that the gene record did not carry. ClinGen classifies the relationship as Definitive, against `complex neurodevelopmental disorder`.

Show evidence (1 reference)

CGGV:assertion_82e77410-49d7-41b8-a5b8-278afac7dc26-2024-10-15T100000.000Z SUPPORT Other

Intellectual disability, autosomal dominant 54 (CAMK2B-related) MONDO:0030920

CAMK2B hgnc:1461 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records CAMK2B as its causal gene by RO:0004003. This is the paralogue subtype of MRD53: CAMK2A and CAMK2B were established together in one multi-centre trio-sequencing study, and both belong to this entry's synaptic transmission and plasticity module. No ClinGen Gene-Disease Validity curation was found for CAMK2B in the gene-validity release read for this pass, searched by gene symbol across the full download. CAMK2A is curated there as Definitive, so the asymmetry is a gap in ClinGen coverage rather than a negative assessment of CAMK2B.

Show evidence (1 reference)

PMID:29100089 SUPPORT Human Clinical

"Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability."

The joint study establishing both CAMK2A and CAMK2B as de novo heterozygous causes of intellectual disability.

Intellectual disability, autosomal dominant 55, with seizures (NUS1-related) MONDO:0030921

NUS1 hgnc:21042 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records NUS1 as its causal gene by RO:0004003. The gene-disease link was established in developmental and epileptic encephalopathy cohorts rather than in non-syndromic intellectual disability series. ClinGen curates NUS1 as Definitive for `progressive myoclonus epilepsy`, a different disease concept from the one MONDO places here, so the two resources disagree about what the NUS1 phenotype is rather than about whether the gene is causal.

Show evidence (2 references)

CGGV:assertion_e50efc63-0235-4c75-a4ab-6c129485a117-2025-05-20T160000.000Z SUPPORT Other

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 the causal link for NUS1, in a developmental and epileptic encephalopathy series rather than a non-syndromic intellectual disability one.

Intellectual disability, autosomal dominant 56 (CLTC-related) MONDO:0030922

CLTC hgnc:2092 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records CLTC as its causal gene by RO:0004003. CLTC encodes clathrin heavy chain 1, and clathrin-mediated endocytosis serves synaptic vesicle recycling, so this subtype sits mechanistically beside MRD60 (AP2M1), which disables the AP-2 adaptor that recruits clathrin - two members of this series converging on one trafficking step. Like NUS1, CLTC was established as causal in a developmental and epileptic encephalopathy series. No ClinGen Gene-Disease Validity curation was found for CLTC in the gene-validity release read for this pass, searched by gene symbol across the full download.

Show evidence (3 references)

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 the causal link for CLTC in the same whole-genome sequencing series that established NUS1.

PMID:41091397 SUPPORT Human Clinical

"The spectrum of CLTC variants, causing intellectual developmental disorder 56 (OMIM 617854) has been expanded by two novel variants."

Ties the CLTC gene-disease relationship explicitly to the OMIM entity that MONDO:0030922 represents.

PMID:41091397 SUPPORT INDIRECT BACKGROUND Human Clinical

"Clathrin-mediated endocytosis is involved in synaptic vesicle recycling and pathogenic variants in the CLTC gene, encoding clathrin heavy chain 1 are associated with delayed development and cognitive difficulties."

Source for the gene product and for the synaptic-vesicle-recycling role that pairs this subtype with MRD60.

Intellectual disability, autosomal dominant 57 (TLK2-related) MONDO:0054837

TLK2 hgnc:11842 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records TLK2 as its causal gene by RO:0004003. TLK2 is a serine/threonine kinase whose physiological substrates include the H3-H4 chaperone ASF1 and histone H3, linking it to chromatin assembly and placing the subtype in this entry's chromatin and transcription module. ClinGen classifies the relationship as Definitive, against `complex neurodevelopmental disorder`. The defining 40-individual study calls the entity a distinct syndrome with a consistent facial gestalt and severe gastrointestinal involvement, and supports haploinsufficiency. RNA experiments demonstrated decay for two tested alleles, while a last-exon stop allele escaped decay. Some individuals had normal or borderline cognition, including a transmitting mother with low-normal IQ; neither every allele nor every carrier implies intellectual disability. The expert summary also notes possible dominant-negative effects for inactive kinase-domain alleles.

Show evidence (6 references)

CGGV:assertion_ecd1054d-80b0-4292-a901-65de788b7820-2024-06-05T100000.000Z SUPPORT Other

PMID:29861108 SUPPORT Human Clinical

"Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers"

The defining cohort, and the source of the observation that the authors describe a distinct syndrome rather than isolated cognitive impairment.

PMID:29861108 SUPPORT Human Clinical

"Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad..."

The recurrent extra-cognitive features behind the syndromic characterisation recorded above.

+ 3 more references

Intellectual disability, autosomal dominant 58 (SET-related) MONDO:0020847

SET hgnc:10760 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records SET as its causal gene by RO:0004003. SET is a component of the INHAT complex, which acts in transcriptional silencing, so the subtype is a chromatin and transcription module lesion and the first Nucleosome Assembly Protein family member implicated in intellectual disability. ClinGen classifies the relationship as Definitive, and this is the one gene in the series it curates against a plain `intellectual disability` concept rather than a complex or syndromic one. The defining report also describes an affected mother and child carrying a frameshift variant, making this subtype another instance of the entry-level caveat that autosomal dominant is not a synonym for de novo.

Show evidence (4 references)

CGGV:assertion_4d7c9aa2-0a9a-4359-af98-6097cc6a3b91-2021-11-17T170000.000Z SUPPORT Other

PMID:29688601 SUPPORT INDIRECT BACKGROUND Human Clinical

"We describe mutations in the "SET nuclear proto-oncogene" (SET), encoding a component of the "inhibitor of histone acetyltransferases" (INHAT) complex, involved in transcriptional silencing."

Establishes SET's molecular role and places the subtype in the chromatin and transcription module.

PMID:29688601 SUPPORT Human Clinical

"Additionally, an affected mother and child were detected who carried a frameshift variant in SET."

The transmitted lesion behind the caveat that this class is not exclusively de novo.

+ 1 more reference

Intellectual developmental disorder 59 (CAMK2G-related) MONDO:0032795

CAMK2G hgnc:1463 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records CAMK2G as its causal gene by RO:0004003. This is the third CAMK2 paralogue subtype in the series, alongside MRD53 (CAMK2A) and MRD54 (CAMK2B), with limited clinical evidence in the cited sources. ClinGen's Syndromic Disorders Gene Curation Expert Panel classifies the relationship as `Limited` and does so against MONDO:0032795 itself, the same identifier this row binds, so the validity assessment applies to this exact disease identifier. The mechanism is also not haploinsufficiency - the recurrent p.Arg292Pro variant acts as a gain of function - so it follows the altered-protein-activity branch. The expert summary considers three individuals with two missense alleles, extending beyond the two p.Arg292Pro cases in the cited functional study.

Show evidence (5 references)

CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2025-04-04T160000.000Z SUPPORT Other

PMID:30184290 SUPPORT Human Clinical

"Here, we identified a second, unrelated individual, with a de novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro assays to assess the impact of this mutation on CAMK2G and neuronal function."

The paper adds a second unrelated individual carrying p.Arg292Pro. This is the sample in this study, not a current total of all reported cases.

PMID:30184290 SUPPORT In Vitro

"We further found that the CAMK2G p.Arg292Pro mutation acts as a highly pathogenic gain-of-function mutation, leading to increased phosphotransferase activity and impaired neuronal maturation as well as impaired targeting of the nuclear CAMK2G isoform."

Kinase assays and cultured-neuron experiments support increased activity and abnormal maturation/localization. Separate in-utero mouse experiments tested migration. Kinase inactivation rescued arborization and migration but did not rescue abnormal nuclear targeting.

+ 2 more references

Intellectual developmental disorder 60 with seizures (AP2M1-related) MONDO:0032823

AP2M1 hgnc:564 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records AP2M1 as its causal gene by RO:0004003. AP2M1 encodes the mu subunit of the AP-2 adaptor complex, which acts in clathrin-mediated endocytosis and synaptic vesicle recycling. The subtype was established in developmental and epileptic encephalopathy cohorts around a single recurrent p.Arg170Trp missense variant, and the reported mechanism is functional impairment of the AP-2 complex rather than reduced gene dosage, so it follows the altered-activity and endocytosis branch. Transferrin uptake was tested in human cells and cultured mouse astrocytes; these experiments do not directly measure neuronal synaptic-vesicle recycling. It pairs mechanistically with MRD56 (CLTC), which encodes the clathrin coat that AP-2 recruits. ClinGen's Epilepsy Gene Curation Expert Panel classifies the relationship as Definitive, against `complex neurodevelopmental disorder`. This MONDO class is already cited as a differential diagnosis on `Cardiofacioneurodevelopmental_Syndrome`, which models the AP-2 assembly chaperone CCDC32; that record describes the differential, while this row places the concept in the MRD series, so the two are complementary rather than duplicative. The panel leaves the gene-wide mechanism unresolved; the functional claim here is limited to the experimentally tested recurrent allele.

Show evidence (5 references)

CGGV:assertion_800ffff6-7cf0-4131-aa96-e3bb4f0bde76-2024-10-01T040000.000Z SUPPORT Other

PMID:31104773 SUPPORT Human Clinical

"We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy."

The study establishing AP2M1 as causal, and the source of the endocytic mechanism statement.

PMID:31104773 SUPPORT Human Clinical

"We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures."

Source for the recurrent p.Arg170Trp variant recorded above.

+ 2 more references

Intellectual developmental disorder, autosomal dominant 73 (TAF4-related) MONDO:0957536

TAF4 hgnc:11537 Autosomal dominant inheritance

MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this entry's own term, MONDO:0015802, and records TAF4 as its causal gene by RO:0004003. It is the highest-numbered member of the series MONDO files under this entry. TAF4 is a subunit of the TFIID general transcription factor complex, so the subtype belongs to this entry's chromatin and transcription module and shares features with the other TAF-opathies. The defining cohort of eight individuals reports facial dysmorphisms alongside the intellectual disability and names the entity `TAF4-related NDD`, not a non-syndromic intellectual disability. No ClinGen Gene-Disease Validity curation was found for TAF4 in the gene-validity release read for this pass, searched by gene symbol across the full download. Seven of eight individuals had ID; one improved to normal cognitive performance. Loss of function was predicted from variant position rather than directly demonstrated for every allele, and mild facial findings did not define a recognizable gestalt.

Show evidence (4 references)

PMID:35904126 SUPPORT Human Clinical

"We here present a cohort of eight individuals, each carrying de novo putative loss-of-function (pLoF) variants in TAF4 and expressing phenotypes consistent with a neuro-developmental disorder (NDD)."

The defining cohort establishing TAF4 as a dominant neurodevelopmental disease gene.

PMID:35904126 SUPPORT Human Clinical

"We propose TAF4 as a novel dominant disease gene for NDD, and coin this novel disorder "TAF4-related NDD" (T4NDD)."

The authors' own naming of the entity, and the source of the observation that they do not describe it as non-syndromic.

PMID:35904126 SUPPORT Human Clinical

"We place T4NDD in the context of other disorders related to TFIID subunits, revealing shared features of T4NDD with other TAF-opathies."

Source for the TAF-opathy statement recorded above.

+ 1 more reference

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Mechanistic Hypotheses

The non-syndromic/syndromic boundary reflects depth of phenotyping rather than a distinct mechanism

nonsyndromic_boundary_is_ascertainment EMERGING

Evidence balance 3 support

The non-syndromic label can reflect the phenotype recognized at a particular age and depth of assessment. Larger gene-specific series may reveal recurrent clinical patterns. Tissue expression may influence presentation but does not by itself prove an exclusively cognitive phenotype. These explanations can coexist; this category does not establish a unique common disease mechanism.

Show evidence (3 references)

PMID:23020937 SUPPORT Human Clinical

"Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions."

Explicitly attributes syndromic/non-syndromic misclassification to bias in existing clinical syndrome descriptions.

PMID:23020937 SUPPORT Human Clinical

"The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes."

Notes that patients ascertained as non-syndromic frequently carry variants in genes catalogued as syndromic.

PMID:26989088 SUPPORT Human Clinical

"SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers."

Worked example of the predicted migration: SYNGAP1, first reported as a cause of NON-syndromic ID, is redescribed as a recognisable developmental and epileptic encephalopathy once a larger series is phenotyped.

Regulatory variants may contribute to unresolved intellectual disability

adnsid_regulatory_variants EMERGING

Evidence balance 2 support

A severe-ID study of 47 coding-negative individuals identified de novo variants in fetal-brain enhancers. Candidate target assignment combined chromatin contacts, epigenomic correlations and proximity; only the POU3F3 enhancer cluster showed significant enrichment in the larger replication cohort. Selected variants increased or decreased reporter activity. For one SOX8 candidate, precise variant introduction into HEK293T cells reduced SOX8 expression, while separate CRISPR interference of the whole enhancer in neural progenitors supported its regulatory role. These experiments distinguish sequence alteration, regulatory target and expression consequence, but do not establish clinical causality or penetrance for every candidate allele.

Show evidence (2 references)

PMID:36854624 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"We found that regulatory DNMs were selectively enriched in fetal brain-specific enhancers as compared with adult brain enhancers."

Enrichment among regulatory candidates in a small, selected severe-ID cohort; it does not establish every variant as disease-causing.

PMID:36854624 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Using CRISPR-mediated mutation and editing of epigenomic marks, we show that DNMs at regulatory elements affect the expression of putative target genes."

The precise SOX8-associated allele was tested in HEK293T cells; neural-progenitor CRISPR interference perturbed the enhancer rather than reproducing that allele.

Discussions and Knowledge Gaps

Is `autosomal dominant non-syndromic intellectual disability` a disease concept that any gene-disease curation resource actually uses, or is it an ontology-only category that no expert panel curates against?

KNOWLEDGE GAP OPEN adnsid_clingen_disease_concept

Attached to

has_subtypes#

This entry now carries 18 `has_subtypes` rows, one per gene-defined MONDO class that MONDO asserts as a direct subclass of MONDO:0015802 and for which a causal gene is recorded. Sixteen of the 21 classes MONDO files here have a ClinGen Gene-Disease Validity curation, and not one is curated against a disease concept whose own label says non-syndromic. Eleven are curated against `complex neurodevelopmental disorder` (MONDO:0100038), one against `syndromic intellectual disability` (MONDO:0000508, NAA15), one against plain `intellectual disability` (MONDO:0001071, SET), one against `progressive myoclonus epilepsy` (MONDO:0020074, NUS1), one against `Coffin-Siris syndrome` (MONDO:0015452, ARID2) and one against an MRD-series identifier (MONDO:0032795, CAMK2G). That last is the only ClinGen record in the set naming an MRD term at all; it is graded `Limited`, and the same record describes the entity as `autosomal dominant syndromic intellectual disability`. The five genes with no ClinGen record are TAF4, HIVEP2, KCNQ5, CAMK2B and CLTC. The primary literature points the same way: the defining series for TLK2, STAG1, TAF4, NAA15 and HIVEP2 each report recurrent dysmorphic or extra-cognitive features, and two of them - TLK2 and STAG1 - call the entity syndromic in their own words. This is a second, independent line of evidence for the ascertainment-category hypothesis already recorded in `mechanistic_hypotheses`, and it is a different kind of evidence from the gene-by-gene reclassification anecdotes, because it is a property of the whole set. What it does not settle is whether the right response is to retire the category, to rebuild this entry as a Grouping over per-gene entries, or to keep it as the class-level home for shared diagnostic and counselling content while treating the non-syndromic label as ascertainment rather than biology.

Proposed experiments

Systematic census of the disease concepts expert panels curate these genes against

exp_adnsid_clingen_concept_census

For every gene-defined MONDO class asserted under MONDO:0015802, record the disease concept each of ClinGen, OMIM, Orphanet and GeneReviews curates the gene against, and test whether any resource independently uses a non-syndromic concept. A category that no curation resource instantiates is an ontology artefact; one that several use independently is a real clinical entity.

Which of the remaining Open Targets gene associations for MONDO:0015802 warrant curation as full genetic records in this entry, and which are better placed on gene-specific syndromic entries?

KNOWLEDGE GAP OPEN adnsid_opentargets_gene_backlog

Attached to

pathophysiology#Haploinsufficiency of a Dosage-Sensitive Neurodevelopmental Gene

Open Targets associates MONDO:0015802 with TLK2, ASH1L, STAG1, CLTC, CAMK2A, CIC, NAA15, TRIP12, KMT5B, TRIO, SET and DLG4. This entry curates four of those (CAMK2A, DLG4, KMT5B, TRIO) alongside six genes drawn from the general de novo ID literature (SYNGAP1, STXBP1, ZBTB18, GRIN2B, GATAD2B, MED13L). The gene list is deliberately illustrative of the major functional modules rather than exhaustive, so the remaining eight associations - TLK2, ASH1L, STAG1, CLTC, CIC, NAA15, TRIP12, SET - are recorded here as an explicit backlog rather than left as a silent omission. Triage is not purely mechanical: several of these are already described with recognisable syndromic features, so for each the curation decision is entangled with the syndromic/non-syndromic boundary question tracked in the adnsid_entity_boundary discussion. Note also that Open Targets associations are themselves reassessed over time, so the target list is a moving one. Update (series-019, issue 12226): seven of those eight - TLK2, STAG1, CLTC, CIC, NAA15, TRIP12 and SET - now have `has_subtypes` rows carrying the MONDO class and the gene binding, so they are no longer silent omissions; each row records whether the gene-disease pair looks syndromic and what ClinGen curated it against, which is the triage this discussion asked for. They are deliberately not promoted to full `genetic:` records, because that block remains illustrative of the functional modules by design. The eighth, ASH1L, resolves differently and is now closed: MONDO records ASH1L as the causal gene of `intellectual disability, autosomal dominant 52` (MONDO:0030918), a direct subclass of this entry's own term, and that class is already curated in this knowledge base as the standalone entry `Intellectual_Disability_Autosomal_Dominant_52`. ASH1L therefore needs neither a subtype row nor a genetic record here; it has a home.

Proposed experiments

Deep-phenotype triage of the remaining Open Targets associations

exp_adnsid_opentargets_gene_triage

For each of TLK2, ASH1L, STAG1, CLTC, CIC, NAA15, TRIP12 and SET, systematically review the published case series for recurrent dysmorphic, malformative, growth or neuroimaging features, and classify the gene-disease pair as (a) genuinely non-syndromic and therefore a curation target for this entry, or (b) syndromic and therefore better served by a dedicated gene-specific entry cross-referenced from here. The classification should record which specific feature drove any syndromic call, so the boundary decision is auditable rather than asserted.

How many autosomal dominant non-syndromic intellectual disability genes remain undiscovered, and why has discovery not plateaued?

KNOWLEDGE GAP OPEN adnsid_gene_list_incomplete

Attached to

pathophysiology#Haploinsufficiency of a Dosage-Sensitive Neurodevelopmental Gene

Modeling of de novo variant burden in 31,058 developmental-disorder trios predicted many undiscovered genes under specified mutation-rate and enrichment assumptions. Reduced penetrance or prenatal lethality are possible explanations for lower enrichment, not measured properties of every candidate. These estimates concern broader developmental disorders, not the number of AD-NSID genes specifically.

Proposed experiments

Scale trio sequencing to the calculated discovery-power threshold

exp_adnsid_scale_trio_sequencing

Expand pooled clinical and research parent-offspring trio sequencing toward the ~350,000-trio sample size calculated to give 80% power to detect a 10-fold de novo protein-truncating-variant enrichment for an average gene, and re-run gene-level enrichment testing.

Biobank penetrance test for low-enrichment candidate genes

exp_adnsid_penetrance_biobank

For candidate genes showing lower-than-expected de novo PTV enrichment, measure PTV frequency in unselected adult population biobanks to distinguish reduced penetrance from limited statistical power.

Show evidence (2 references)

PMID:33057194 SUPPORT Computational

"Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes."

Quantifies the size and expected properties of the undiscovered gene set.

PMID:33057194 SUPPORT INDIRECT Computational

"We calculated that a sample size of ~350,000 parent-offspring trios would be needed to have 80% power to detect a 10-fold enrichment of de novo PTVs for an average gene."

A modeled power calculation for an average gene and specified enrichment, not a guarantee of completing the gene list.

Which outcomes remain reversible at different ages in each gene-associated disorder, and how do mouse restoration experiments translate to humans?

HUMAN MODEL MISMATCH OPEN adnsid_critical_window_translational_validity

Attached to

pathophysiology#Altered Development and Function of Neural Circuits

Earlier SYNGAP1 mouse studies found developmental restrictions for particular outcomes, while later adult restoration rescued remote memory and selected epileptiform phenotypes. Reversibility is endpoint- and model-dependent. These findings support further study of treatment timing rather than a class-wide prohibition on adult molecular therapy.

Proposed experiments

Adult-rescue test in chromatin-module AD-NSID mouse models

exp_adnsid_adult_rescue_chromatin_module

Repeat the conditional adult-restoration experiment in mouse models of chromatin-module AD-NSID genes (e.g. Gatad2b, Zbtb18) to test whether the critical-window property generalises beyond synaptic genes or is specific to the SYNGAP1 spine-maturation mechanism.

Human cortical organoid staged-correction window mapping

exp_adnsid_organoid_window_mapping

Use human iPSC-derived cortical organoids carrying an AD-NSID variant with an inducible correction system, applying correction at staged timepoints, to map the equivalent plasticity window on a human rather than murine developmental timetable.

Compare age-dependent rescue across distinct endpoints

exp_adnsid_partial_rescue_endpoints

Compare memory, adaptive behaviors and seizure-related outcomes using the same restoration schedule, without assuming that all cognitive endpoints share one closure time.

Show evidence (2 references)

PMID:23141534 SUPPORT Model Organism

"Inducing SYNGAP1 mutations after critical developmental windows closed had minimal impact on spine synapse function, whereas repairing these pathogenic mutations in adulthood did not improve behavior and cognition."

Earlier endpoint-specific mouse findings must be interpreted alongside subsequent adult-rescue experiments.

PMID:31025938 SUPPORT DIRECT PRIMARY RESULT Model Organism

"genetic reversal ofSyngap1pathogenicity in adult mice reverses deficits in remote memory"

Adult genetic restoration improved remote contextual memory in mice; this is endpoint-specific preclinical evidence and does not establish human therapeutic efficacy.

Is autosomal dominant non-syndromic intellectual disability a coherent disease entity, or an ascertainment bin that should be dissolved into per-gene entries?

CONTROVERSY OPEN adnsid_entity_boundary

Attached to

pathophysiology#Impaired Intellectual and Adaptive Function

This category combines an inheritance pattern with the absence of a recognizable syndrome at ascertainment. It does not define one mechanism, complete penetrance, an exclusively de novo origin or a uniform trajectory. Several historical members now have gene-specific clinical descriptions. The existing subtype identities and historical context are retained while a future Grouping migration remains an explicit project-level scope decision.

Show evidence (2 references)

PMID:26989088 SUPPORT Human Clinical

The flagship member of the class redescribed as a recognisable syndrome, the core argument for dissolving the category.

PMID:23020937 SUPPORT Human Clinical

"After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity."

The counter-argument: the class does describe a real, quantified, shared genetic architecture even if its members are mechanistically diverse.

What is the population prevalence of AD-NSID under an explicit clinical and molecular case definition?

KNOWLEDGE GAP OPEN adnsid_population_prevalence

Published all-cause intellectual-disability prevalence and modeled birth prevalence of de novo developmental disorders describe different populations. Neither is a measured prevalence of AD-NSID. The DDD birth model includes recognizable syndromes and other dominant developmental disorders, while AD-NSID can also be inherited; the DDD estimate is therefore not an upper bound for this entire category.

Show evidence (2 references)

PMID:21236634 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"The prevalence of intellectual disability across all 52 studies included in the meta-analysis was 10.37/1000 population."

Provides the all-cause ID denominator; supports the order of magnitude but not an AD-NSID-specific rate.

PMID:28135719 SUPPORT INDIRECT PRIMARY RESULT Computational

"We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age."

Mutation-rate modeling estimates parental-age-dependent birth prevalence of broader de novo developmental disorders, not AD-NSID prevalence.

⚙

Pathophysiology

Heterozygous Pathogenic Variant in a Neurodevelopmental Gene

Heterozygous coding variants, splice variants or structural disruptions can arise de novo or be inherited. A pathogenic effect requires gene- and allele-specific evidence; rarity, de novo occurrence and population constraint alone do not establish causality. Loss of function and altered activity lead to different downstream branches. Candidate regulatory variants are discussed separately as an emerging hypothesis.

nervous system development GO:0007399

Downstream

Haploinsufficiency of a Dosage-Sensitive Neurodevelopmental Gene For dosage-sensitive genes, particular loss-of-function variants reduce functional gene product.

Altered Activity of a Neurodevelopmental Protein Some missense alleles alter activity without acting through simple haploinsufficiency.

Show evidence (3 references)

PMID:19196676 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation."

The discovery series links heterozygous truncating SYNGAP1 variants to dominant intellectual disability; the selected cohort does not establish a category-wide diagnostic yield.

PMID:29861108 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In two individuals, variants were inherited from a similarly affected parent, while all other variants (n = 34) occurred de novo."

PMID:28135719 SUPPORT INDIRECT PRIMARY RESULT Computational

"We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function."

The broader DDD cohort supports multiple mechanisms. Its modeled proportions are not AD-NSID penetrance or diagnostic yield.

Haploinsufficiency of a Dosage-Sensitive Neurodevelopmental Gene

Reduced functional dosage is an established mechanism for particular genes and variants. Transcript decay or loss of protein function can leave insufficient activity for neuronal development and function. The magnitude of reduction is assay- and allele-dependent, and a population constraint score is not a direct protein-dosage measurement. This branch does not represent activating or other altered-function alleles.

TRIP12 hgnc:12306 NAA15 hgnc:30782 TLK2 hgnc:11842

nervous system development GO:0007399

Downstream

Disrupted Synaptic Transmission and Plasticity For the synaptic module of AD-NSID genes, reduced gene dosage directly perturbs postsynaptic signalling complexes and receptor trafficking.

Disrupted Chromatin and Transcriptional Regulation For the chromatin/transcription module, reduced dosage of a chromatin-modifying or transcription-regulating factor dysregulates neurodevelopmental gene expression programmes.

Disrupted Neuronal Cytoskeletal Dynamics and Rho GTPase Signalling For the cytoskeletal module, reduced dosage of a cytoskeletal regulator or Rho GTPase pathway component impairs actin and microtubule dynamics in developing neurons.

Show evidence (2 references)

PMID:29861108 SUPPORT DIRECT PRIMARY RESULT In Vitro

"By analyzing TLK2 transcripts in cell lines of three different individuals, we were able to confirm that transcripts were subjected to NMD in two of them, causing haploinsufficiency of TLK2."

Patient-derived fibroblast and lymphoblastoid experiments support nonsense-mediated decay for two tested alleles; the tested last-exon stop variant escaped decay.

PMID:28288114 SUPPORT DIRECT PRIMARY RESULT In Vitro

"both the protein and RNA levels of CIC were reduced to almost 50%"

Measured in fibroblasts from one CIC patient; this is direct dosage evidence for that allele, not a universal 50% rule.

Altered Activity of a Neurodevelopmental Protein

Activating and other altered-function alleles require functional interpretation separate from protein abundance. CAMK2G p.Arg292Pro increases kinase activity despite reduced protein stability; KCNQ5 variants can increase or decrease channel function. These findings do not establish one direction of neuronal excitability for all affected genes. AP2M1 p.Arg170Trp impairs adaptor-complex function without decreasing expression or stability in the tested cell systems.

CAMK2G hgnc:1463 KCNQ5 hgnc:6299 AP2M1 hgnc:564

Downstream

Disrupted Synaptic Transmission and Plasticity Allele-specific changes in channel or signaling-protein function can alter neuronal and synaptic physiology; direction and intermediate steps vary.

Impaired Clathrin-Mediated Endocytosis The tested AP2M1 missense variant impairs clathrin-mediated transferrin uptake.

Show evidence (2 references)

PMID:30184290 SUPPORT DIRECT PRIMARY RESULT In Vitro

"although CAMK2GArg292Pro has reduced protein stability, this mutation does not lead to a loss of function of CAMK2G, but instead appears to result in a paradoxical gain‐of‐function."

HEK293T and primary-neuron expression experiments distinguish increased activity from reduced abundance. The developmental migration assay was separately performed in mouse embryos.

PMID:28669405 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology."

Frog-oocyte electrophysiology establishes altered channel function for tested KCNQ5 alleles. The proposed consequences for patient neurons remain an inference.

Impaired Clathrin-Mediated Endocytosis

AP2M1 p.Arg170Trp impairs AP-2-dependent endocytosis without reduced expression, stability or membrane recruitment in the tested systems. This is a variant-specific trafficking mechanism distinct from haploinsufficiency. Its contribution to neuronal synaptic function is inferred from AP-2 biology rather than directly measured by the transferrin assay.

AP2M1 hgnc:564

Downstream

Disrupted Synaptic Transmission and Plasticity Defective endocytic trafficking is proposed to impair neuronal and synaptic function; the cited assay does not resolve the neuronal intermediates.

Show evidence (1 reference)

PMID:31104773 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin."

Cellular transferrin uptake assays establish impaired endocytosis for the tested variant. They do not directly measure synaptic-vesicle recycling or cognition.

Disrupted Synaptic Transmission and Plasticity

Representative synaptic genes affect postsynaptic signaling, receptor trafficking or presynaptic vesicle release. SYNGAP1 restrains Ras-associated signaling and AMPA receptor insertion; STXBP1 participates in presynaptic release. Other genes and alleles have distinct effects. These routes can disturb plasticity without implying that every subtype has increased excitatory transmission.

glutamatergic (excitatory) neuron CL:0000679 hippocampal neuron CL:0002608

SYNGAP1 hgnc:11497 STXBP1 hgnc:11444 GRIN2B hgnc:4586 DLG4 hgnc:2903 CAMK2A hgnc:1460 CAMK2B hgnc:1461

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL regulation of synaptic plasticity GO:0048167 ⚠ ABNORMAL regulation of postsynaptic AMPA receptor levels GO:0099072 ⚠ ABNORMAL learning or memory GO:0007611 ↓ DECREASED

Ras GTPase-activating protein activity (SYNGAP1) GO:0005096 ↓ DECREASED

Downstream

Premature Dendritic Spine Maturation In the SYNGAP1 model, de-repressed excitatory synaptic signalling accelerates spine maturation and raises circuit excitability.

Show evidence (5 references)

PMID:23141534 SUPPORT INDIRECT BACKGROUND Other

"Mutations that cause intellectual disability (ID) and autism spectrum disorder (ASD) are commonly found in genes that encode for synaptic proteins."

States the synaptic-gene convergence that defines this pathophysiology module.

PMID:19196676 SUPPORT INDIRECT Human Clinical

"We sequenced the autosomal gene SYNGAP1, which encodes a ras GTPase-activating protein that is critical for cognition and synapse function, in 94 patients with nonsyndromic mental retardation."

Identifies the molecular function (Ras GTPase-activating protein) whose loss underlies the paradigmatic AD-NSID gene.

PMID:19196676 SUPPORT INDIRECT BACKGROUND Other

"SYNGAP1, a GTPase-activating protein that is selectively expressed in the brain and is a component of the NMDA-receptor complex, acts downstream of the receptor, blocking the insertion of the AMPA receptor at the postsynaptic membrane"

Describes the specific postsynaptic signalling step (restraint of AMPA receptor insertion via inhibition of RAS-ERK) that haploinsufficiency de-represses.

+ 2 more references

Disrupted Chromatin and Transcriptional Regulation

Chromatin modifiers and transcriptional regulators affect developmental gene expression through diverse mechanisms. Dosage loss is demonstrated for selected alleles, while missense variants can have distinct effects. Computational clustering identifies chromatin-related groups among broader ID-associated genes; it does not prove that every gene reduces protein abundance by half or changes the same targets.

ZBTB18 hgnc:13030 GATAD2B hgnc:30778 MED13L hgnc:22962 KMT5B hgnc:24283 TBL1XR1 hgnc:29529 HIVEP2 hgnc:4921 CIC hgnc:14214 TLK2 hgnc:11842 SET hgnc:10760 TAF4 hgnc:11537

chromatin organization GO:0006325 ⚠ ABNORMAL regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL

Downstream

Altered Development and Function of Neural Circuits Dysregulated transcriptional programmes alter neuronal differentiation and connectivity during cortical development.

Disrupted Synaptic Transmission and Plasticity Specific chromatin-regulator models alter dendritic and synaptic development; the direction and timing differ between genes.

Show evidence (5 references)

PMID:26748517 SUPPORT Computational

"Systematic identification of highly enriched functional themes and phenotypes revealed typical phenotype combinations characterizing process-defined groups of ID disorders, such as chromatin-related disorders and deficiencies in DNA repair."

Establishes chromatin regulation as a distinct, statistically coherent functional module among ID-associated genes.

PMID:26748517 SUPPORT Computational

"we show that ID-AGs are substantially enriched with co-expression, protein-protein interactions, and specific biological functions."

Demonstrates that the genetically heterogeneous ID gene set is functionally convergent rather than random.

PMID:25356899 SUPPORT Human Clinical

"A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%."

The recovered gene list is dominated by chromatin and transcriptional regulators, illustrating this module in a real ID cohort.

+ 2 more references

Disrupted Neuronal Cytoskeletal Dynamics and Rho GTPase Signalling

Cytoskeletal regulators influence neuronal migration, neurite growth and later synaptic function. In TRIO, selected GEF1-domain variants reduce Rac1 activation, whereas another tested variant outside that domain did not alter that assay. Cytoskeletal and synaptic processes overlap in time; this module is not necessarily upstream of all synaptic defects.

neuron CL:0000540 pyramidal neuron CL:0000598

TRIO hgnc:12303

actin cytoskeleton organization GO:0030036 ⚠ ABNORMAL neuron migration GO:0001764 ⚠ ABNORMAL neuron projection development GO:0031175 ⚠ ABNORMAL

Downstream

Altered Development and Function of Neural Circuits Disrupted migration, neurite development and plasticity can alter circuit organization through gene-specific intermediates.

Show evidence (4 references)

PMID:34200511 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Bibliomic analysis reveals that ID genes converge onto a few biological modules, including cytoskeleton dynamics, whose regulation depends on Rho GTPases transduction."

Establishes cytoskeletal dynamics under Rho GTPase control as one of the small number of convergent biological modules among ID genes.

PMID:34200511 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Thus, cytoskeleton alterations that have an impact on cell processes such as neuronal migration, neuritogenesis, and synaptic plasticity rebound on the overall establishment of an effective network and consequently on the cognitive phenotype."

Specifies the cellular processes disrupted and the propagation from cytoskeletal lesion through network formation to cognition.

PMID:34200511 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"More than 1000 genes have been found mutated in ID patients pointing out that, despite the common phenotype, the genetic bases are highly heterogeneous and apparently unrelated."

A review of broader intellectual disability genetics, not the size of the AD-NSID gene set.

+ 1 more reference

Premature Dendritic Spine Maturation

Mechanism confidence: Provisional

In the cited SYNGAP1 mouse model, reduced SynGAP dosage accelerates early postnatal dendritic spine-synapse maturation. This establishes a developmental phenotype in that model; it does not show that timing is the sole determinant of later function or that adult restoration cannot improve selected outcomes.

hippocampal neuron CL:0002608

SYNGAP1 hgnc:11497

dendritic spine development GO:0060996 ⚠ ABNORMAL

hippocampal formation UBERON:0002421

Downstream

Cortical Hyperexcitability Prematurely mature spines drive excessive excitability in the developing hippocampus.

Show evidence (1 reference)

PMID:23141534 SUPPORT Model Organism

"In the SYNGAP1 mouse model of ID/ASD, we found that dendritic spine synapses develop prematurely during the early postnatal period."

Directly demonstrates accelerated dendritic spine synapse maturation in a genetic mouse model of AD-NSID.

Cortical Hyperexcitability

Mechanism confidence: Provisional

SYNGAP1 mouse studies demonstrate increased excitability in developing hippocampal circuits. Later experiments also implicate ongoing adult SynGAP function in seizure susceptibility and interictal discharges. These findings are not a universal excitation model for every dominant ID subtype.

hippocampal neuron CL:0002608

SYNGAP1 hgnc:11497

excitatory postsynaptic potential GO:0060079 ↑ INCREASED

cerebral cortex UBERON:0000956 hippocampal formation UBERON:0002421

Downstream

Altered Development and Function of Neural Circuits Mistimed synaptic development is proposed to affect circuit refinement; the cited authors frame the causal interpretation as a model.

Seizures In SYNGAP1-related disease, altered excitability contributes to seizure susceptibility. Human epilepsy observations and adult mouse restoration support this route without establishing the intermediates or its applicability to every subtype.

Show evidence (1 reference)

PMID:23141534 SUPPORT Model Organism

"These data demonstrate that SynGAP protein acts as a critical developmental repressor of neural excitability that promotes the development of life-long cognitive abilities."

Frames the gene product's normal role as a developmental brake on excitability whose loss produces the hyperexcitable state.

Altered Development and Function of Neural Circuits

Mechanism confidence: Provisional

Changes in neuronal maturation and connectivity can contribute to cognitive impairment, while ongoing gene function also remains relevant in mature circuits. Earlier SYNGAP1 mouse experiments found developmental restrictions for particular behavioral outcomes. Later adult restoration rescued remote contextual memory and selected seizure and electrophysiological outcomes, while some other behaviors remained abnormal. These model-specific results do not establish a universal early deadline for human treatment.

neuron CL:0000540

cerebral cortex development GO:0021987 ⚠ ABNORMAL modulation of chemical synaptic transmission GO:0050804 ⚠ ABNORMAL

cerebral cortex UBERON:0000956 hippocampal formation UBERON:0002421

Animal models

Adult-restorable Syngap1 haploinsufficiency mouse Mouse rescues Adult restoration reverses selected functional outcomes despite developmental haploinsufficiency.

Downstream

Impaired Intellectual and Adaptive Function Altered neural development and ongoing circuit function can contribute to cognitive and adaptive impairment through subtype-specific intermediates.

Show evidence (3 references)

PMID:23141534 SUPPORT INDIRECT Model Organism

The earlier mouse experiment reported failure to rescue the tested behaviors in adulthood. Later experiments used different endpoints and found substantial adult reversibility.

PMID:23141534 SUPPORT INDIRECT Model Organism

"We propose that the pace of dendritic spine synapse maturation in early life is a critical determinant of normal intellectual development."

States the developmental-timing model linking synaptic maturation pace to intellectual outcome.

PMID:31025938 SUPPORT DIRECT PRIMARY RESULT Model Organism

"genetic reversal ofSyngap1pathogenicity in adult mice reverses deficits in remote memory"

Adult genetic restoration improved remote contextual memory in mice; this is endpoint-specific preclinical evidence and does not establish human therapeutic efficacy.

Impaired Intellectual and Adaptive Function

Intellectual and adaptive impairment begins during development. Severity and trajectory vary by diagnosis; a lack of a recognizable syndrome at presentation does not prove brain-restricted biology, absence of other features or a uniformly static course. Some gene-associated cohorts include regression or individuals without formal intellectual disability.

Downstream

Intellectual Disability The clinical phenotype records the intellectual and adaptive impairment represented by this terminal disease process.

Show evidence (4 references)

PMID:19196676 SUPPORT INDIRECT BACKGROUND Human Clinical

"The absence of specific dysmorphic features and growth abnormalities in these patients is consistent with the fact that SYNGAP1 is exclusively expressed in the brain."

An interpretation of three selected SYNGAP1 cases in the 2009 paper; brain expression does not prove that all associated clinical findings are restricted to cognition.

PMID:19196676 SUPPORT INDIRECT BACKGROUND Other

"Most patients have the nonsyndromic form of the disorder, which is characterized by the absence of associated morphologic, radiologic, and metabolic features."

Defines the non-syndromic category operationally.

PMID:33057194 SUPPORT INDIRECT Computational

"patients with DNMs in the same novel DD-associated gene were less phenotypically similar to each other, on average, than patients with DNMs in a consensus gene"

Phenotypic-similarity analysis in a broader developmental-disorder cohort; it supports an ascertainment hypothesis rather than proving every newly discovered gene is non-syndromic.

+ 1 more reference

⬡

Pathograph

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

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Phenotypes

Musculoskeletal 1

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:26989088 SUPPORT Human Clinical

"Hypotonia and unstable gait were frequent associated neurological features."

Reported as frequent in the 17-person SYNGAP1 series; no class-wide frequency is inferred.

Nervous System 6

Intellectual Disability OBLIGATE HP:0001249

Show evidence (2 references)

PMID:23033978 SUPPORT Human Clinical

"We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents."

Defines the core cognitive phenotype and the severity band of the cohorts in which the disease class was characterised.

PMID:19196676 SUPPORT Human Clinical

"Scores on the Mullen Scales of Early Learning and the Vineland Adaptive Behavior Scales showed profiles that were consistent with moderate-to-severe mental retardation in all patients."

Intellectual disability defines inclusion in this clinical category. This does not mean that every carrier of a variant in a listed gene has intellectual disability; some broader gene-associated cohorts include individuals with normal or borderline cognition.

Global Developmental Delay HP:0001263

Show evidence (2 references)

PMID:26989088 SUPPORT Human Clinical

"Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients."

Documents developmental delay as the presenting manifestation preceding an established ID diagnosis. Frequency is intentionally omitted: this snippet establishes the temporal ordering of the phenotype, not a cohort proportion, and no class-level frequency estimate exists.

PMID:19196676 SUPPORT Human Clinical

"Their early development was characterized by global delay and hypotonia, with the onset of walking at the age of 2 years."

Direct description of global developmental delay in molecularly confirmed AD-NSID.

Delayed Speech and Language Development HP:0000750

Show evidence (2 references)

PMID:19196676 SUPPORT Human Clinical

"The disruption of SYNGAP1 appears to be associated with a homogeneous clinical phenotype that is characterized by moderate-to-severe mental retardation accompanied by severe language impairment."

Identifies severe language impairment as a prominent feature of the paradigmatic AD-NSID entity.

PMID:38215144 SUPPORT Human Clinical

"He struggles with expressing themselves and forming complete sentences, relying mostly on gestures and pointing."

Expressive language impairment in a molecularly confirmed MRD22 case.

Seizures HP:0001250

Show evidence (3 references)

PMID:19196676 SUPPORT Human Clinical

"Two of the patients were mildly epileptic."

Epilepsy present in 2 of the 3 patients in the original non-syndromic SYNGAP1 series, and mild/controllable in both.

PMID:19557857 SUPPORT Human Clinical

"We identified de novo mutations in STXBP1 (nonsense, p.R388X; splicing, c.169+1G>A) in two patients with severe mental retardation and nonsyndromic epilepsy."

Documents epilepsy co-occurring with non-syndromic ID under a de novo autosomal dominant lesion.

PMID:38215144 SUPPORT Human Clinical

"However, he did not have growth retardation, microcephaly, corpus callosum hypoplasia, epilepsy, or dysmorphic facial features."

A reported ZBTB18 case lacked epilepsy. Different selected gene-specific cohorts do not provide a pooled class-wide frequency; the 17-person SYNGAP1 series included 16 with epilepsy and one with a single seizure.

Autistic Behaviour Autism HP:0000717

Show evidence (3 references)

PMID:26989088 SUPPORT Human Clinical

"intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients"

Autistic behaviour in 8 of 17 patients in a molecularly defined AD-NSID series.

PMID:21237447 SUPPORT Human Clinical

"We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism."

Establishes the conditional ("can be also associated") rather than obligate relationship between AD-NSID and autism.

PMID:19196676 REFUTE Human Clinical

"Nonverbal social interactions were within the normal range. In particular, evaluation of Patient 3 with the Autism Diagnostic Observation Schedule was negative."

The 2009 SYNGAP1 paper reports a negative formal ADOS assessment for patient 3 and other clinical observations for the remaining patients; it does not report three negative structured assessments.

Delayed Ability to Walk HP:0031936

Show evidence (1 reference)

PMID:19196676 SUPPORT Human Clinical

"Their early development was characterized by global delay and hypotonia, with the onset of walking at the age of 2 years."

Documents delayed independent ambulation in the index AD-NSID series. Frequency is intentionally omitted: the source describes three patients and reports no proportion.

🧬

Genetic Associations

SYNGAP1

Gene: SYNGAP1 hgnc:11497 gene page relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:19196676 SUPPORT Human Clinical

"We identified de novo truncating mutations (K138X, R579X, and L813RfsX22) in three of these patients."

Three independent de novo protein-truncating variants in 94 patients with non-syndromic ID.

PMID:21237447 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism."

The replication study identified three variants in 60 additional selected sporadic cases, including one patient with autism. Its reference to three of 94 in the background describes the original cohort.

STXBP1

Gene: STXBP1 hgnc:11444 gene page relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:19557857 SUPPORT Human Clinical

"These results suggest that STXBP1 disruption is associated with autosomal dominant mental retardation and nonsyndromic epilepsy."

Establishes STXBP1 as an autosomal dominant non-syndromic ID gene.

PMID:23020937 SUPPORT Human Clinical

"16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A)."

Independent replication of STXBP1 recurrence in a severe sporadic non-syndromic ID cohort.

ZBTB18

Gene: ZBTB18 hgnc:13030 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:38215144 SUPPORT Human Clinical

"Clinical whole exome sequencing revealed a de novo pathogenic variant in the ZBTB18 gene (c.1207delC, p. Arg403Alafs*60), which is a previously unreported site."

De novo frameshift variant in a patient diagnosed with MRD22.

PMID:38215144 SUPPORT Human Clinical

"It is noteworthy that only 31 cases of this disorder have been reported thus far."

A historical count reported in the 2024 article, not a current census or causal explanation of diagnostic classification.

GRIN2B

Gene: GRIN2B hgnc:4586 gene page relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (1 reference)

PMID:25356899 SUPPORT Human Clinical

GRIN2B recovered as a de novo cause in a moderate-to-severe ID trio cohort.

GATAD2B

Gene: GATAD2B hgnc:30778 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (1 reference)

PMID:25356899 SUPPORT Human Clinical

GATAD2B recovered as a de novo cause in a moderate-to-severe ID trio cohort.

MED13L

Gene: MED13L hgnc:22962 gene page relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (1 reference)

PMID:25356899 SUPPORT INDIRECT Human Clinical

Supports MED13L as a dominant ID gene in a cohort selected by severity, not by absence of syndromic features.

TRIO

Gene: TRIO hgnc:12303 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:27418539 SUPPORT INDIRECT BACKGROUND Human Clinical

"Trio is a Dbl family guanine nucleotide exchange factor (GEF) and a major regulator of neuronal development, controlling actin cytoskeleton dynamics by activating the GTPase Rac1."

Places TRIO in the cytoskeletal/Rho GTPase pathophysiology module.

PMID:27418539 SUPPORT Human Clinical

"We identified a frameshift deletion in TRIO that segregated autosomal dominantly. By scrutinising data from DDD, we further identified three unrelated children with a similar phenotype who harboured de novo missense mutations in TRIO."

Documents both an inherited autosomal dominant lesion and de novo lesions in the same gene, supporting the caveat that AD-NSID is not exclusively a de novo class.

PMID:27418539 SUPPORT INDIRECT Human Clinical

"Additionally, we identify pathogenic de novo missense mutations in TRIO associated with the same consistent phenotype, intellectual disability, microcephaly and dysmorphism with striking digital features."

The reported microcephaly and dysmorphism limit the use of this series as evidence for a non-syndromic category.

CAMK2A

Gene: CAMK2A hgnc:1460 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:29100089 SUPPORT Human Clinical

Establishes CAMK2A as a de novo heterozygous cause of intellectual disability in a multi-centre trio-sequencing cohort.

PMID:29100089 SUPPORT Model Organism

"We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment."

Neuronal migration was tested after in-utero electroporation of E14.5 mouse embryos; cultured-cell phosphorylation assays were separate. This is preclinical mechanism evidence, not a direct patient measurement.

DLG4

Gene: DLG4 hgnc:2903 gene page relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:33597769 SUPPORT Human Clinical

"The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder."

Predominantly neurodevelopmental findings in the 53-person series; this does not demonstrate absence of extra-neurological manifestations.

PMID:33597769 SUPPORT Human Clinical

"despite some overlapping features, a distinct facial dysmorphism could not be established"

Explicit negative finding for a recognisable dysmorphic gestalt, supporting non-syndromic classification on positive grounds rather than by default.

KMT5B

Gene: KMT5B hgnc:24283 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:35433545 SUPPORT INDIRECT BACKGROUND Human Clinical

"Recently, deleterious heterozygous variants in KMT5B were implicated in individuals with intellectual disability (ID) and/or autism spectrum disorder."

Establishes heterozygous KMT5B variants as a cause of intellectual disability, placing the gene in the chromatin/transcription module.

PMID:35433545 SUPPORT INDIRECT Human Clinical

"suggest that this gene should be considered in the differential diagnosis of neurodevelopmental disorders accompanied by macrocephaly and/or overgrowth"

Recurrent macrocephaly or overgrowth suggests a broader clinical pattern and limits a strictly non-syndromic interpretation; one feature alone is not a syndromic diagnosis.

DPP6

Gene: DPP6 hgnc:3010 gene page relationship_type: DISPUTED

Show evidence (4 references)

CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T100000.000Z REFUTE Other

The expert-panel classification itself: Disputed, not Definitive or Limited.

CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T100000.000Z REFUTE Other

"Taken together, the available genetic evidence fails to support a role for heterozygous disruption of DPP6 in ID, autism or other neurodevelopmental disorders."

The panel's summary judgement, which is the reason MONDO:0014580 has no subtype row on this entry.

CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T100000.000Z REFUTE Other

"Given the lack of evidence supporting their role in disease and the fact that no other DPP6 variants have been reported in association with microcephaly and ID, these variants were not scored."

Establishes that the panel examined the same variants the MRD33 concept is built on and declined to score them, so this is a re-assessment of the founding evidence rather than an independent negative study.

+ 1 more reference

💊

Medical Actions

Genetic Counselling and Recurrence-Risk Assessment

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic counseling uses the molecular result, parental testing and phenotype to assess recurrence. Apparently de novo variants can reflect parental somatic or germline mosaicism. A negative blood test does not exclude germline mosaicism, and the blood variant fraction is not an individual gamete-based recurrence probability. The broader genomic-disorder models cited here do not provide one recurrence rate for all AD-NSID.

Show evidence (4 references)

PMID:25087610 SUPPORT Human Clinical

"Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated."

Establishes that apparently de novo variants in simplex cases can arise from underdetected parental mosaicism, the basis for a non-zero recurrence-risk counselling message.

PMID:25087610 SUPPORT INDIRECT Computational

"Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline."

A probabilistic model of genomic-disorder recurrence, not an individualized risk rule inferred from blood mosaicism.

PMID:34697084 SUPPORT Human Clinical

"Here we present 12 cases of apparent mosaicism identified in the CAUSES cohort: nine cases of parental mosaicism for a disease-causing variant found in a child and three cases of mosaicism in the proband for a de novo variant."

Mosaicism found in 500 trios referred for suspected genetic disease, not an unselected population or an AD-NSID-specific frequency.

+ 1 more reference

Early Intervention, Rehabilitation, and Special Education

Action: early intervention and special education Ontology label: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Management includes individualized developmental, educational and rehabilitation support. Needs and services vary by age, function and molecular diagnosis. The cited evidence does not establish a universal treatment deadline or a single disease-modifying treatment status across all gene-associated disorders.

Show evidence (2 references)

PMID:38215144 SUPPORT Human Clinical

"INTERVENTIONS: Rehabilitation training."

Rehabilitation was reported in one ZBTB18 case; treatment use alone does not demonstrate efficacy or absence of other therapeutic options.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK547654/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Educational support is a crucial component of the management of intellectual disability."

General intellectual-disability care guidance supports educational services tailored to individual needs; it is not evidence of molecular correction or an AD-NSID-specific treatment effect.

Speech and Language Therapy

Action: speech therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Communication support is tailored to language and adaptive needs. Severe language impairment in SYNGAP1 motivates assessment and intervention, but the discovery series does not evaluate speech-therapy efficacy.

Target Phenotypes: Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:19196676 SUPPORT INDIRECT Human Clinical

"The disruption of SYNGAP1 appears to be associated with a homogeneous clinical phenotype that is characterized by moderate-to-severe mental retardation accompanied by severe language impairment."

Establishes the language impairment that this therapy targets; the citation supports the indication, not the efficacy of the intervention.

Physical and Occupational Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Motor and adaptive support is tailored to hypotonia, delayed walking and gait difficulties when present. The cited SYNGAP1 phenotype series identifies treatment needs but does not establish the efficacy of physical or occupational therapy.

Target Phenotypes: Hypotonia HP:0001252 Delayed ability to walk HP:0031936

Show evidence (1 reference)

PMID:26989088 SUPPORT INDIRECT Human Clinical

"Hypotonia and unstable gait were frequent associated neurological features."

Documents the motor impairments that motivate physiotherapy; supports the indication rather than the efficacy.

Antiseizure Pharmacotherapy for Comorbid Epilepsy

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

When epilepsy is present, standard antiseizure medication is used. Response is variable and gene-dependent: seizures were well controlled by topiramate or valproate in the original SYNGAP1 series, whereas roughly half the patients in a larger SYNGAP1 cohort were pharmacoresistant. There is a mechanistic rationale for AMPA-directed agents in SYNGAP1 haploinsufficiency, but it is a hypothesis generated from mouse work and small case observations, not a validated precision-therapy indication.

Mechanism Target:

INHIBITS Cortical Hyperexcitability — The authors proposed reduced AMPA-associated excitation as one rationale for observed seizure responses. This is not a complete account of either drug's action and does not establish precision efficacy or absence of cognitive benefit.

Show evidence (1 reference)

PMID:19196676 SUPPORT INDIRECT BACKGROUND Other

"Indeed, topiramate directly inhibits AMPA-receptor activity, whereas valproate reduces the level of GluR1 AMPA-receptor subunit at hippocampal synapses and therefore indirectly reduces AMPA-receptor activity."

Mechanistic rationale for the drug acting on the hyperexcitability node; authors' interpretation rather than a controlled trial.

Target Phenotypes: Seizure HP:0001250

Show evidence (2 references)

PMID:19196676 SUPPORT INDIRECT BACKGROUND Other

Gives the mechanistic rationale linking drug choice to the AMPA-receptor-mediated hyperexcitability node; this is authors' interpretation, not a controlled comparison.

PMID:26989088 SUPPORT Human Clinical

"Seizures were pharmacoresistant in half of the patients."

The larger series reports pharmacoresistance in half of patients. The remaining patients cannot automatically be counted as seizure-free, and this is not a category-wide response rate.

Topiramate for Associated Epilepsy

Action: Pharmacotherapy NCIT:C15986

Agent: topiramate CHEBI:63631

Platform: Small molecule

Seizure freedom in one reported SYNGAP1 patient; an uncontrolled observation, not comparative efficacy.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:19196676 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patient 1 had brief, generalized tonic–clonic seizures and was seizure-free while taking topiramate"

Seizure freedom in one reported SYNGAP1 patient; an uncontrolled observation, not comparative efficacy.

Valproic acid for Associated Epilepsy

Action: Pharmacotherapy NCIT:C15986

Agent: valproic acid CHEBI:39867

Platform: Small molecule

Reported seizure control in a second SYNGAP1 patient; an uncontrolled observation, not a precision-treatment indication.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:19196676 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patient 2 had some myoclonic and absence seizures, which were well controlled with valproate."

Reported seizure control in a second SYNGAP1 patient; an uncontrolled observation, not a precision-treatment indication.

🔬

Diagnosis

Molecular Diagnosis by Exome or Genome Sequencing

Exome or genome sequencing is used early in the evaluation of unexplained developmental delay or intellectual disability. The 2021 ACMG guideline recommends it as a first- or second-tier test, guided by clinical context. Parental samples improve interpretation of de novo occurrence and segregation, but testing the child alone or with one parent remains useful when a trio is unavailable. A diagnosis requires a pathogenic or likely pathogenic result consistent with the gene mechanism and phenotype; de novo status or a variant of uncertain significance alone is insufficient. Copy-number sensitivity depends on the platform and analysis, and chromosomal microarray or other complementary testing may still be needed.

molecular genetic testing NCIT:C19770

Show evidence (3 references)

PMID:31182824 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions."

Meta-analysis of broader neurodevelopmental cohorts, including causes outside AD-NSID. The isolated-NDD yield is not a yield for confirmed autosomal dominant disease.

PMID:31182824 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs."

The 2019 consensus supports early exome sequencing; it does not establish that chromosomal microarray is unnecessary in every workflow.

url:https://www.nature.com/articles/s41436-021-01242-6 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Best practice includes familial comparators (“trio”) if available"

The same guideline paragraph explicitly allows effective proband-only or duo analysis with somewhat lower yield; trio design is preferred when available, not mandatory.

Exclusion of Recognised Syndromic and Metabolic Causes

Clinical history, developmental assessment and examination guide the search for a recognizable syndrome or alternative cause. A non-syndromic presentation can change with age or deeper phenotyping. Tests for repeat expansions, methylation abnormalities, metabolic disease or structural brain findings should follow clinical context and assay limitations; the historical workup of a discovery cohort is not a universal modern prerequisite.

disease screening NCIT:C15419

Show evidence (2 references)

PMID:19196676 SUPPORT INDIRECT Human Clinical

"Mental retardation was unexplained in these patients despite standard investigations, including karyotyping, subtelomeric fluorescence in situ hybridization analysis, or comparative genomic hybridization targeting regions associated with known syndromes, molecular testing for the common..."

Describes enrollment investigations in the 2009 discovery cohort, rather than prescribing the same workup for every current patient.

PMID:19196676 SUPPORT Human Clinical

"All patients were examined by at least one experienced clinical geneticist, who ruled out the presence of specific dysmorphic features."

Expert dysmorphology assessment is the clinical step that assigns a case to the non-syndromic category.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Non-Syndromic Intellectual Disability:

Syndromic Intellectual Disability

Overlapping Features A recognizable combination of findings can support a gene-specific syndrome. Mild dysmorphism, altered head size or a single imaging finding alone does not automatically settle the distinction. Presentation can become more recognizable with age and deeper phenotyping.

Distinguishing Features

Presence of a recognisable dysmorphic gestalt or major malformation
Growth abnormality, microcephaly, or structural brain anomaly on imaging

Show evidence (1 reference)

PMID:23020937 SUPPORT Human Clinical

"Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions."

Documents the instability of the syndromic/non-syndromic distinction in real cohorts.

X-linked Intellectual Disability

Overlapping Features X-linked causes can be inherited or de novo and can affect males or females. Chromosomal location, variant interpretation and segregation distinguish these disorders from autosomal causes; absence of a maternal family history does not exclude an X-linked diagnosis.

Distinguishing Features

A pathogenic variant in an X-linked disease gene with compatible phenotype and inheritance
An affected maternal lineage can be informative, but de novo occurrence and affected females are possible

Show evidence (1 reference)

PMID:23033978 SUPPORT Human Clinical

"A total of 10 de novo mutations and 3 X-linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients."

This cohort includes maternally inherited X-linked diagnoses; it does not define all X-linked inheritance patterns.

Autosomal Recessive Non-Syndromic Intellectual Disability

Overlapping Features Biallelic causes remain a differential in both consanguineous and outbred families. Their frequency depends on ascertainment and ancestry. A low contribution in one selected outbred cohort does not exclude recessive disease in another patient or population.

Distinguishing Features

Consanguinity or an endogamous founder population
Biallelic (homozygous or compound heterozygous) variants inherited from unaffected carrier parents

Show evidence (1 reference)

PMID:23020937 SUPPORT Human Clinical

"Autosomal recessive inheritance seems to contribute little in the outbred population investigated."

A qualitative conclusion limited to the investigated outbred cohort, not a universal estimate.

Copy Number Variant Intellectual Disability

Overlapping Features Pathogenic deletions or duplications can affect one gene or a larger interval and can be de novo or inherited. Some CNVs cause dominant gene-dosage disorders within this category rather than a mutually exclusive diagnosis. Detection depends on assay and pipeline; chromosomal microarray and suitably analyzed exome or genome sequencing have complementary capabilities.

Distinguishing Features

A pathogenic dosage change affecting one gene or a multi-gene interval
Interpretation of the affected interval and gene dosage, using an assay validated for the relevant CNV class

Show evidence (1 reference)

PMID:21076407 SUPPORT INDIRECT BACKGROUND Human Clinical

"Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population."

The authors proposed combined contributions from de novo CNVs and sequence variants; this is not a measured population fraction or proof that sequencing cannot detect CNVs.

🐁

Animal Models

Adult-restorable Syngap1 haploinsufficiency mouse

Tamoxifen-triggered restoration of endogenous SynGAP in adult mice rescued remote contextual memory and selected seizure and electrophysiological outcomes. Locomotor hyperactivity persisted, and earlier working-memory experiments found no rescue. These are outcome-specific preclinical findings, not evidence of a human treatment effect.

Species

Mouse

Genotype

Syngap1 heterozygous Lox-Stop allele with inducible Cre-ER

Pathograph links

Altered Development and Function of Neural Circuits rescues Adult restoration reverses selected functional outcomes despite developmental haploinsufficiency.

Limitations: The model does not demonstrate reversal of every developmental abnormality or rescue of all cognitive outcomes.

Show evidence (1 reference)

PMID:31025938 SUPPORT DIRECT PRIMARY RESULT Model Organism

"genetic reversal ofSyngap1pathogenicity in adult mice reverses deficits in remote memory"

Adult genetic restoration improved remote contextual memory in mice; this is endpoint-specific preclinical evidence and does not establish human therapeutic efficacy.

Show evidence (1 reference)

PMID:31025938 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Adult restoration of SynGAP protein improved behavioral and electrophysiological measures of memory and seizure."

Genetic restoration tests adult functional reversibility in mice; it does not establish the efficacy or delivery of a human therapy.

{ }

Source YAML

click to show

name: Autosomal Dominant Non-Syndromic Intellectual Disability
creation_date: "2026-07-31T00:00:00Z"
description: >-
  Autosomal dominant non-syndromic intellectual disability is a genetically heterogeneous category in
  which intellectual and adaptive impairment initially lacks a recognizable syndromic pattern. Historical
  MRD-series diagnoses overlap with subsequently delineated neurodevelopmental syndromes, including disorders
  with epilepsy, behavioral differences and extra-neurological features. De novo variants are common in
  severe sporadic cohorts, but inherited variants and parental mosaicism also occur. Haploinsufficiency,
  gain of function and other altered-function mechanisms depend on the gene and allele; neither complete
  penetrance nor a uniform reduction of protein abundance defines this category. Candidate-gene sequencing
  identified SYNGAP1-related disease in 2009, followed by wider discovery through trio exome sequencing.
  Representative mechanisms affect synaptic function, gene regulation, cytoskeletal dynamics and neuronal
  development. Their inclusion here does not imply that every subtype
  follows one causal sequence. This entry retains its existing class-level scope and subtype identities
  while distinguishing that scope from individual clinical syndromes.
category: Genetic
disease_term:
  preferred_term: autosomal dominant non-syndromic intellectual disability
  term:
    id: MONDO:0015802
    label: autosomal dominant non-syndromic intellectual disability
parents:
- Non-Syndromic Intellectual Disability
- Intellectual Disability, Autosomal Dominant
synonyms:
- non-syndromic intellectual disability, autosomal dominant
- autosomal dominant mental retardation
- mental retardation, autosomal dominant (MRD)
- autosomal dominant nonsyndromic mental retardation
- AD-NSID

has_subtypes:
- name: MRD22
  display_name: Intellectual disability, autosomal dominant 22 (ZBTB18-related)
  subtype_term:
    preferred_term: ZBTB18-related autosomal dominant intellectual disability
    term:
      id: MONDO:0012869
      label: intellectual disability, autosomal dominant 22
  genes:
  - preferred_term: ZBTB18
    term:
      id: hgnc:13030
      label: ZBTB18
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO defines this concept as any autosomal dominant non-syndromic intellectual disability in which
    the cause of the disease is a mutation in the ZBTB18 gene. ZBTB18 is already curated in this entry's
    `genetic:` block with its own primary-literature evidence and is assigned there to the chromatin and
    transcription module; this row adds the MONDO subtype identity that the gene record did not carry.
    ClinGen classifies the gene-disease relationship as Definitive, against `complex neurodevelopmental
    disorder`. Truncating alleles occur in the last exon and are not expected to undergo nonsense-mediated
    decay; selected missense alleles alter transcriptional repression in different ways.
  evidence:
  - reference: CGGV:assertion_d8ea518c-64da-4d4f-8551-66a005307e94-2026-05-22T100000.000Z
    reference_title: "ZBTB18 / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ZBTB18 | HGNC:13030 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Definitive | SOP12 | Intellectual
      Disability and Autism Gene Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.

  - reference: CGGV:assertion_d8ea518c-64da-4d4f-8551-66a005307e94-2026-05-22T100000.000Z
    reference_title: ZBTB18 / complex neurodevelopmental disorder (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Nonsense and frameshift variants lead to a premature termination codon in the last (second) exon and are not expected to result in nonsense-mediated decay.
    explanation: 'Expert synthesis: predicted decay escape means truncation must not be equated with transcript loss; altered transcriptional repression remains variant-dependent.'
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: MRD41
  display_name: Intellectual disability, autosomal dominant 41 (TBL1XR1-related)
  subtype_term:
    preferred_term: TBL1XR1-related autosomal dominant intellectual disability
    term:
      id: MONDO:0014842
      label: intellectual disability, autosomal dominant 41
  genes:
  - preferred_term: TBL1XR1
    term:
      id: hgnc:29529
      label: TBL1XR1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO defines this concept as any autosomal dominant non-syndromic intellectual disability in which
    the cause of the disease is a mutation in the TBL1XR1 gene. TBL1XR1 encodes an F-box-like/WD40 repeat-containing
    protein acting in nuclear-receptor-mediated transcription, which places the subtype in this entry's
    chromatin and transcription module. ClinGen classifies the relationship as Definitive, against `complex
    neurodevelopmental disorder`. A caregiver-reported survey of 41 individuals described marked language
    impairment and regression in a subset. Recruitment, recall and incomplete molecular verification limit
    generalization; regression does not itself prove neurodegeneration.
  evidence:
  - reference: CGGV:assertion_8352a921-43c0-4097-9147-2618a4165b57-2020-07-07T170000.000Z
    reference_title: "TBL1XR1 / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TBL1XR1 | HGNC:29529 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Definitive | SOP7 | Intellectual Disability
      and Autism Gene Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - reference: PMID:38378692
    reference_title: "The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that
      plays a role in transcription mediated by nuclear receptors and
      is a known genetic cause of neurodevelopmental disease of
      childhood
    explanation: >-
      States the gene's molecular role and its established status as a
      neurodevelopmental disease gene. Quoted from the survey study's
      background rather than from its own results.
    directness: INDIRECT
  - reference: PMID:38378692
    reference_title: "The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Language appeared most significantly affected with only a
      minority of the cohort achieving more advanced milestones in
      this domain.
    explanation: >-
      The survey result behind the statement that language is the most
      severely affected domain.
  - reference: PMID:38378692
    reference_title: "The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TBL1XR1-related disorder encompasses a spectrum of clinical
      presentations, marked by early developmental delay ranging in
      severity, with a subset of patients experiencing developmental
      regression in later childhood.
    explanation: >-
      Reports regression in a subset of this caregiver survey, rather than a uniformly static course or
      proof of neurodegeneration.

- name: MRD43
  display_name: Intellectual disability, autosomal dominant 43 (HIVEP2-related)
  subtype_term:
    preferred_term: HIVEP2-related autosomal dominant intellectual disability
    term:
      id: MONDO:0014858
      label: intellectual disability, autosomal dominant 43
  genes:
  - preferred_term: HIVEP2
    term:
      id: hgnc:4921
      label: HIVEP2
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO defines this concept as any autosomal dominant non-syndromic
    intellectual disability in which the cause of the disease is a
    mutation in the HIVEP2 gene. HIVEP2 encodes a large transcription
    factor regulating neurodevelopmental pathways, placing the subtype
    in this entry's chromatin and transcription module. No ClinGen
    Gene-Disease Validity curation was found for HIVEP2 in the
    gene-validity release read for this pass, searched by gene symbol
    across the full download. The subtype therefore rests on
    primary-literature series alone. Those series report dysmorphic
    features alongside the developmental delay, which is the same
    non-syndromic boundary problem this entry already documents for
    SYNGAP1, TRIO, MED13L and KMT5B.
  evidence:
  - reference: PMID:27003583
    reference_title: "Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe six patients with developmental delay,
      intellectual disability, and dysmorphic features with de novo
      likely gene-damaging variants in HIVEP2 identified by
      whole-exome sequencing (WES).
    explanation: >-
      Six further probands with de novo likely gene-damaging HIVEP2
      variants, and the source of the dysmorphism caveat recorded
      above.
  - reference: PMID:27003583
    reference_title: "Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HIVEP2 encodes a large transcription factor that regulates
      various neurodevelopmental pathways.
    explanation: >-
      Places HIVEP2 in this entry's chromatin and transcriptional
      regulation module.

    directness: INDIRECT
- name: MRD45
  display_name: Intellectual disability, autosomal dominant 45 (CIC-related)
  subtype_term:
    preferred_term: CIC-related autosomal dominant intellectual disability
    term:
      id: MONDO:0030910
      label: intellectual disability, autosomal dominant 45
  genes:
  - preferred_term: CIC
    term:
      id: hgnc:14214
      label: CIC
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the
    class as a direct subclass of this entry's own term, MONDO:0015802,
    and records CIC as its causal gene by RO:0004003. CIC encodes the
    transcriptional repressor capicua, which forms a repressor complex
    with ataxin 1, so the subtype is a chromatin and transcription
    module lesion. ClinGen classifies the relationship as Definitive,
    against `complex neurodevelopmental disorder`. The human probands
    were ascertained by reverse phenotyping from conditional mouse
    mutants rather than from a human non-syndromic intellectual
    disability cohort, which is worth recording because the
    ascertainment route shapes which features get reported.
  evidence:
  - reference: CGGV:assertion_a0f9a222-8872-4054-b767-25f8fb4e404a-2023-01-18T110000.000Z
    reference_title: "CIC / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CIC | HGNC:14214 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Definitive | SOP11 | Intellectual
      Disability and Autism Gene Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - reference: PMID:28288114
    reference_title: "Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one individual with an inherited nonsense variant from a father who is low-grade mosaic
    explanation: >-
      The full text identifies four de novo variants and one variant inherited from a mosaic father among
      the five initial individuals; two additional siblings suggest parental germline mosaicism. This
      corrects the abstract shorthand describing all five as de novo.

    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: MRD46
  display_name: Intellectual disability, autosomal dominant 46 (KCNQ5-related)
  subtype_term:
    preferred_term: KCNQ5-related autosomal dominant intellectual disability
    term:
      id: MONDO:0030911
      label: intellectual disability, autosomal dominant 46
  genes:
  - preferred_term: KCNQ5
    term:
      id: hgnc:6299
      label: KCNQ5
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this
    entry's own term, MONDO:0015802, and records KCNQ5 as its causal gene by RO:0004003. KCNQ5 is widely
    expressed in the brain and generates the neuronal M-type potassium current. Frog-oocyte assays found
    both reduced and increased channel function for disease-associated variants. This subtype follows
    the altered-protein-activity branch; the assays do not directly establish an identical excitability
    change in patients for both directions. No ClinGen Gene-Disease Validity curation was found for KCNQ5
    in the gene-validity release read for this pass, searched by gene symbol across the full download.
  evidence:
  - reference: PMID:28669405
    reference_title: "Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified de novo heterozygous missense
      mutations in four probands with intellectual disability,
      abnormal neurological findings, and treatment-resistant epilepsy
      (in two of four).
    explanation: >-
      The four-proband series establishing de novo KCNQ5 missense
      variants as a cause of intellectual disability.
  - reference: PMID:28669405
    reference_title: "Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KCNQ5 is a highly conserved gene encoding an important channel
      for neuronal function; it is widely expressed in the brain and
      generates M-type current.
    explanation: >-
      Channel-function background; this is not a direct measurement of patient neuronal excitability.
    directness: INDIRECT
  - reference: PMID:28669405
    reference_title: "Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Specifically, both loss-of-function and gain-of-function KCNQ5
      mutations, associated with increased excitability and decreased
      repolarization reserve, lead to pathophysiology.
    explanation: >-
      Oocyte electrophysiology demonstrates bidirectional changes in channel function. The proposed neuronal
      consequences are not a direct measurement in patient neurons.

- name: MRD47
  display_name: Intellectual disability, autosomal dominant 47 (STAG1-related)
  subtype_term:
    preferred_term: STAG1-related autosomal dominant intellectual disability
    term:
      id: MONDO:0030912
      label: intellectual disability, autosomal dominant 47
  genes:
  - preferred_term: STAG1
    term:
      id: hgnc:11354
      label: STAG1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this
    entry's own term, MONDO:0015802, and records STAG1 as its causal gene by RO:0004003. STAG1 belongs
    to the STAG subunit of the core cohesin complex, making this subtype a cohesinopathy. ClinGen classifies
    the relationship as Definitive, against `complex neurodevelopmental disorder`. Its non-syndromic placement
    conflicts with its clinical description: MONDO itself also asserts MONDO:0030912 as a subclass of
    `multiple congenital anomalies/dysmorphic syndrome-intellectual disability`, so the two placements
    contradict each other within one ontology, and the defining case series reports shared facial features
    and calls the phenotype syndromic.
  evidence:
  - reference: CGGV:assertion_30cc66e4-e3cf-428d-9f27-58e8427c94f1-2022-09-20T060000.000Z
    reference_title: "STAG1 / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      STAG1 | HGNC:11354 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Definitive | SOP9 | Intellectual Disability
      and Autism Gene Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - reference: PMID:28119487
    reference_title: "STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report an international series of 17 individuals from 16
      families presenting with syndromic unspecific ID that could be
      attributed to a STAG1 deletion or point mutation.
    explanation: >-
      The defining series, and the source of the observation that the
      authors themselves describe the phenotype as syndromic.
  - reference: PMID:28119487
    reference_title: "STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 17 patients shared common facial features, with wide mouth
      and deep-set eyes.
    explanation: >-
      The specific shared dysmorphic findings behind the syndromic
      characterisation.
  - reference: PMID:28119487
    reference_title: "STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STAG1 belongs to the STAG subunit of the core cohesin complex,
      along with five other subunits.
    explanation: >-
      Places the subtype among the cohesinopathies.

    directness: INDIRECT
- name: MRD49
  display_name: Clark-Baraitser syndrome (TRIP12-related, MRD49)
  subtype_term:
    preferred_term: TRIP12-related autosomal dominant intellectual disability
    term:
      id: MONDO:0030914
      label: Clark-Baraitser syndrome
  genes:
  - preferred_term: TRIP12
    term:
      id: hgnc:12306
      label: TRIP12
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    The one member of this series MONDO labels with an eponym rather than an MRD number; `MRD49` and `intellectual
    disability, autosomal dominant 49` are both MONDO synonyms of the same class, and MONDO asserts it
    as a direct subclass of this entry's own term with TRIP12 as its causal gene by RO:0004003. TRIP12
    encodes a HECT-domain E3 ubiquitin ligase on chromosome 2q36.3 and acts through haploinsufficiency,
    with variant-level support from reduced transcript abundance for one splice allele. Its proposed ubiquitin-proteasome
    consequences are distinct from the synaptic, chromatin and cytoskeletal examples in the graph. MONDO
    cross-references the class to both OMIM:617752 and OMIM:300602. ClinGen classifies the gene-disease
    relationship as Definitive, against `complex neurodevelopmental disorder`, and a peripheral-blood
    DNA methylation episignature has been reported. This is an adjunct to variant interpretation; two
    affected discovery samples were excluded as outliers, so the study does not
    establish perfect sensitivity for all alleles.
  evidence:
  - reference: CGGV:assertion_011b99b3-0d17-4615-800e-36f4bacd8117-2022-04-05T060000.000Z
    reference_title: "TRIP12 / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TRIP12 | HGNC:12306 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Definitive | SOP9 | Intellectual Disability
      and Autism Gene Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - reference: PMID:36430143
    reference_title: "Episignature Mapping of TRIP12 Provides Functional Insight into Clark-Baraitser Syndrome."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clark-Baraitser syndrome is a rare autosomal dominant
      intellectual disability syndrome caused by pathogenic variants
      in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene.
    explanation: >-
      Establishes that the eponymous syndrome is TRIP12-related and
      autosomal dominant.
  - reference: PMID:36430143
    reference_title: "Episignature Mapping of TRIP12 Provides Functional Insight into Clark-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a specific and sensitive DNA methylation (DNAm)
      episignature associated with pathogenic TRIP12 variants,
      establishing its utility as a clinical biomarker for
      Clark-Baraitser syndrome.
    explanation: >-
      Peripheral-blood classifier development and validation. Two discovery outliers were excluded; this
      supports a potential diagnostic adjunct, not universal sensitivity or a brain mechanism.
  - reference: PMID:28251352
    reference_title: "Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      qPCR data showed dramatic reduction of TRIP12 mRNA level in the proband compared to three unaffected
      family member controls
    explanation: >-
      RNA measured in the patient whole-blood sample supports reduced transcript abundance for c.3743+1G>A.
      The paper later classifies p.A761V as a VUS despite the abstract calling all nine variants pathogenic;
      de novo occurrence alone does not resolve that uncertainty.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:28251352
    reference_title: "Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only a handful of single-nucleotide variants (SNVs) and
      copy-number variants (CNVs) involving TRIP12, encoding a member
      of the HECT domain E3 ubiquitin ligases family on chromosome
      2q36.3 have been reported.
    explanation: >-
      Source for the protein family and the chromosomal location
      recorded above.

    directness: INDIRECT
- name: MRD50
  display_name: Intellectual disability, autosomal dominant 50 (NAA15-related)
  subtype_term:
    preferred_term: NAA15-related autosomal dominant intellectual disability
    term:
      id: MONDO:0030916
      label: intellectual disability, autosomal dominant 50
  genes:
  - preferred_term: NAA15
    term:
      id: hgnc:30782
      label: NAA15
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the
    class as a direct subclass of this entry's own term, MONDO:0015802,
    and records NAA15 as its causal gene by RO:0004003. NAA15 is the
    auxiliary subunit of the NatA N-terminal acetyltransferase complex,
    and haploinsufficiency is supported by both transcript degradation
    and copy-number deletions. ClinGen classifies the relationship as
    Definitive but curates it explicitly against `syndromic intellectual
    disability`, and the defining 38-individual cohort reports
    craniofacial dysmorphology, congenital cardiac anomalies and
    seizures in some subjects - so both the expert panel and the primary
    cohort contradict a non-syndromic placement.
  evidence:
  - reference: CGGV:assertion_f9732e0c-1306-4fb5-b1b3-873258903e75-2022-01-05T170000.000Z
    reference_title: "NAA15 / syndromic intellectual disability (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NAA15 | HGNC:30782 | syndromic intellectual disability |
      MONDO:0000508 | AD | Definitive | SOP8 | Intellectual Disability
      and Autism Gene Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - reference: PMID:29656860
    reference_title: "Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of affected individuals with LGD variants in
      NAA15 include variable levels of intellectual disability,
      delayed speech and motor milestones, and autism spectrum
      disorder.
    explanation: >-
      The 38-individual cohort establishing NAA15 as a dominant
      neurodevelopmental gene.
  - reference: PMID:29656860
    reference_title: "Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, mild craniofacial dysmorphology, congenital
      cardiac anomalies, and seizures are present in some subjects.
    explanation: >-
      The extra-cognitive features behind the syndromic caveat
      recorded above.
  - reference: PMID:29656860
    reference_title: "Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further supporting a mechanism of haploinsufficiency,
      individuals with copy-number variant (CNV) deletions involving
      NAA15 and surrounding genes can present with mild intellectual
      disability, mild dysmorphic features, motor delays, and
      decreased growth.
    explanation: >-
      Supports haploinsufficiency as the mechanism, connecting this
      subtype to the entry's root pathophysiology node.

- name: MRD51
  display_name: Intellectual disability, autosomal dominant 51 (KMT5B-related)
  subtype_term:
    preferred_term: KMT5B-related autosomal dominant intellectual disability
    term:
      id: MONDO:0030917
      label: intellectual disability, autosomal dominant 51
  genes:
  - preferred_term: KMT5B
    term:
      id: hgnc:24283
      label: KMT5B
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the
    class as a direct subclass of this entry's own term, MONDO:0015802,
    and records KMT5B as its causal gene by RO:0004003. KMT5B is already
    curated in this entry's `genetic:` block with its own
    primary-literature evidence, including the caveat that the recurring
    macrocephaly and overgrowth constitute an emerging recognisable
    gestalt; this row adds the MONDO subtype identity that the gene
    record did not carry. ClinGen classifies the relationship as
    Definitive, against `complex neurodevelopmental disorder`. A
    `stubs/Intellectual_Disability_Autosomal_Dominant_51.yaml` entry
    proposes this same MONDO class as a standalone Disease; that stub is
    deliberately left in place rather than resolved here, because
    promoting it is a lump/split decision about the whole series and not
    about one member of it.
  evidence:
  - reference: CGGV:assertion_885d56b0-a2b0-4a3d-9f11-4034298e074e-2022-04-08T072351.945Z
    reference_title: "KMT5B / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      KMT5B | HGNC:24283 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Definitive | SOP8 | Syndromic Disorders
      Gene Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.

- name: MRD53
  display_name: Intellectual disability, autosomal dominant 53 (CAMK2A-related)
  subtype_term:
    preferred_term: CAMK2A-related autosomal dominant intellectual disability
    term:
      id: MONDO:0030919
      label: intellectual disability, autosomal dominant 53
  genes:
  - preferred_term: CAMK2A
    term:
      id: hgnc:1460
      label: CAMK2A
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the
    class as a direct subclass of this entry's own term, MONDO:0015802,
    and records CAMK2A as its causal gene by RO:0004003. CAMK2A is
    already curated in this entry's `genetic:` block with its own
    primary-literature and functional evidence, and is assigned there to
    the synaptic transmission and plasticity module; this row adds the
    MONDO subtype identity that the gene record did not carry. ClinGen
    classifies the relationship as Definitive, against `complex
    neurodevelopmental disorder`.
  evidence:
  - reference: CGGV:assertion_82e77410-49d7-41b8-a5b8-278afac7dc26-2024-10-15T100000.000Z
    reference_title: "CAMK2A / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CAMK2A | HGNC:1460 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Definitive | SOP11 | Intellectual
      Disability and Autism Gene Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.

- name: MRD54
  display_name: Intellectual disability, autosomal dominant 54 (CAMK2B-related)
  subtype_term:
    preferred_term: CAMK2B-related autosomal dominant intellectual disability
    term:
      id: MONDO:0030920
      label: intellectual disability, autosomal dominant 54
  genes:
  - preferred_term: CAMK2B
    term:
      id: hgnc:1461
      label: CAMK2B
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the
    class as a direct subclass of this entry's own term, MONDO:0015802,
    and records CAMK2B as its causal gene by RO:0004003. This is the
    paralogue subtype of MRD53: CAMK2A and CAMK2B were established
    together in one multi-centre trio-sequencing study, and both belong
    to this entry's synaptic transmission and plasticity module. No
    ClinGen Gene-Disease Validity curation was found for CAMK2B in the
    gene-validity release read for this pass, searched by gene symbol
    across the full download. CAMK2A is curated there as Definitive, so
    the asymmetry is a gap in ClinGen coverage rather than a negative
    assessment of CAMK2B.
  evidence:
  - reference: PMID:29100089
    reference_title: "De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through a multi-center collaborative study based on a
      whole-exome sequencing approach, we identified 19 exceedingly
      rare de novo CAMK2A or CAMK2B variants in 24 unrelated
      individuals with intellectual disability.
    explanation: >-
      The joint study establishing both CAMK2A and CAMK2B as de novo
      heterozygous causes of intellectual disability.

- name: MRD55
  display_name: Intellectual disability, autosomal dominant 55, with seizures (NUS1-related)
  subtype_term:
    preferred_term: NUS1-related autosomal dominant intellectual disability with seizures
    term:
      id: MONDO:0030921
      label: intellectual disability, autosomal dominant 55, with seizures
  genes:
  - preferred_term: NUS1
    term:
      id: hgnc:21042
      label: NUS1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the
    class as a direct subclass of this entry's own term, MONDO:0015802,
    and records NUS1 as its causal gene by RO:0004003. The gene-disease
    link was established in developmental and epileptic encephalopathy
    cohorts rather than in non-syndromic intellectual disability series.
    ClinGen curates NUS1 as Definitive for `progressive myoclonus
    epilepsy`, a different disease concept from the one MONDO places
    here, so the two resources disagree about what the NUS1 phenotype is
    rather than about whether the gene is causal.
  evidence:
  - reference: CGGV:assertion_e50efc63-0235-4c75-a4ab-6c129485a117-2025-05-20T160000.000Z
    reference_title: "NUS1 / progressive myoclonus epilepsy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NUS1 | HGNC:21042 | progressive myoclonus epilepsy |
      MONDO:0020074 | AD | Definitive | SOP11 | Epilepsy Gene Curation
      Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - 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 the causal link for NUS1, in a developmental and
      epileptic encephalopathy series rather than a non-syndromic
      intellectual disability one.

- name: MRD56
  display_name: Intellectual disability, autosomal dominant 56 (CLTC-related)
  subtype_term:
    preferred_term: CLTC-related autosomal dominant intellectual disability
    term:
      id: MONDO:0030922
      label: intellectual disability, autosomal dominant 56
  genes:
  - preferred_term: CLTC
    term:
      id: hgnc:2092
      label: CLTC
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the
    class as a direct subclass of this entry's own term, MONDO:0015802,
    and records CLTC as its causal gene by RO:0004003. CLTC encodes
    clathrin heavy chain 1, and clathrin-mediated endocytosis serves
    synaptic vesicle recycling, so this subtype sits mechanistically
    beside MRD60 (AP2M1), which disables the AP-2 adaptor that recruits
    clathrin - two members of this series converging on one trafficking
    step. Like NUS1, CLTC was established as causal in a developmental
    and epileptic encephalopathy series. No ClinGen Gene-Disease
    Validity curation was found for CLTC in the gene-validity release
    read for this pass, searched by gene symbol across the full
    download.
  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 the causal link for CLTC in the same whole-genome
      sequencing series that established NUS1.
  - reference: PMID:41091397
    reference_title: "Intellectual developmental disorder 56 associated with novel variants in the clathrin heavy chain encoding CLTC gene and brief review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The spectrum of CLTC variants, causing intellectual
      developmental disorder 56 (OMIM 617854) has been expanded by two
      novel variants.
    explanation: >-
      Ties the CLTC gene-disease relationship explicitly to the OMIM
      entity that MONDO:0030922 represents.
  - reference: PMID:41091397
    reference_title: "Intellectual developmental disorder 56 associated with novel variants in the clathrin heavy chain encoding CLTC gene and brief review of the literature."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clathrin-mediated endocytosis is involved in synaptic vesicle
      recycling and pathogenic variants in the CLTC gene, encoding
      clathrin heavy chain 1 are associated with delayed development
      and cognitive difficulties.
    explanation: >-
      Source for the gene product and for the
      synaptic-vesicle-recycling role that pairs this subtype with
      MRD60.

    directness: INDIRECT
- name: MRD57
  display_name: Intellectual disability, autosomal dominant 57 (TLK2-related)
  subtype_term:
    preferred_term: TLK2-related autosomal dominant intellectual disability
    term:
      id: MONDO:0054837
      label: intellectual disability, autosomal dominant 57
  genes:
  - preferred_term: TLK2
    term:
      id: hgnc:11842
      label: TLK2
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this
    entry's own term, MONDO:0015802, and records TLK2 as its causal gene by RO:0004003. TLK2 is a serine/threonine
    kinase whose physiological substrates include the H3-H4 chaperone ASF1 and histone H3, linking it
    to chromatin assembly and placing the subtype in this entry's chromatin and transcription module.
    ClinGen classifies the relationship as Definitive, against `complex neurodevelopmental disorder`.
    The defining 40-individual study calls the entity a distinct syndrome with a consistent facial gestalt
    and severe gastrointestinal involvement, and supports haploinsufficiency. RNA experiments demonstrated
    decay for two tested alleles, while a last-exon stop allele escaped decay. Some individuals had normal
    or borderline cognition, including a transmitting mother with low-normal IQ; neither every allele
    nor every carrier implies intellectual disability. The expert summary also notes possible
    dominant-negative effects for inactive kinase-domain alleles.
  evidence:
  - reference: CGGV:assertion_ecd1054d-80b0-4292-a901-65de788b7820-2024-06-05T100000.000Z
    reference_title: "TLK2 / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TLK2 | HGNC:11842 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Definitive | SOP11 | Intellectual
      Disability and Autism Gene Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - reference: PMID:29861108
    reference_title: "De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the identification of a distinct syndrome due to
      de novo or inherited heterozygous mutations in Tousled-like
      kinase 2 (TLK2) in 38 unrelated individuals and two affected
      mothers
    explanation: >-
      The defining cohort, and the source of the observation that the
      authors describe a distinct syndrome rather than isolated
      cognitive impairment.
  - reference: PMID:29861108
    reference_title: "De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals had a consistent phenotype, characterized
      by mild-borderline neurodevelopmental delay (86%), behavioral
      disorders (68%), severe gastro-intestinal problems (63%), and
      facial dysmorphism including blepharophimosis (82%), telecanthus
      (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin
      vermilion of the upper lip (62%), and upslanting palpebral
      fissures (55%).
    explanation: >-
      The recurrent extra-cognitive features behind the syndromic
      characterisation recorded above.
  - reference: PMID:29861108
    reference_title: "De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that haploinsufficiency of TLK2 is the most likely
      underlying disease mechanism, leading to a consistent
      neurodevelopmental phenotype.
    explanation: >-
      The authors infer a shared dosage mechanism from phenotype and molecular findings; direct NMD evidence
      concerns two tested alleles, not every variant.
    directness: INDIRECT
  - reference: PMID:29861108
    reference_title: "De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With the discovery of both H3-H4 chaperone Asf1 and histone H3
      as physiological substrates of TLKs, its protein function has
      been linked to chromatin assembly.
    explanation: >-
      Places TLK2 in this entry's chromatin and transcriptional
      regulation module.

    directness: INDIRECT
  - reference: CGGV:assertion_ecd1054d-80b0-4292-a901-65de788b7820-2024-06-05T100000.000Z
    reference_title: TLK2 / complex neurodevelopmental disorder (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: TLK2 activation requires dimerization through a coiled-coil domain, suggesting that inactive mutants could have a dominant negative effect
    explanation: The expert summary notes a possible dominant-negative mechanism for selected kinase-domain alleles; transcript-decay evidence cannot be generalized to every allele.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: MRD58
  display_name: Intellectual disability, autosomal dominant 58 (SET-related)
  subtype_term:
    preferred_term: SET-related autosomal dominant intellectual disability
    term:
      id: MONDO:0020847
      label: intellectual disability, autosomal dominant 58
  genes:
  - preferred_term: SET
    term:
      id: hgnc:10760
      label: SET
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the
    class as a direct subclass of this entry's own term, MONDO:0015802,
    and records SET as its causal gene by RO:0004003. SET is a component
    of the INHAT complex, which acts in transcriptional silencing, so
    the subtype is a chromatin and transcription module lesion and the
    first Nucleosome Assembly Protein family member implicated in
    intellectual disability. ClinGen classifies the relationship as
    Definitive, and this is the one gene in the series it curates
    against a plain `intellectual disability` concept rather than a
    complex or syndromic one. The defining report also describes an
    affected mother and child carrying a frameshift variant, making this
    subtype another instance of the entry-level caveat that autosomal
    dominant is not a synonym for de novo.
  evidence:
  - reference: CGGV:assertion_4d7c9aa2-0a9a-4359-af98-6097cc6a3b91-2021-11-17T170000.000Z
    reference_title: "SET / intellectual disability (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SET | HGNC:10760 | intellectual disability | MONDO:0001071 | AD
      | Definitive | SOP8 | Intellectual Disability and Autism Gene
      Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - reference: PMID:29688601
    reference_title: "De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe mutations in the "SET nuclear proto-oncogene" (SET),
      encoding a component of the "inhibitor of histone
      acetyltransferases" (INHAT) complex, involved in transcriptional
      silencing.
    explanation: >-
      Establishes SET's molecular role and places the subtype in the
      chromatin and transcription module.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:29688601
    reference_title: "De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, an affected mother and child were detected who
      carried a frameshift variant in SET.
    explanation: >-
      The transmitted lesion behind the caveat that this class is not
      exclusively de novo.
  - reference: PMID:29688601
    reference_title: "De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study identifies SET as a new component of epigenetic
      regulatory modules underlying human cognitive disorders, and as
      a first member of the Nucleosome Assembly Protein (NAP) family
      implicated in ID.
    explanation: >-
      Source for the NAP-family statement recorded above.

- name: MRD59
  display_name: Intellectual developmental disorder 59 (CAMK2G-related)
  subtype_term:
    preferred_term: CAMK2G-related autosomal dominant intellectual disability
    term:
      id: MONDO:0032795
      label: intellectual developmental disorder 59
  genes:
  - preferred_term: CAMK2G
    term:
      id: hgnc:1463
      label: CAMK2G
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this
    entry's own term, MONDO:0015802, and records CAMK2G as its causal gene by RO:0004003. This is the
    third CAMK2 paralogue subtype in the series, alongside MRD53 (CAMK2A) and MRD54 (CAMK2B), with limited
    clinical evidence in the cited sources. ClinGen's Syndromic Disorders Gene Curation Expert Panel classifies
    the relationship as `Limited` and does so against MONDO:0032795 itself, the same identifier this row
    binds, so the validity assessment applies to this exact disease identifier. The mechanism is also
    not haploinsufficiency - the recurrent p.Arg292Pro variant acts as a gain of function - so it follows
    the altered-protein-activity branch. The expert summary considers three individuals with two missense
    alleles, extending beyond the two p.Arg292Pro cases in the cited functional study.
  evidence:
  - reference: CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2025-04-04T160000.000Z
    reference_title: "CAMK2G / intellectual developmental disorder 59 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CAMK2G | HGNC:1463 | intellectual developmental disorder 59 |
      MONDO:0032795 | AD | Limited | SOP11 | Syndromic Disorders Gene
      Curation Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - reference: PMID:30184290
    reference_title: "The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we identified a second, unrelated individual, with a de
      novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro
      assays to assess the impact of this mutation on CAMK2G and
      neuronal function.
    explanation: >-
      The paper adds a second unrelated individual carrying p.Arg292Pro. This is the sample in this study,
      not a current total of all reported cases.
  - reference: PMID:30184290
    reference_title: "The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We further found that the CAMK2G p.Arg292Pro mutation acts as a
      highly pathogenic gain-of-function mutation, leading to
      increased phosphotransferase activity and impaired neuronal
      maturation as well as impaired targeting of the nuclear CAMK2G
      isoform.
    explanation: >-
      Kinase assays and cultured-neuron experiments support increased activity and abnormal maturation/localization.
      Separate in-utero mouse experiments tested migration. Kinase inactivation rescued arborization and
      migration but did not rescue abnormal nuclear targeting.
  - reference: CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2025-04-04T160000.000Z
    reference_title: "CAMK2G / intellectual developmental disorder 59 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CAMK2G was first reported in relation to autosomal dominant
      syndromic intellectual disability in 2012 (de Ligt et al., PMID
      23033978).
    explanation: >-
      The same ClinGen record that binds MONDO:0032795 describes the
      entity as syndromic intellectual disability, which is the
      disagreement with MONDO's non-syndromic placement recorded in
      this row's description.

  - reference: CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2025-04-04T160000.000Z
    reference_title: CAMK2G / intellectual developmental disorder 59 (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Two missense variants have been identified in three unrelated heterozygous individuals with de novo inheritance and similar phenotypic presentations
    explanation: The panel summary includes three individuals and two alleles; the two p.Arg292Pro cases in the 2018 study are not the complete subsequent clinical evidence.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: MRD60
  display_name: Intellectual developmental disorder 60 with seizures (AP2M1-related)
  subtype_term:
    preferred_term: AP2M1-related intellectual developmental disorder with seizures
    term:
      id: MONDO:0032823
      label: intellectual developmental disorder 60 with seizures
  genes:
  - preferred_term: AP2M1
    term:
      id: hgnc:564
      label: AP2M1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this
    entry's own term, MONDO:0015802, and records AP2M1 as its causal gene by RO:0004003. AP2M1 encodes
    the mu subunit of the AP-2 adaptor complex, which acts in clathrin-mediated endocytosis and synaptic
    vesicle recycling. The subtype was established in developmental and epileptic encephalopathy cohorts
    around a single recurrent p.Arg170Trp missense variant, and the reported mechanism is functional impairment
    of the AP-2 complex rather than reduced gene dosage, so it follows the altered-activity and endocytosis
    branch. Transferrin uptake was tested in human cells and cultured mouse astrocytes; these experiments
    do not directly measure neuronal synaptic-vesicle recycling. It pairs mechanistically with MRD56 (CLTC),
    which encodes the clathrin coat that AP-2 recruits. ClinGen's Epilepsy Gene Curation Expert Panel
    classifies the relationship as Definitive, against `complex neurodevelopmental
    disorder`. This MONDO class is already cited as a differential diagnosis on `Cardiofacioneurodevelopmental_Syndrome`,
    which models the AP-2 assembly chaperone CCDC32; that record describes the differential, while this
    row places the concept in the MRD series, so the two are complementary rather than duplicative. The
    panel leaves the gene-wide mechanism unresolved; the functional claim here is limited to the experimentally
    tested recurrent allele.
  evidence:
  - reference: CGGV:assertion_800ffff6-7cf0-4131-aa96-e3bb4f0bde76-2024-10-01T040000.000Z
    reference_title: "AP2M1 / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AP2M1 | HGNC:564 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Definitive | SOP11 | Epilepsy Gene Curation
      Expert Panel
    explanation: >-
      ClinGen's expert-panel gene-disease validity classification for
      this gene. The row also records which disease concept the panel
      curated against, which for this series is generally not the
      MRD-series term the subtype binds; the
      adnsid_clingen_disease_concept discussion on this entry collects
      that observation across all the subtypes.
  - reference: PMID:31104773
    reference_title: "A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We establish a recurrent pathogenic variant in AP2M1 as a cause
      of DEEs with distinct phenotypic features, and we implicate
      dysfunction of the early steps of endocytosis as a disease
      mechanism in epilepsy.
    explanation: >-
      The study establishing AP2M1 as causal, and the source of the
      endocytic mechanism statement.
  - reference: PMID:31104773
    reference_title: "A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1
      in two individuals with a phenotypic similarity that was higher
      than expected by chance (p = 0.003) and a phenotype related to
      epilepsy with myoclonic-atonic seizures.
    explanation: >-
      Source for the recurrent p.Arg170Trp variant recorded above.
  - reference: PMID:31104773
    reference_title: "A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AP2M1 encodes the μ-subunit of the adaptor protein complex 2
      (AP-2), which is involved in clathrin-mediated endocytosis (CME)
      and synaptic vesicle recycling.
    explanation: >-
      Places AP2M1 and CLTC on the same trafficking step, supporting
      the pairing with MRD56 recorded above.

    directness: INDIRECT
  - reference: CGGV:assertion_800ffff6-7cf0-4131-aa96-e3bb4f0bde76-2024-10-01T040000.000Z
    reference_title: AP2M1 / complex neurodevelopmental disorder (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The mechanism of pathogenicity is currently unknown.
    explanation: The panel does not assign one gene-wide mechanism. The endocytosis experiment in this entry therefore remains explicitly limited to p.Arg170Trp.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: MRD73
  display_name: Intellectual developmental disorder, autosomal dominant 73 (TAF4-related)
  subtype_term:
    preferred_term: TAF4-related autosomal dominant intellectual disability
    term:
      id: MONDO:0957536
      label: intellectual developmental disorder, autosomal dominant 73
  genes:
  - preferred_term: TAF4
    term:
      id: hgnc:11537
      label: TAF4
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    MONDO carries no textual definition for this class; it asserts the class as a direct subclass of this
    entry's own term, MONDO:0015802, and records TAF4 as its causal gene by RO:0004003. It is the highest-numbered
    member of the series MONDO files under this entry. TAF4 is a subunit of the TFIID general transcription
    factor complex, so the subtype belongs to this entry's chromatin and transcription module and shares
    features with the other TAF-opathies. The defining cohort of eight individuals reports facial dysmorphisms
    alongside the intellectual disability and names the entity `TAF4-related NDD`, not a non-syndromic
    intellectual disability. No ClinGen Gene-Disease Validity curation was found for TAF4 in the gene-validity
    release read for this pass, searched by gene symbol across the full download. Seven of eight individuals
    had ID; one improved to normal cognitive performance. Loss of function was predicted from variant
    position rather than directly demonstrated for every allele, and
    mild facial findings did not define a recognizable gestalt.
  evidence:
  - reference: PMID:35904126
    reference_title: "De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We here present a cohort of eight individuals, each carrying de
      novo putative loss-of-function (pLoF) variants in TAF4 and
      expressing phenotypes consistent with a neuro-developmental
      disorder (NDD).
    explanation: >-
      The defining cohort establishing TAF4 as a dominant
      neurodevelopmental disease gene.
  - reference: PMID:35904126
    reference_title: "De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose TAF4 as a novel dominant disease gene for NDD, and
      coin this novel disorder "TAF4-related NDD" (T4NDD).
    explanation: >-
      The authors' own naming of the entity, and the source of the
      observation that they do not describe it as non-syndromic.
  - reference: PMID:35904126
    reference_title: "De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We place T4NDD in the context of other disorders related to
      TFIID subunits, revealing shared features of T4NDD with other
      TAF-opathies.
    explanation: >-
      Source for the TAF-opathy statement recorded above.
  - reference: PMID:35904126
    reference_title: "De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TATA-binding protein associated factor 4 (TAF4) is a subunit of
      the Transcription Factor IID (TFIID) complex, a central player
      in transcription initiation.
    explanation: >-
      Places TAF4 in this entry's chromatin and transcriptional
      regulation module.

    directness: INDIRECT
references:
- reference: PMID:26503795
  title: "Genetic studies in intellectual disability and related disorders."
- reference: PMID:26748517
  title: "Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules."

- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK547654/?report=reader
  title: Intellectual Disability - StatPearls - NCBI Bookshelf
  tags:
  - StatPearls
inheritance:
- name: Autosomal dominant inheritance
  description: A heterozygous pathogenic variant can cause disease through a gene- and allele-specific mechanism. De novo variants are frequent in selected severe sporadic cohorts, while vertical transmission and parental mosaicism are documented. Penetrance and expressivity vary; a negative family history does not exclude a genetic diagnosis.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  evidence:
  - reference: PMID:19196676
    reference_title: Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation.
    explanation: First demonstration that de novo truncating variants in a single autosomal gene cause non-syndromic ID by an autosomal dominant mechanism.
  - reference: PMID:29861108
    reference_title: 'De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In two individuals, variants were inherited from a similarly affected parent, while all other variants (n = 34) occurred de novo.
    explanation: The TLK2 series includes inherited and de novo variants; two additional probands had unknown inheritance. One affected mother had low-normal IQ, so dominant inheritance does not imply complete penetrance for ID.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:28288114
    reference_title: Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: one individual with an inherited nonsense variant from a father who is low-grade mosaic
    explanation: The CIC full text distinguishes transmission from a mosaic father from the other de novo or presumed germline-mosaic cases.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
pathophysiology:
- name: Heterozygous Pathogenic Variant in a Neurodevelopmental Gene
  biological_scale: MOLECULAR
  description: Heterozygous coding variants, splice variants or structural disruptions can arise de novo or be inherited. A pathogenic effect requires gene- and allele-specific evidence; rarity, de novo occurrence and population constraint alone do not establish causality. Loss of function and altered activity lead to different downstream branches. Candidate regulatory variants are discussed separately as an emerging hypothesis.
  role: trigger
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
  evidence:
  - reference: PMID:19196676
    reference_title: Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation.
    explanation: The discovery series links heterozygous truncating SYNGAP1 variants to dominant intellectual disability; the selected cohort does not establish a category-wide diagnostic yield.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:29861108
    reference_title: 'De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In two individuals, variants were inherited from a similarly affected parent, while all other variants (n = 34) occurred de novo.
    explanation: The TLK2 series includes inherited and de novo variants; two additional probands had unknown inheritance. One affected mother had low-normal IQ, so dominant inheritance does not imply complete penetrance for ID.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:28135719
    reference_title: Prevalence and architecture of de novo mutations in developmental disorders.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function.
    explanation: The broader DDD cohort supports multiple mechanisms. Its modeled proportions are not AD-NSID penetrance or diagnostic yield.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  downstream:
  - target: Haploinsufficiency of a Dosage-Sensitive Neurodevelopmental Gene
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: For dosage-sensitive genes, particular loss-of-function variants reduce functional gene product.
    evidence:
    - reference: PMID:29861108
      reference_title: 'De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: By analyzing TLK2 transcripts in cell lines of three different individuals, we were able to confirm that transcripts were subjected to NMD in two of them, causing haploinsufficiency of TLK2.
      explanation: Patient-derived fibroblast and lymphoblastoid experiments support nonsense-mediated decay for two tested alleles; the tested last-exon stop variant escaped decay.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Altered Activity of a Neurodevelopmental Protein
    causal_link_type: DIRECT
    description: Some missense alleles alter activity without acting through simple haploinsufficiency.
    evidence:
    - reference: PMID:28669405
      reference_title: Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.
      explanation: Frog-oocyte electrophysiology establishes altered channel function for tested KCNQ5 alleles. The proposed consequences for patient neurons remain an inference.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: Haploinsufficiency of a Dosage-Sensitive Neurodevelopmental Gene
  genes:
  - preferred_term: TRIP12
    term:
      id: hgnc:12306
      label: TRIP12
  - preferred_term: NAA15
    term:
      id: hgnc:30782
      label: NAA15
  - preferred_term: TLK2
    term:
      id: hgnc:11842
      label: TLK2
  biological_scale: MOLECULAR
  description: >-
    Reduced functional dosage is an established mechanism for particular genes and variants. Transcript
    decay or loss of protein function can leave insufficient activity for neuronal development and function.
    The magnitude of reduction is assay- and allele-dependent, and a population constraint score is not
    a direct protein-dosage measurement. This branch does not represent activating or other altered-function
    alleles.
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
  evidence:
  - reference: PMID:29861108
    reference_title: >-
      De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation
      of a Distinct Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      By analyzing TLK2 transcripts in cell lines of three different individuals, we were able to confirm
      that transcripts were subjected to NMD in two of them, causing haploinsufficiency of TLK2.
    explanation: >-
      Patient-derived fibroblast and lymphoblastoid experiments support nonsense-mediated decay for two
      tested alleles; the tested last-exon stop variant escaped decay.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:28288114
    reference_title: >-
      Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and
      humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      both the protein and RNA levels of CIC were reduced to almost 50%
    explanation: >-
      Measured in fibroblasts from one CIC patient; this is direct dosage evidence for that allele, not
      a universal 50% rule.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Disrupted Synaptic Transmission and Plasticity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      For the synaptic module of AD-NSID genes, reduced gene dosage directly
      perturbs postsynaptic signalling complexes and receptor trafficking.
  - target: Disrupted Chromatin and Transcriptional Regulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      For the chromatin/transcription module, reduced dosage of a
      chromatin-modifying or transcription-regulating factor dysregulates
      neurodevelopmental gene expression programmes.
  - target: Disrupted Neuronal Cytoskeletal Dynamics and Rho GTPase Signalling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      For the cytoskeletal module, reduced dosage of a cytoskeletal regulator
      or Rho GTPase pathway component impairs actin and microtubule dynamics
      in developing neurons.

- name: Altered Activity of a Neurodevelopmental Protein
  biological_scale: MOLECULAR
  description: Activating and other altered-function alleles require functional interpretation separate from protein abundance. CAMK2G p.Arg292Pro increases kinase activity despite reduced protein stability; KCNQ5 variants can increase or decrease channel function. These findings do not establish one direction of neuronal excitability for all affected genes. AP2M1 p.Arg170Trp impairs adaptor-complex function without decreasing expression or stability in the tested cell systems.
  genes:
  - preferred_term: CAMK2G
    term:
      id: hgnc:1463
      label: CAMK2G
  - preferred_term: KCNQ5
    term:
      id: hgnc:6299
      label: KCNQ5
  - preferred_term: AP2M1
    term:
      id: hgnc:564
      label: AP2M1
  evidence:
  - reference: PMID:30184290
    reference_title: The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: although CAMK2GArg292Pro has reduced protein stability, this mutation does not lead to a loss of function of CAMK2G, but instead appears to result in a paradoxical gain‐of‐function.
    explanation: HEK293T and primary-neuron expression experiments distinguish increased activity from reduced abundance. The developmental migration assay was separately performed in mouse embryos.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:28669405
    reference_title: Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.
    explanation: Frog-oocyte electrophysiology establishes altered channel function for tested KCNQ5 alleles. The proposed consequences for patient neurons remain an inference.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Disrupted Synaptic Transmission and Plasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Allele-specific changes in channel or signaling-protein function can alter neuronal and synaptic physiology; direction and intermediate steps vary.
  - target: Impaired Clathrin-Mediated Endocytosis
    causal_link_type: DIRECT
    description: The tested AP2M1 missense variant impairs clathrin-mediated transferrin uptake.
    evidence:
    - reference: PMID:31104773
      reference_title: A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin.
      explanation: Cellular transferrin uptake assays establish impaired endocytosis for the tested variant. They do not directly measure synaptic-vesicle recycling or cognition.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: Impaired Clathrin-Mediated Endocytosis
  biological_scale: CELLULAR
  description: AP2M1 p.Arg170Trp impairs AP-2-dependent endocytosis without reduced expression, stability or membrane recruitment in the tested systems. This is a variant-specific trafficking mechanism distinct from haploinsufficiency. Its contribution to neuronal synaptic function is inferred from AP-2 biology rather than directly measured by the transferrin assay.
  genes:
  - preferred_term: AP2M1
    term:
      id: hgnc:564
      label: AP2M1
  evidence:
  - reference: PMID:31104773
    reference_title: A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin.
    explanation: Cellular transferrin uptake assays establish impaired endocytosis for the tested variant. They do not directly measure synaptic-vesicle recycling or cognition.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Disrupted Synaptic Transmission and Plasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Defective endocytic trafficking is proposed to impair neuronal and synaptic function; the cited assay does not resolve the neuronal intermediates.
    evidence:
    - reference: PMID:31104773
      reference_title: A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin.
      explanation: Cellular transferrin uptake assays establish impaired endocytosis for the tested variant. They do not directly measure synaptic-vesicle recycling or cognition.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
- name: Disrupted Synaptic Transmission and Plasticity
  genes:
  - preferred_term: SYNGAP1
    term:
      id: hgnc:11497
      label: SYNGAP1
  - preferred_term: STXBP1
    term:
      id: hgnc:11444
      label: STXBP1
  - preferred_term: GRIN2B
    term:
      id: hgnc:4586
      label: GRIN2B
  - preferred_term: DLG4
    term:
      id: hgnc:2903
      label: DLG4
  - preferred_term: CAMK2A
    term:
      id: hgnc:1460
      label: CAMK2A
  - preferred_term: CAMK2B
    term:
      id: hgnc:1461
      label: CAMK2B
  biological_scale: CELLULAR
  description: >-
    Representative synaptic genes affect postsynaptic signaling, receptor trafficking or presynaptic vesicle
    release. SYNGAP1 restrains Ras-associated signaling and AMPA receptor insertion; STXBP1 participates
    in presynaptic release. Other genes and alleles have distinct effects. These routes can disturb plasticity
    without implying that every subtype has increased excitatory transmission.
  cell_types:
  - preferred_term: glutamatergic (excitatory) neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  - preferred_term: hippocampal neuron
    term:
      id: CL:0002608
      label: hippocampal neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: ABNORMAL
  - preferred_term: regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    modifier: ABNORMAL
  - preferred_term: regulation of postsynaptic AMPA receptor levels
    term:
      id: GO:0099072
      label: regulation of postsynaptic membrane neurotransmitter receptor levels
    modifier: ABNORMAL
  - preferred_term: learning or memory
    term:
      id: GO:0007611
      label: learning or memory
    modifier: DECREASED
  molecular_functions:
  - preferred_term: Ras GTPase-activating protein activity (SYNGAP1)
    term:
      id: GO:0005096
      label: GTPase activator activity
    modifier: DECREASED
  evidence:
  - reference: PMID:23141534
    reference_title: "Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mutations that cause intellectual disability (ID) and autism spectrum
      disorder (ASD) are commonly found in genes that encode for synaptic
      proteins.
    explanation: >-
      States the synaptic-gene convergence that defines this pathophysiology
      module.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We sequenced the autosomal gene SYNGAP1, which encodes a ras
      GTPase-activating protein that is critical for cognition and synapse
      function, in 94 patients with nonsyndromic mental retardation.
    explanation: >-
      Identifies the molecular function (Ras GTPase-activating protein) whose
      loss underlies the paradigmatic AD-NSID gene.
    directness: INDIRECT
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SYNGAP1, a GTPase-activating protein that is selectively expressed in
      the brain and is a component of the NMDA-receptor complex, acts
      downstream of the receptor, blocking the insertion of the AMPA receptor
      at the postsynaptic membrane
    explanation: >-
      Describes the specific postsynaptic signalling step (restraint of AMPA
      receptor insertion via inhibition of RAS-ERK) that haploinsufficiency
      de-represses.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:19557857
    reference_title: "De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We sequenced genes coding for components of the SNARE complex (STX1A,
      VAMP2, SNAP25) and their regulatory proteins (STXBP1/Munc18-1, SYT1),
      which are essential for neurotransmission, in 95 patients with
      idiopathic mental retardation.
    explanation: >-
      Extends the synaptic module to the presynaptic release machinery,
      identifying STXBP1 as an AD-NSID gene.
    directness: INDIRECT
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The classic observation that various forms of mental retardation are
      associated with abnormalities in the morphology of dendritic spines
      suggests that disruption of pathways involved in synaptic plasticity may
      be a common mechanism of this disorder.
    explanation: >-
      States the long-standing convergence of ID pathophysiology on dendritic
      spine morphology and synaptic plasticity.
    quote_role: BACKGROUND
    directness: INDIRECT
  downstream:
  - target: Premature Dendritic Spine Maturation
    causal_link_type: DIRECT
    description: >-
      In the SYNGAP1 model, de-repressed excitatory synaptic signalling
      accelerates spine maturation and raises circuit excitability.
    evidence:
    - reference: PMID:23141534
      reference_title: "Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In the SYNGAP1 mouse model of ID/ASD, we found that dendritic spine
        synapses develop prematurely during the early postnatal period.
        Premature spine maturation dramatically enhanced excitability in the
        developing hippocampus, which corresponded with the emergence of
        behavioral abnormalities.
      explanation: >-
        Demonstrates the causal step from synaptic-gene haploinsufficiency to
        accelerated spine maturation and hyperexcitability.

- name: Disrupted Chromatin and Transcriptional Regulation
  genes:
  - preferred_term: ZBTB18
    term:
      id: hgnc:13030
      label: ZBTB18
  - preferred_term: GATAD2B
    term:
      id: hgnc:30778
      label: GATAD2B
  - preferred_term: MED13L
    term:
      id: hgnc:22962
      label: MED13L
  - preferred_term: KMT5B
    term:
      id: hgnc:24283
      label: KMT5B
  - preferred_term: TBL1XR1
    term:
      id: hgnc:29529
      label: TBL1XR1
  - preferred_term: HIVEP2
    term:
      id: hgnc:4921
      label: HIVEP2
  - preferred_term: CIC
    term:
      id: hgnc:14214
      label: CIC
  - preferred_term: TLK2
    term:
      id: hgnc:11842
      label: TLK2
  - preferred_term: SET
    term:
      id: hgnc:10760
      label: SET
  - preferred_term: TAF4
    term:
      id: hgnc:11537
      label: TAF4
  biological_scale: MOLECULAR
  description: >-
    Chromatin modifiers and transcriptional regulators affect developmental gene expression through diverse
    mechanisms. Dosage loss is demonstrated for selected alleles, while missense variants can have distinct
    effects. Computational clustering identifies chromatin-related groups among broader ID-associated
    genes; it does not prove that every gene reduces protein abundance by half or changes the same targets.
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26748517
    reference_title: "Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Systematic identification of highly enriched functional themes and
      phenotypes revealed typical phenotype combinations characterizing
      process-defined groups of ID disorders, such as chromatin-related
      disorders and deficiencies in DNA repair.
    explanation: >-
      Establishes chromatin regulation as a distinct, statistically coherent
      functional module among ID-associated genes.
  - reference: PMID:26748517
    reference_title: "Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      we show that ID-AGs are substantially enriched with co-expression,
      protein-protein interactions, and specific biological functions.
    explanation: >-
      Demonstrates that the genetically heterogeneous ID gene set is
      functionally convergent rather than random.
  - reference: PMID:25356899
    reference_title: "De novo mutations in moderate or severe intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 12 likely pathogenic DNMs were identified in genes previously
      associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5,
      MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of
      ∼29%.
    explanation: >-
      The recovered gene list is dominated by chromatin and transcriptional
      regulators, illustrating this module in a real ID cohort.
  - reference: PMID:38215144
    reference_title: "A de novo variant in ZBTB18 gene caused autosomal dominant non-syndromic intellectual disability 22 syndrome: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant non-syndromic intellectual disability 22 is a rare
      genetic disorder caused by the ZBTB18 gene.
    explanation: >-
      A ZBTB18-associated clinical diagnosis; the case report alone does not measure protein dosage or
      establish the mechanism of every allele.
    directness: INDIRECT
  - reference: PMID:36743289
    reference_title: "Dendritic spine and synapse pathology in chromatin modifier-associated autism spectrum disorders and intellectual disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Emerging evidence highlights the critical status of these chromatin
      remodeling molecules in dendritic spine morphogenesis and synaptic
      functions.
    explanation: >-
      Links the chromatin module to the same dendritic-spine and synaptic
      endpoint as the synaptic module, supporting the convergence of the two
      arms rather than treating them as parallel unrelated pathways.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  downstream:
  - target: Altered Development and Function of Neural Circuits
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dysregulated transcriptional programmes alter neuronal differentiation
      and connectivity during cortical development.
  - target: Disrupted Synaptic Transmission and Plasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Specific chromatin-regulator models alter dendritic and synaptic development; the direction and
      timing differ between genes.
    evidence:
    - reference: PMID:36743289
      reference_title: "Dendritic spine and synapse pathology in chromatin modifier-associated autism spectrum disorders and intellectual disability."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Emerging evidence highlights the critical status of these chromatin
        remodeling molecules in dendritic spine morphogenesis and synaptic
        functions.
      explanation: >-
        Review of ARID1B, KANSL1 and WDR5 models; it does not support premature spine maturation for every
        chromatin-related subtype.

      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
- name: Disrupted Neuronal Cytoskeletal Dynamics and Rho GTPase Signalling
  genes:
  - preferred_term: TRIO
    term:
      id: hgnc:12303
      label: TRIO
  biological_scale: CELLULAR
  description: >-
    Cytoskeletal regulators influence neuronal migration, neurite growth and later synaptic function.
    In TRIO, selected GEF1-domain variants reduce Rac1 activation, whereas another tested variant outside
    that domain did not alter that assay. Cytoskeletal and synaptic processes overlap in time; this module
    is not necessarily upstream of all synaptic defects.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: ABNORMAL
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: ABNORMAL
  - preferred_term: neuron projection development
    term:
      id: GO:0031175
      label: neuron projection development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34200511
    reference_title: "Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Bibliomic analysis reveals that ID genes converge onto a few biological
      modules, including cytoskeleton dynamics, whose regulation depends on
      Rho GTPases transduction.
    explanation: >-
      Establishes cytoskeletal dynamics under Rho GTPase control as one of the
      small number of convergent biological modules among ID genes.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:34200511
    reference_title: "Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Thus, cytoskeleton alterations that have an impact on cell processes
      such as neuronal migration, neuritogenesis, and synaptic plasticity
      rebound on the overall establishment of an effective network and
      consequently on the cognitive phenotype.
    explanation: >-
      Specifies the cellular processes disrupted and the propagation from
      cytoskeletal lesion through network formation to cognition.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:34200511
    reference_title: "Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More than 1000 genes have been found mutated in ID patients pointing out
      that, despite the common phenotype, the genetic bases are highly
      heterogeneous and apparently unrelated.
    explanation: >-
      A review of broader intellectual disability genetics, not the size of the AD-NSID gene set.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:27418539
    reference_title: Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The p.N1080I mutant (in individual 6) did not affect Trio-mediated Rac1 activation.
    explanation: HEK293T pull-down assays found reduced Rac1 activation for three other tested variants, demonstrating that the result is allele-specific.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Altered Development and Function of Neural Circuits
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted migration, neurite development and plasticity can alter circuit organization through gene-specific
      intermediates.
    evidence:
    - reference: PMID:34200511
      reference_title: "Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Thus, cytoskeleton alterations that have an impact on cell processes
        such as neuronal migration, neuritogenesis, and synaptic plasticity
        rebound on the overall establishment of an effective network and
        consequently on the cognitive phenotype.
      explanation: >-
        A review-level mechanistic synthesis, not direct experimental proof of every intervening step.

      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
- name: Premature Dendritic Spine Maturation
  genes:
  - preferred_term: SYNGAP1
    term:
      id: hgnc:11497
      label: SYNGAP1
  biological_scale: CELLULAR
  description: >-
    In the cited SYNGAP1 mouse model, reduced SynGAP dosage accelerates early postnatal dendritic spine-synapse
    maturation. This establishes a developmental phenotype in that model; it does not show that timing
    is the sole determinant of later function or that adult restoration cannot improve selected outcomes.
  locations:
  - preferred_term: hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  cell_types:
  - preferred_term: hippocampal neuron
    term:
      id: CL:0002608
      label: hippocampal neuron
  biological_processes:
  - preferred_term: dendritic spine development
    term:
      id: GO:0060996
      label: dendritic spine development
    modifier: ABNORMAL
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:23141534
    reference_title: "Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the SYNGAP1 mouse model of ID/ASD, we found that dendritic spine
      synapses develop prematurely during the early postnatal period.
    explanation: >-
      Directly demonstrates accelerated dendritic spine synapse maturation in
      a genetic mouse model of AD-NSID.
  downstream:
  - target: Cortical Hyperexcitability
    causal_link_type: DIRECT
    description: >-
      Prematurely mature spines drive excessive excitability in the developing
      hippocampus.
    evidence:
    - reference: PMID:23141534
      reference_title: "Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Premature spine maturation dramatically enhanced excitability in the
        developing hippocampus, which corresponded with the emergence of
        behavioral abnormalities.
      explanation: >-
        States the causal step from mistimed spine maturation to
        hyperexcitability in the same model.

- name: Cortical Hyperexcitability
  genes:
  - preferred_term: SYNGAP1
    term:
      id: hgnc:11497
      label: SYNGAP1
  biological_scale: CELLULAR
  description: >-
    SYNGAP1 mouse studies demonstrate increased excitability in developing hippocampal circuits. Later
    experiments also implicate ongoing adult SynGAP function in seizure susceptibility and interictal
    discharges. These findings are not a universal excitation model for every dominant ID subtype.
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  cell_types:
  - preferred_term: hippocampal neuron
    term:
      id: CL:0002608
      label: hippocampal neuron
  biological_processes:
  - preferred_term: excitatory postsynaptic potential
    term:
      id: GO:0060079
      label: excitatory postsynaptic potential
    modifier: INCREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:23141534
    reference_title: "Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data demonstrate that SynGAP protein acts as a critical
      developmental repressor of neural excitability that promotes the
      development of life-long cognitive abilities.
    explanation: >-
      Frames the gene product's normal role as a developmental brake on
      excitability whose loss produces the hyperexcitable state.
  downstream:
  - target: Altered Development and Function of Neural Circuits
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mistimed synaptic development is proposed to affect circuit refinement; the cited authors frame
      the causal interpretation as a model.
    evidence:
    - reference: PMID:23141534
      reference_title: "Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We propose that the pace of dendritic spine synapse maturation in early
        life is a critical determinant of normal intellectual development.
      explanation: >-
        An explicit mechanistic proposal rather than a demonstration that hyperexcitability alone causes
        cognitive impairment.

      directness: INDIRECT
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: In SYNGAP1-related disease, altered excitability contributes to seizure susceptibility. Human epilepsy observations and adult mouse restoration support this route without establishing the intermediates or its applicability to every subtype.
    evidence:
    - reference: PMID:19196676
      reference_title: Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Two of the patients were mildly epileptic.
      explanation: Epilepsy present in 2 of the 3 patients in the original non-syndromic SYNGAP1 series, and mild/controllable in both.
    - reference: PMID:31025938
      reference_title: Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Adult restoration of SynGAP protein improved behavioral and electrophysiological measures of memory and seizure.
      explanation: Adult mouse genetic restoration supports an ongoing contribution to seizure-related physiology; it is indirect evidence for the human causal path.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
- name: Altered Development and Function of Neural Circuits
  biological_scale: TISSUE
  description: Changes in neuronal maturation and connectivity can contribute to cognitive impairment, while ongoing gene function also remains relevant in mature circuits. Earlier SYNGAP1 mouse experiments found developmental restrictions for particular behavioral outcomes. Later adult restoration rescued remote contextual memory and selected seizure and electrophysiological outcomes, while some other behaviors remained abnormal. These model-specific results do not establish a universal early deadline for human treatment.
  biological_processes:
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
    modifier: ABNORMAL
  - preferred_term: modulation of chemical synaptic transmission
    term:
      id: GO:0050804
      label: modulation of chemical synaptic transmission
    modifier: ABNORMAL
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:23141534
    reference_title: Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Inducing SYNGAP1 mutations after critical developmental windows closed had minimal impact on spine synapse function, whereas repairing these pathogenic mutations in adulthood did not improve behavior and cognition.
    explanation: The earlier mouse experiment reported failure to rescue the tested behaviors in adulthood. Later experiments used different endpoints and found substantial adult reversibility.
    directness: INDIRECT
  - reference: PMID:23141534
    reference_title: Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We propose that the pace of dendritic spine synapse maturation in early life is a critical determinant of normal intellectual development.
    explanation: States the developmental-timing model linking synaptic maturation pace to intellectual outcome.
    directness: INDIRECT
  - reference: PMID:31025938
    reference_title: Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: genetic reversal ofSyngap1pathogenicity in adult mice reverses deficits in remote memory
    explanation: Adult genetic restoration improved remote contextual memory in mice; this is endpoint-specific preclinical evidence and does not establish human therapeutic efficacy.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Impaired Intellectual and Adaptive Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Altered neural development and ongoing circuit function can contribute to cognitive and adaptive impairment through subtype-specific intermediates.
    evidence:
    - reference: PMID:34200511
      reference_title: 'Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Thus, cytoskeleton alterations that have an impact on cell processes such as neuronal migration, neuritogenesis, and synaptic plasticity rebound on the overall establishment of an effective network and consequently on the cognitive phenotype.
      explanation: A review-level mechanistic synthesis, not direct experimental proof of every intervening step.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
- name: Impaired Intellectual and Adaptive Function
  biological_scale: ORGANISM
  description: Intellectual and adaptive impairment begins during development. Severity and trajectory vary by diagnosis; a lack of a recognizable syndrome at presentation does not prove brain-restricted biology, absence of other features or a uniformly static course. Some gene-associated cohorts include regression or individuals without formal intellectual disability.
  evidence:
  - reference: PMID:19196676
    reference_title: Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The absence of specific dysmorphic features and growth abnormalities in these patients is consistent with the fact that SYNGAP1 is exclusively expressed in the brain.
    explanation: An interpretation of three selected SYNGAP1 cases in the 2009 paper; brain expression does not prove that all associated clinical findings are restricted to cognition.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:19196676
    reference_title: Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Most patients have the nonsyndromic form of the disorder, which is characterized by the absence of associated morphologic, radiologic, and metabolic features.
    explanation: Defines the non-syndromic category operationally.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:33057194
    reference_title: Evidence for 28 genetic disorders discovered by combining healthcare and research data.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: patients with DNMs in the same novel DD-associated gene were less phenotypically similar to each other, on average, than patients with DNMs in a consensus gene
    explanation: Phenotypic-similarity analysis in a broader developmental-disorder cohort; it supports an ascertainment hypothesis rather than proving every newly discovered gene is non-syndromic.
    directness: INDIRECT
  - reference: PMID:38378692
    reference_title: The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a subset of patients experiencing developmental regression in later childhood.
    explanation: Caregiver survey of TBL1XR1-related disorders supports variable trajectory; recall, selection and diagnostic-verification limitations preclude a class-wide frequency estimate.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Intellectual Disability
    causal_link_type: DIRECT
    description: The clinical phenotype records the intellectual and adaptive impairment represented by this terminal disease process.
    evidence:
    - reference: PMID:19196676
      reference_title: Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation.
      explanation: The SYNGAP1 cases provide a clinical example of the intellectual-disability endpoint; this edge names the manifestation of intellectual and adaptive impairment rather than a separate molecular step.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
mechanistic_hypotheses:
- hypothesis_group_id: nonsyndromic_boundary_is_ascertainment
  hypothesis_label: >-
    The non-syndromic/syndromic boundary reflects depth of phenotyping rather
    than a distinct mechanism
  status: EMERGING
  description: >-
    The non-syndromic label can reflect the phenotype recognized at a particular age and depth of assessment.
    Larger gene-specific series may reveal recurrent clinical patterns. Tissue expression may influence
    presentation but does not by itself prove an exclusively cognitive phenotype. These explanations can
    coexist; this category does not establish a unique common disease mechanism.
  evidence:
  - reference: PMID:23020937
    reference_title: "Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several patients did not meet the expected syndromic manifestation,
      suggesting a strong bias in present clinical syndrome descriptions.
    explanation: >-
      Explicitly attributes syndromic/non-syndromic misclassification to bias
      in existing clinical syndrome descriptions.
  - reference: PMID:23020937
    reference_title: "Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The large number of de-novo variants in known intellectual disability
      genes is only partially attributable to known non-specific phenotypes.
    explanation: >-
      Notes that patients ascertained as non-syndromic frequently carry
      variants in genes catalogued as syndromic.
  - reference: PMID:26989088
    reference_title: "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SYNGAP1 encephalopathy is characterised by early neurodevelopmental
      delay typically preceding the onset of a relatively recognisable
      epilepsy comprising generalised seizures (absences, myoclonic jerks) and
      frequent triggers.
    explanation: >-
      Worked example of the predicted migration: SYNGAP1, first reported as a
      cause of NON-syndromic ID, is redescribed as a recognisable
      developmental and epileptic encephalopathy once a larger series is
      phenotyped.

- hypothesis_group_id: adnsid_regulatory_variants
  hypothesis_label: Regulatory variants may contribute to unresolved intellectual disability
  status: EMERGING
  description: A severe-ID study of 47 coding-negative individuals identified de novo variants in fetal-brain enhancers. Candidate target assignment combined chromatin contacts, epigenomic correlations and proximity; only the POU3F3 enhancer cluster showed significant enrichment in the larger replication cohort. Selected variants increased or decreased reporter activity. For one SOX8 candidate, precise variant introduction into HEK293T cells reduced SOX8 expression, while separate CRISPR interference of the whole enhancer in neural progenitors supported its regulatory role. These experiments distinguish sequence alteration, regulatory target and expression consequence, but do not establish clinical causality or penetrance for every candidate allele.
  evidence:
  - reference: PMID:36854624
    reference_title: Regulatory de novo mutations underlying intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We found that regulatory DNMs were selectively enriched in fetal brain-specific enhancers as compared with adult brain enhancers.
    explanation: Enrichment among regulatory candidates in a small, selected severe-ID cohort; it does not establish every variant as disease-causing.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  - reference: PMID:36854624
    reference_title: Regulatory de novo mutations underlying intellectual disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Using CRISPR-mediated mutation and editing of epigenomic marks, we show that DNMs at regulatory elements affect the expression of putative target genes.
    explanation: The precise SOX8-associated allele was tested in HEK293T cells; neural-progenitor CRISPR interference perturbed the enhancer rather than reproducing that allele.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
phenotypes:
- category: Neurologic
  name: Intellectual Disability
  description: >-
    Significantly impaired intellectual functioning and adaptive behaviour
    with onset in the developmental period. Severity across the AD-NSID class
    spans mild to severe; cohorts ascertained for trio exome sequencing have
    been enriched for moderate-to-severe disability (e.g. IQ below 50).
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:23033978
    reference_title: "Diagnostic exome sequencing in persons with severe intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We then sequenced the coding regions of more than 21,000 genes obtained
      from 100 patients with an IQ below 50 and their unaffected parents.
    explanation: >-
      Defines the core cognitive phenotype and the severity band of the
      cohorts in which the disease class was characterised.
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Scores on the Mullen Scales of Early Learning and the Vineland Adaptive
      Behavior Scales showed profiles that were consistent with
      moderate-to-severe mental retardation in all patients.
    explanation: >-
      Intellectual disability defines inclusion in this clinical category. This does not mean that every
      carrier of a variant in a listed gene has intellectual disability; some broader gene-associated
      cohorts include individuals with normal or borderline cognition.

- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Delay across multiple developmental streams is the presenting feature in
    infancy and early childhood, before an IQ-based diagnosis of intellectual
    disability can be established.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:26989088
    reference_title: "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental delay was the first manifestation of SYNGAP1-related
      encephalopathy; intellectual disability became progressively obvious and
      was associated with autistic behaviours in eight patients.
    explanation: >-
      Documents developmental delay as the presenting manifestation preceding
      an established ID diagnosis. Frequency is intentionally omitted: this
      snippet establishes the temporal ordering of the phenotype, not a
      cohort proportion, and no class-level frequency estimate exists.
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their early development was characterized by global delay and hypotonia,
      with the onset of walking at the age of 2 years.
    explanation: >-
      Direct description of global developmental delay in molecularly
      confirmed AD-NSID.

- category: Neurologic
  name: Delayed Speech and Language Development
  description: >-
    Expressive language is disproportionately affected in several AD-NSID
    entities; severe language impairment was a defining feature of the
    original SYNGAP1 series and remains a common presenting complaint.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disruption of SYNGAP1 appears to be associated with a homogeneous
      clinical phenotype that is characterized by moderate-to-severe mental
      retardation accompanied by severe language impairment.
    explanation: >-
      Identifies severe language impairment as a prominent feature of the
      paradigmatic AD-NSID entity.
  - reference: PMID:38215144
    reference_title: "A de novo variant in ZBTB18 gene caused autosomal dominant non-syndromic intellectual disability 22 syndrome: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He struggles with expressing themselves and forming complete sentences,
      relying mostly on gestures and pointing.
    explanation: >-
      Expressive language impairment in a molecularly confirmed MRD22 case.
- category: Neurologic
  name: Hypotonia
  description: >-
    Hypotonia occurs in several gene-associated disorders. It is nonspecific, and its frequency in individual
    series is not a frequency for this heterogeneous category.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:26989088
    reference_title: "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotonia and unstable gait were frequent associated neurological
      features.
    explanation: >-
      Reported as frequent in the 17-person SYNGAP1 series; no class-wide frequency is inferred.

- category: Neurologic
  name: Seizures
  description: >-
    Epilepsy is a common comorbidity in several AD-NSID entities, ranging from
    well-controlled generalised seizures to a pharmacoresistant developmental
    and epileptic encephalopathy. Its presence is one of the features that
    most often triggers reclassification of a nominally non-syndromic
    gene-disease pair as a recognisable syndrome; conversely, some MRD-series
    entities (e.g. ZBTB18/MRD22) present without epilepsy.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of the patients were mildly epileptic."
    explanation: >-
      Epilepsy present in 2 of the 3 patients in the original non-syndromic
      SYNGAP1 series, and mild/controllable in both.
  - reference: PMID:19557857
    reference_title: "De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified de novo mutations in STXBP1 (nonsense, p.R388X; splicing,
      c.169+1G>A) in two patients with severe mental retardation and
      nonsyndromic epilepsy.
    explanation: >-
      Documents epilepsy co-occurring with non-syndromic ID under a de novo
      autosomal dominant lesion.
  - reference: PMID:38215144
    reference_title: "A de novo variant in ZBTB18 gene caused autosomal dominant non-syndromic intellectual disability 22 syndrome: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, he did not have growth retardation, microcephaly, corpus
      callosum hypoplasia, epilepsy, or dysmorphic facial features.
    explanation: >-
      A reported ZBTB18 case lacked epilepsy. Different selected gene-specific cohorts do not provide
      a pooled class-wide frequency; the 17-person SYNGAP1 series included 16 with epilepsy and one with
      a single seizure.

- category: Behavioral
  name: Autistic Behaviour
  description: >-
    Autistic behaviors and autism diagnoses can occur in several gene-associated disorders, but they are
    not universal or interchangeable. The 17-person SYNGAP1 series reported autistic behaviors in eight;
    this does not establish an ASD diagnosis in each or a category-wide frequency.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:26989088
    reference_title: "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intellectual disability became progressively obvious and was associated
      with autistic behaviours in eight patients
    explanation: >-
      Autistic behaviour in 8 of 17 patients in a molecularly defined AD-NSID
      series.
  - reference: PMID:21237447
    reference_title: "De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide evidence that truncating mutations in SYNGAP1 are common in
      NSID and can be also associated with autism.
    explanation: >-
      Establishes the conditional ("can be also associated") rather than
      obligate relationship between AD-NSID and autism.
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonverbal social interactions were within the normal range. In
      particular, evaluation of Patient 3 with the Autism Diagnostic
      Observation Schedule was negative.
    explanation: >-
      The 2009 SYNGAP1 paper reports a negative formal ADOS assessment for patient 3 and other clinical
      observations for the remaining patients; it does not report three negative structured assessments.

- category: Neurologic
  name: Delayed Ability to Walk
  description: >-
    Independent walking can be delayed, with timing varying substantially by gene, allele and severity.
    Ages in a three-patient series do not establish the typical age for the whole category.
  phenotype_term:
    preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
  evidence:
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their early development was characterized by global delay and hypotonia,
      with the onset of walking at the age of 2 years.
    explanation: >-
      Documents delayed independent ambulation in the index AD-NSID series.
      Frequency is intentionally omitted: the source describes three patients
      and reports no proportion.

genetic:
- name: SYNGAP1
  gene_term:
    preferred_term: SYNGAP1
    term:
      id: hgnc:11497
      label: SYNGAP1
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    MRD5. The paradigmatic AD-NSID gene: a brain-restricted Ras
    GTPase-activating protein in the NMDA receptor complex. Note that larger
    later series redescribe SYNGAP1 disease as a recognisable developmental
    and epileptic encephalopathy, making it the clearest worked example of the
    non-syndromic-to-syndromic migration.
  evidence:
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified de novo truncating mutations (K138X, R579X, and
      L813RfsX22) in three of these patients.
    explanation: >-
      Three independent de novo protein-truncating variants in 94 patients
      with non-syndromic ID.
  - reference: PMID:21237447
    reference_title: "De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated
      with autism.
    explanation: >-
      The replication study identified three variants in 60 additional selected sporadic cases, including
      one patient with autism. Its reference to three of 94 in the background describes the original cohort.

    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: STXBP1
  gene_term:
    preferred_term: STXBP1
    term:
      id: hgnc:11444
      label: STXBP1
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    Encodes Munc18-1, an essential regulator of SNARE-mediated synaptic
    vesicle fusion. One of the three recurrently mutated genes in the Rauch
    severe sporadic non-syndromic ID cohort.
  evidence:
  - reference: PMID:19557857
    reference_title: "De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results suggest that STXBP1 disruption is associated with
      autosomal dominant mental retardation and nonsyndromic epilepsy.
    explanation: >-
      Establishes STXBP1 as an autosomal dominant non-syndromic ID gene.
  - reference: PMID:23020937
    reference_title: "Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      16 patients carried de-novo variants in known intellectual disability
      genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A).
    explanation: >-
      Independent replication of STXBP1 recurrence in a severe sporadic
      non-syndromic ID cohort.

- name: ZBTB18
  gene_term:
    preferred_term: ZBTB18
    term:
      id: hgnc:13030
      label: ZBTB18
  relationship_type: CAUSATIVE
  subtype: MRD22
  variant_origin: DE_NOVO
  notes: >-
    MRD22. ZBTB18 encodes a transcriptional repressor. The 2024 case report counted 31 previously reported
    cases; that historical count is neither current prevalence nor proof that the phenotype remains non-syndromic.
  evidence:
  - reference: PMID:38215144
    reference_title: "A de novo variant in ZBTB18 gene caused autosomal dominant non-syndromic intellectual disability 22 syndrome: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical whole exome sequencing revealed a de novo pathogenic variant in
      the ZBTB18 gene (c.1207delC, p. Arg403Alafs*60), which is a previously
      unreported site.
    explanation: >-
      De novo frameshift variant in a patient diagnosed with MRD22.
  - reference: PMID:38215144
    reference_title: "A de novo variant in ZBTB18 gene caused autosomal dominant non-syndromic intellectual disability 22 syndrome: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is noteworthy that only 31 cases of this disorder have been reported
      thus far.
    explanation: >-
      A historical count reported in the 2024 article, not a current census or causal explanation of diagnostic
      classification.

- name: GRIN2B
  gene_term:
    preferred_term: GRIN2B
    term:
      id: hgnc:4586
      label: GRIN2B
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    MRD6. Encodes the GluN2B subunit of the NMDA receptor - the receptor
    complex that SYNGAP1 also acts within - placing it squarely in the
    synaptic module.
  evidence:
  - reference: PMID:25356899
    reference_title: "De novo mutations in moderate or severe intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 12 likely pathogenic DNMs were identified in genes previously
      associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5,
      MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of
      ∼29%.
    explanation: >-
      GRIN2B recovered as a de novo cause in a moderate-to-severe ID trio
      cohort.

- name: GATAD2B
  gene_term:
    preferred_term: GATAD2B
    term:
      id: hgnc:30778
      label: GATAD2B
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    A subunit of the NuRD chromatin-remodelling complex; a member of the
    chromatin/transcription module.
  evidence:
  - reference: PMID:25356899
    reference_title: "De novo mutations in moderate or severe intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 12 likely pathogenic DNMs were identified in genes previously
      associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5,
      MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of
      ∼29%.
    explanation: >-
      GATAD2B recovered as a de novo cause in a moderate-to-severe ID trio
      cohort.

- name: MED13L
  gene_term:
    preferred_term: MED13L
    term:
      id: hgnc:22962
      label: MED13L
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    MED13L encodes a Mediator-complex subunit. It is retained as a historical dominant-ID example; the
    cited severity-selected cohort does not establish membership in a non-syndromic category. Gene-specific
    clinical interpretation belongs to MED13L syndrome.
  evidence:
  - reference: PMID:25356899
    reference_title: "De novo mutations in moderate or severe intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 12 likely pathogenic DNMs were identified in genes previously
      associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5,
      MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of
      ∼29%.
    explanation: >-
      Supports MED13L as a dominant ID gene in a cohort selected by severity, not by absence of syndromic
      features.

    directness: INDIRECT
- name: TRIO
  gene_term:
    preferred_term: TRIO
    term:
      id: hgnc:12303
      label: TRIO
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Illustrates the cytoskeletal/Rho GTPase module: TRIO is a Dbl-family
    guanine nucleotide exchange factor that activates Rac1 and controls actin
    dynamics in developing neurons. Included here with two explicit caveats
    that make it instructive rather than clean. First, the best-characterised
    TRIO series reports microcephaly and dysmorphism alongside the ID, so this
    gene-disease pair sits on the syndromic side of an unstable boundary.
    Second, that series includes an autosomal dominant frameshift that
    SEGREGATED through a family as well as de novo missense variants,
    demonstrating that the class is not exclusively de novo. Both caveats
    argue against treating "autosomal dominant" and "de novo" as synonyms.
    A third caveat is that the head-size feature is not directionally fixed:
    TRIO-related disease includes both MRD44 with microcephaly and MRD63 with
    macrocephaly. The dedicated TRIO-Related Neurodevelopmental Disorder entry
    now models that domain-resolved, RAC1-direction-dependent split and is the
    canonical home for TRIO variants and mechanisms. TRIO is retained here only
    as a boundary exemplar, not as a clean non-syndromic gene; the cephalic and
    dysmorphic findings illustrate why umbrella AD-NSID membership is partial
    (see GitHub issue 6041).
  evidence:
  - reference: PMID:27418539
    reference_title: "Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trio is a Dbl family guanine nucleotide exchange factor (GEF) and a
      major regulator of neuronal development, controlling actin cytoskeleton
      dynamics by activating the GTPase Rac1.
    explanation: >-
      Places TRIO in the cytoskeletal/Rho GTPase pathophysiology module.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:27418539
    reference_title: "Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a frameshift deletion in TRIO that segregated autosomal
      dominantly. By scrutinising data from DDD, we further identified three
      unrelated children with a similar phenotype who harboured de novo
      missense mutations in TRIO.
    explanation: >-
      Documents both an inherited autosomal dominant lesion and de novo
      lesions in the same gene, supporting the caveat that AD-NSID is not
      exclusively a de novo class.
  - reference: PMID:27418539
    reference_title: "Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, we identify pathogenic de novo missense mutations in TRIO
      associated with the same consistent phenotype, intellectual disability,
      microcephaly and dysmorphism with striking digital features.
    explanation: >-
      The reported microcephaly and dysmorphism limit the use of this series as evidence for a non-syndromic
      category.
    directness: INDIRECT
- name: CAMK2A
  gene_term:
    preferred_term: CAMK2A
    term:
      id: hgnc:1460
      label: CAMK2A
  relationship_type: CAUSATIVE
  subtype: MRD53
  variant_origin: DE_NOVO
  notes: >-
    Included because Open Targets lists CAMK2A among the genes associated with
    MONDO:0015802 specifically, anchoring this entry to the curated umbrella
    entity rather than to the general de novo ID literature. The alpha subunit
    of calcium/calmodulin-dependent protein kinase II - a synaptic-module gene
    whose autophosphorylation state governs plasticity and neuronal migration.
  evidence:
  - reference: PMID:29100089
    reference_title: "De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through a multi-center collaborative study based on a whole-exome
      sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or
      CAMK2B variants in 24 unrelated individuals with intellectual
      disability.
    explanation: >-
      Establishes CAMK2A as a de novo heterozygous cause of intellectual
      disability in a multi-centre trio-sequencing cohort.
  - reference: PMID:29100089
    reference_title: "De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We further found that all mutations affecting auto-phosphorylation also
      affected neuronal migration, highlighting the importance of tightly
      regulated CAMK2 auto-phosphorylation in neuronal function and
      neurodevelopment.
    explanation: >-
      Neuronal migration was tested after in-utero electroporation of E14.5 mouse embryos; cultured-cell
      phosphorylation assays were separate. This is preclinical mechanism evidence, not a direct patient
      measurement.

- name: DLG4
  gene_term:
    preferred_term: DLG4
    term:
      id: hgnc:2903
      label: DLG4
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    DLG4 encodes the postsynaptic scaffold PSD-95. The cited 53-person series found prominent neurodevelopmental
    features without a distinct facial gestalt; this does not establish exclusively cerebral biology.
    The dedicated DLG4-related synaptopathy entry carries gene-specific clinical detail.
  evidence:
  - reference: PMID:33597769
    reference_title: "DLG4-related synaptopathy: a new rare brain disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical picture was predominated by early onset global
      developmental delay, intellectual disability, autism spectrum disorder,
      and attention deficit-hyperactivity disorder, all of which point to a
      brain disorder.
    explanation: >-
      Predominantly neurodevelopmental findings in the 53-person series; this does not demonstrate absence
      of extra-neurological manifestations.
  - reference: PMID:33597769
    reference_title: "DLG4-related synaptopathy: a new rare brain disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      despite some overlapping features, a distinct facial dysmorphism could
      not be established
    explanation: >-
      Explicit negative finding for a recognisable dysmorphic gestalt,
      supporting non-syndromic classification on positive grounds rather than
      by default.

- name: KMT5B
  gene_term:
    preferred_term: KMT5B
    term:
      id: hgnc:24283
      label: KMT5B
  relationship_type: CAUSATIVE
  subtype: MRD51
  variant_origin: DE_NOVO
  notes: >-
    A histone H4K20 methyltransferase; a chromatin/transcription-module gene
    listed by Open Targets against MONDO:0015802. Included with the caveat
    that the associated macrocephaly/overgrowth is itself a recognisable
    feature, so KMT5B is a further candidate for migration out of the
    non-syndromic class.
  evidence:
  - reference: PMID:35433545
    reference_title: "Refining the Phenotypic Spectrum of KMT5B-Associated Developmental Delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, deleterious heterozygous variants in KMT5B were implicated in
      individuals with intellectual disability (ID) and/or autism spectrum
      disorder.
    explanation: >-
      Establishes heterozygous KMT5B variants as a cause of intellectual
      disability, placing the gene in the chromatin/transcription module.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:35433545
    reference_title: "Refining the Phenotypic Spectrum of KMT5B-Associated Developmental Delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      suggest that this gene should be considered in the differential
      diagnosis of neurodevelopmental disorders accompanied by macrocephaly
      and/or overgrowth
    explanation: >-
      Recurrent macrocephaly or overgrowth suggests a broader clinical pattern and limits a strictly non-syndromic
      interpretation; one feature alone is not a syndromic diagnosis.

    directness: INDIRECT
- name: DPP6
  gene_term:
    preferred_term: DPP6
    term:
      id: hgnc:3010
      label: DPP6
  relationship_type: DISPUTED
  notes: >-
    Recorded as a disposition, not as a cause. MONDO asserts
    `intellectual disability, autosomal dominant 33` (MONDO:0014580) as
    a direct subclass of this entry's own term and defines it as any
    autosomal dominant non-syndromic intellectual disability caused by a
    mutation in DPP6. No `has_subtypes` row was created for
    MONDO:0014580, because ClinGen's Intellectual Disability and Autism
    Gene Curation Expert Panel classifies the DPP6 gene-disease
    relationship as Disputed and states that no valid evidence remains
    to support it. The panel re-examined the same 2013 microcephaly
    variants that the OMIM and MONDO concept rests on and did not score
    them. DPP6 is curated elsewhere in this knowledge base for an
    unrelated cardiac phenotype
    (`Paroxysmal_Familial_Ventricular_Fibrillation`); nothing here bears
    on that.
  evidence:
  - reference: CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T100000.000Z
    reference_title: "DPP6 / complex neurodevelopmental disorder (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      DPP6 | HGNC:3010 | complex neurodevelopmental disorder |
      MONDO:0100038 | AD | Disputed | SOP8 | Intellectual Disability
      and Autism Gene Curation Expert Panel
    explanation: >-
      The expert-panel classification itself: Disputed, not Definitive
      or Limited.
  - reference: CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T100000.000Z
    reference_title: "DPP6 / complex neurodevelopmental disorder (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Taken together, the available genetic evidence fails to support
      a role for heterozygous disruption of DPP6 in ID, autism or
      other neurodevelopmental disorders.
    explanation: >-
      The panel's summary judgement, which is the reason MONDO:0014580
      has no subtype row on this entry.
  - reference: CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T100000.000Z
    reference_title: "DPP6 / complex neurodevelopmental disorder (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Given the lack of evidence supporting their role in disease and
      the fact that no other DPP6 variants have been reported in
      association with microcephaly and ID, these variants were not
      scored.
    explanation: >-
      Establishes that the panel examined the same variants the MRD33
      concept is built on and declined to score them, so this is a
      re-assessment of the founding evidence rather than an
      independent negative study.
  - reference: PMID:23832105
    reference_title: "Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data indicate that the loss-of-function variations in DPP6
      are associated with autosomal dominant microcephaly and mental
      retardation.
    explanation: >-
      The original report the MRD33 concept rests on, recorded so the
      disputed claim is visible alongside the dispute rather than only
      asserted against. Note that even as stated it describes
      microcephaly, not isolated non-syndromic intellectual
      disability.

diagnosis:
- name: Molecular Diagnosis by Exome or Genome Sequencing
  description: Exome or genome sequencing is used early in the evaluation of unexplained developmental delay or intellectual disability. The 2021 ACMG guideline recommends it as a first- or second-tier test, guided by clinical context. Parental samples improve interpretation of de novo occurrence and segregation, but testing the child alone or with one parent remains useful when a trio is unavailable. A diagnosis requires a pathogenic or likely pathogenic result consistent with the gene mechanism and phenotype; de novo status or a variant of uncertain significance alone is insufficient. Copy-number sensitivity depends on the platform and analysis, and chromosomal microarray or other complementary testing may still be needed.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:31182824
    reference_title: 'Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions.
    explanation: Meta-analysis of broader neurodevelopmental cohorts, including causes outside AD-NSID. The isolated-NDD yield is not a yield for confirmed autosomal dominant disease.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:31182824
    reference_title: 'Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.
    explanation: The 2019 consensus supports early exome sequencing; it does not establish that chromosomal microarray is unnecessary in every workflow.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: url:https://www.nature.com/articles/s41436-021-01242-6
    reference_title: 'Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG) | Genetics in Medicine'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Best practice includes familial comparators (“trio”) if available
    explanation: The same guideline paragraph explicitly allows effective proband-only or duo analysis with somewhat lower yield; trio design is preferred when available, not mandatory.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Exclusion of Recognised Syndromic and Metabolic Causes
  description: >-
    Clinical history, developmental assessment and examination guide the search for a recognizable syndrome
    or alternative cause. A non-syndromic presentation can change with age or deeper phenotyping. Tests
    for repeat expansions, methylation abnormalities, metabolic disease or structural brain findings should
    follow clinical context and assay limitations; the historical workup of a discovery cohort is not
    a universal modern prerequisite.
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  evidence:
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mental retardation was unexplained in these patients despite standard
      investigations, including karyotyping, subtelomeric fluorescence in situ
      hybridization analysis, or comparative genomic hybridization targeting
      regions associated with known syndromes, molecular testing for the
      common expansion mutation in FMR1, and computed tomography or magnetic
      resonance imaging of the brain.
    explanation: >-
      Describes enrollment investigations in the 2009 discovery cohort, rather than prescribing the same
      workup for every current patient.
    directness: INDIRECT
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients were examined by at least one experienced clinical
      geneticist, who ruled out the presence of specific dysmorphic features.
    explanation: >-
      Expert dysmorphology assessment is the clinical step that assigns a case
      to the non-syndromic category.

treatments:
- name: Genetic Counselling and Recurrence-Risk Assessment
  description: >-
    Genetic counseling uses the molecular result, parental testing and phenotype to assess recurrence.
    Apparently de novo variants can reflect parental somatic or germline mosaicism. A negative blood test
    does not exclude germline mosaicism, and the blood variant fraction is not an individual gamete-based
    recurrence probability. The broader genomic-disorder models cited here do not provide one recurrence
    rate for all AD-NSID.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25087610
    reference_title: "Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we show that somatic mosaicism for transmitted mutations among
      parents of children with simplex genetic disease is more common than
      currently appreciated.
    explanation: >-
      Establishes that apparently de novo variants in simplex cases can arise
      from underdetected parental mosaicism, the basis for a non-zero
      recurrence-risk counselling message.
  - reference: PMID:25087610
    reference_title: "Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Integrated probabilistic modeling of gametogenesis developed in response
      to our observations predicts that mutations in parental blood increase
      recurrence risk substantially more than parental mutations confined to
      the germline.
    explanation: >-
      A probabilistic model of genomic-disorder recurrence, not an individualized risk rule inferred from
      blood mosaicism.
    directness: INDIRECT
  - reference: PMID:34697084
    reference_title: "Somatic mosaicism detected by genome-wide sequencing in 500 parent-child trios with suspected genetic disease: clinical and genetic counseling implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present 12 cases of apparent mosaicism identified in the CAUSES
      cohort: nine cases of parental mosaicism for a disease-causing variant
      found in a child and three cases of mosaicism in the proband for a de
      novo variant.
    explanation: >-
      Mosaicism found in 500 trios referred for suspected genetic disease, not an unselected population
      or an AD-NSID-specific frequency.
  - reference: PMID:34697084
    reference_title: "Somatic mosaicism detected by genome-wide sequencing in 500 parent-child trios with suspected genetic disease: clinical and genetic counseling implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In six of these cases, there was no evidence of mosaicism on Sanger
      sequencing-the variant was not detected on Sanger sequencing in three
      cases, and it appeared to be heterozygous in three others.
    explanation: >-
      Sanger sequencing did not identify mosaicism in six of these twelve selected cases. This is not
      an estimate of test sensitivity for all mosaic variants.

- name: Early Intervention, Rehabilitation, and Special Education
  description: >-
    Management includes individualized developmental, educational and rehabilitation support. Needs and
    services vary by age, function and molecular diagnosis. The cited evidence does not establish a universal
    treatment deadline or a single disease-modifying treatment status across all gene-associated disorders.
  treatment_term:
    preferred_term: early intervention and special education
    term:
      id: NCIT:C15315
      label: Rehabilitation
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:38215144
    reference_title: "A de novo variant in ZBTB18 gene caused autosomal dominant non-syndromic intellectual disability 22 syndrome: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "INTERVENTIONS: Rehabilitation training."
    explanation: >-
      Rehabilitation was reported in one ZBTB18 case; treatment use alone does not demonstrate efficacy
      or absence of other therapeutic options.

  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK547654/?report=reader
    reference_title: Intellectual Disability - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: Educational support is a crucial component of the management of intellectual disability.
    explanation: General intellectual-disability care guidance supports educational services tailored to individual needs; it is not evidence of molecular correction or an AD-NSID-specific treatment effect.
- name: Speech and Language Therapy
  description: >-
    Communication support is tailored to language and adaptive needs. Severe language impairment in SYNGAP1
    motivates assessment and intervention, but the discovery series does not evaluate speech-therapy efficacy.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disruption of SYNGAP1 appears to be associated with a homogeneous
      clinical phenotype that is characterized by moderate-to-severe mental
      retardation accompanied by severe language impairment.
    explanation: >-
      Establishes the language impairment that this therapy targets; the
      citation supports the indication, not the efficacy of the intervention.

    directness: INDIRECT
- name: Physical and Occupational Therapy
  description: >-
    Motor and adaptive support is tailored to hypotonia, delayed walking and gait difficulties when present.
    The cited SYNGAP1 phenotype series identifies treatment needs but does not establish the efficacy
    of physical or occupational therapy.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  - preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
  evidence:
  - reference: PMID:26989088
    reference_title: "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotonia and unstable gait were frequent associated neurological
      features.
    explanation: >-
      Documents the motor impairments that motivate physiotherapy; supports
      the indication rather than the efficacy.

    directness: INDIRECT
- name: Antiseizure Pharmacotherapy for Comorbid Epilepsy
  description: >-
    When epilepsy is present, standard antiseizure medication is used.
    Response is variable and gene-dependent: seizures were well controlled by
    topiramate or valproate in the original SYNGAP1 series, whereas roughly
    half the patients in a larger SYNGAP1 cohort were pharmacoresistant. There
    is a mechanistic rationale for AMPA-directed agents in SYNGAP1
    haploinsufficiency, but it is a hypothesis generated from mouse work and
    small case observations, not a validated precision-therapy indication.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Cortical Hyperexcitability
    treatment_effect: INHIBITS
    description: >-
      The authors proposed reduced AMPA-associated excitation as one rationale for observed seizure responses.
      This is not a complete account of either drug's action and does not establish precision efficacy
      or absence of cognitive benefit.
    evidence:
    - reference: PMID:19196676
      reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Indeed, topiramate directly inhibits AMPA-receptor activity, whereas
        valproate reduces the level of GluR1 AMPA-receptor subunit at
        hippocampal synapses and therefore indirectly reduces AMPA-receptor
        activity.
      explanation: >-
        Mechanistic rationale for the drug acting on the hyperexcitability
        node; authors' interpretation rather than a controlled trial.
      quote_role: BACKGROUND
      directness: INDIRECT
  evidence:
  - reference: PMID:19196676
    reference_title: "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Indeed, topiramate directly inhibits AMPA-receptor activity, whereas
      valproate reduces the level of GluR1 AMPA-receptor subunit at
      hippocampal synapses and therefore indirectly reduces AMPA-receptor
      activity.
    explanation: >-
      Gives the mechanistic rationale linking drug choice to the
      AMPA-receptor-mediated hyperexcitability node; this is authors'
      interpretation, not a controlled comparison.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:26989088
    reference_title: "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures were pharmacoresistant in half of the patients."
    explanation: >-
      The larger series reports pharmacoresistance in half of patients. The remaining patients cannot
      automatically be counted as seizure-free, and this is not a category-wide response rate.

- name: Topiramate for Associated Epilepsy
  description: Seizure freedom in one reported SYNGAP1 patient; an uncontrolled observation, not comparative efficacy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:19196676
    reference_title: Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 1 had brief, generalized tonic–clonic seizures and was seizure-free while taking topiramate
    explanation: Seizure freedom in one reported SYNGAP1 patient; an uncontrolled observation, not comparative efficacy.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Valproic acid for Associated Epilepsy
  description: Reported seizure control in a second SYNGAP1 patient; an uncontrolled observation, not a precision-treatment indication.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:19196676
    reference_title: Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 2 had some myoclonic and absence seizures, which were well controlled with valproate.
    explanation: Reported seizure control in a second SYNGAP1 patient; an uncontrolled observation, not a precision-treatment indication.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
differential_diagnoses:
- name: Syndromic Intellectual Disability
  description: >-
    A recognizable combination of findings can support a gene-specific syndrome. Mild dysmorphism, altered
    head size or a single imaging finding alone does not automatically settle the distinction. Presentation
    can become more recognizable with age and deeper phenotyping.
  distinguishing_features:
  - Presence of a recognisable dysmorphic gestalt or major malformation
  - Growth abnormality, microcephaly, or structural brain anomaly on imaging
  evidence:
  - reference: PMID:23020937
    reference_title: "Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several patients did not meet the expected syndromic manifestation,
      suggesting a strong bias in present clinical syndrome descriptions.
    explanation: >-
      Documents the instability of the syndromic/non-syndromic distinction in
      real cohorts.

- name: X-linked Intellectual Disability
  description: >-
    X-linked causes can be inherited or de novo and can affect males or females. Chromosomal location,
    variant interpretation and segregation distinguish these disorders from autosomal causes; absence
    of a maternal family history does not exclude an X-linked diagnosis.
  distinguishing_features:
  - A pathogenic variant in an X-linked disease gene with compatible phenotype and inheritance
  - >-
    An affected maternal lineage can be informative, but de novo occurrence and affected females are possible
  evidence:
  - reference: PMID:23033978
    reference_title: "Diagnostic exome sequencing in persons with severe intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 10 de novo mutations and 3 X-linked (maternally inherited)
      mutations that had been previously predicted to compromise the function
      of known intellectual-disability genes were found in 13 patients.
    explanation: >-
      This cohort includes maternally inherited X-linked diagnoses; it does not define all X-linked inheritance
      patterns.

- name: Autosomal Recessive Non-Syndromic Intellectual Disability
  description: >-
    Biallelic causes remain a differential in both consanguineous and outbred families. Their frequency
    depends on ascertainment and ancestry. A low contribution in one selected outbred cohort does not
    exclude recessive disease in another patient or population.
  distinguishing_features:
  - Consanguinity or an endogamous founder population
  - Biallelic (homozygous or compound heterozygous) variants inherited from unaffected carrier parents
  evidence:
  - reference: PMID:23020937
    reference_title: "Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive inheritance seems to contribute little in the
      outbred population investigated.
    explanation: >-
      A qualitative conclusion limited to the investigated outbred cohort, not a universal estimate.

- name: Copy Number Variant Intellectual Disability
  description: >-
    Pathogenic deletions or duplications can affect one gene or a larger interval and can be de novo or
    inherited. Some CNVs cause dominant gene-dosage disorders within this category rather than a mutually
    exclusive diagnosis. Detection depends on assay and pipeline; chromosomal microarray and suitably
    analyzed exome or genome sequencing have complementary capabilities.
  distinguishing_features:
  - A pathogenic dosage change affecting one gene or a multi-gene interval
  - >-
    Interpretation of the affected interval and gene dosage, using an assay validated for the relevant
    CNV class
  evidence:
  - reference: PMID:21076407
    reference_title: "A de novo paradigm for mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Together with de novo copy number variation, de novo point mutations of
      large effect could explain the majority of all mental retardation cases
      in the population.
    explanation: >-
      The authors proposed combined contributions from de novo CNVs and sequence variants; this is not
      a measured population fraction or proof that sequencing cannot detect CNVs.

    quote_role: BACKGROUND
    directness: INDIRECT
discussions:
- discussion_id: adnsid_clingen_disease_concept
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is `autosomal dominant non-syndromic intellectual disability` a
    disease concept that any gene-disease curation resource actually
    uses, or is it an ontology-only category that no expert panel
    curates against?
  attaches_to:
  - has_subtypes#
  rationale: >-
    This entry now carries 18 `has_subtypes` rows, one per gene-defined
    MONDO class that MONDO asserts as a direct subclass of MONDO:0015802
    and for which a causal gene is recorded. Sixteen of the 21 classes
    MONDO files here have a ClinGen Gene-Disease Validity curation, and
    not one is curated against a disease concept whose own label says
    non-syndromic. Eleven are curated against `complex
    neurodevelopmental disorder` (MONDO:0100038), one against `syndromic
    intellectual disability` (MONDO:0000508, NAA15), one against plain
    `intellectual disability` (MONDO:0001071, SET), one against
    `progressive myoclonus epilepsy` (MONDO:0020074, NUS1), one against
    `Coffin-Siris syndrome` (MONDO:0015452, ARID2) and one against an
    MRD-series identifier (MONDO:0032795, CAMK2G). That last is the only
    ClinGen record in the set naming an MRD term at all; it is graded
    `Limited`, and the same record describes the entity as `autosomal
    dominant syndromic intellectual disability`. The five genes with no
    ClinGen record are TAF4, HIVEP2, KCNQ5, CAMK2B and CLTC. The primary
    literature points the same way: the defining series for TLK2, STAG1,
    TAF4, NAA15 and HIVEP2 each report recurrent dysmorphic or
    extra-cognitive features, and two of them - TLK2 and STAG1 - call
    the entity syndromic in their own words. This is a second,
    independent line of evidence for the ascertainment-category
    hypothesis already recorded in `mechanistic_hypotheses`, and it is a
    different kind of evidence from the gene-by-gene reclassification
    anecdotes, because it is a property of the whole set. What it does
    not settle is whether the right response is to retire the category,
    to rebuild this entry as a Grouping over per-gene entries, or to
    keep it as the class-level home for shared diagnostic and
    counselling content while treating the non-syndromic label as
    ascertainment rather than biology.
  proposed_experiments:
  - experiment_id: exp_adnsid_clingen_concept_census
    name: Systematic census of the disease concepts expert panels curate these genes against
    description: >-
      For every gene-defined MONDO class asserted under MONDO:0015802,
      record the disease concept each of ClinGen, OMIM, Orphanet and
      GeneReviews curates the gene against, and test whether any
      resource independently uses a non-syndromic concept. A category
      that no curation resource instantiates is an ontology artefact;
      one that several use independently is a real clinical entity.

- discussion_id: adnsid_opentargets_gene_backlog
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which of the remaining Open Targets gene associations for MONDO:0015802
    warrant curation as full genetic records in this entry, and which are
    better placed on gene-specific syndromic entries?
  attaches_to:
  - pathophysiology#Haploinsufficiency of a Dosage-Sensitive Neurodevelopmental Gene
  rationale: >-
    Open Targets associates MONDO:0015802 with TLK2, ASH1L, STAG1, CLTC,
    CAMK2A, CIC, NAA15, TRIP12, KMT5B, TRIO, SET and DLG4. This entry curates
    four of those (CAMK2A, DLG4, KMT5B, TRIO) alongside six genes drawn from
    the general de novo ID literature (SYNGAP1, STXBP1, ZBTB18, GRIN2B,
    GATAD2B, MED13L). The gene list is deliberately illustrative of the major
    functional modules rather than exhaustive, so the remaining eight
    associations - TLK2, ASH1L, STAG1, CLTC, CIC, NAA15, TRIP12, SET - are
    recorded here as an explicit backlog rather than left as a silent
    omission. Triage is not purely mechanical: several of these are already
    described with recognisable syndromic features, so for each the curation
    decision is entangled with the syndromic/non-syndromic boundary question
    tracked in the adnsid_entity_boundary discussion. Note also that Open
    Targets associations are themselves reassessed over time, so the target
    list is a moving one.

    Update (series-019, issue 12226): seven of those eight - TLK2,
    STAG1, CLTC, CIC, NAA15, TRIP12 and SET - now have `has_subtypes`
    rows carrying the MONDO class and the gene binding, so they are no
    longer silent omissions; each row records whether the gene-disease
    pair looks syndromic and what ClinGen curated it against, which is
    the triage this discussion asked for. They are deliberately not
    promoted to full `genetic:` records, because that block remains
    illustrative of the functional modules by design. The eighth, ASH1L,
    resolves differently and is now closed: MONDO records ASH1L as the
    causal gene of `intellectual disability, autosomal dominant 52`
    (MONDO:0030918), a direct subclass of this entry's own term, and
    that class is already curated in this knowledge base as the
    standalone entry `Intellectual_Disability_Autosomal_Dominant_52`.
    ASH1L therefore needs neither a subtype row nor a genetic record
    here; it has a home.
  proposed_experiments:
  - experiment_id: exp_adnsid_opentargets_gene_triage
    name: Deep-phenotype triage of the remaining Open Targets associations
    description: >-
      For each of TLK2, ASH1L, STAG1, CLTC, CIC, NAA15, TRIP12 and SET,
      systematically review the published case series for recurrent
      dysmorphic, malformative, growth or neuroimaging features, and classify
      the gene-disease pair as (a) genuinely non-syndromic and therefore a
      curation target for this entry, or (b) syndromic and therefore better
      served by a dedicated gene-specific entry cross-referenced from here.
      The classification should record which specific feature drove any
      syndromic call, so the boundary decision is auditable rather than
      asserted.

- discussion_id: adnsid_gene_list_incomplete
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How many autosomal dominant non-syndromic intellectual disability genes
    remain undiscovered, and why has discovery not plateaued?
  attaches_to:
  - pathophysiology#Haploinsufficiency of a Dosage-Sensitive Neurodevelopmental Gene
  rationale: >-
    Modeling of de novo variant burden in 31,058 developmental-disorder trios predicted many undiscovered
    genes under specified mutation-rate and enrichment assumptions. Reduced penetrance or prenatal lethality
    are possible explanations for lower enrichment, not measured properties of every candidate. These
    estimates concern broader developmental disorders, not the number of AD-NSID genes specifically.
  proposed_experiments:
  - experiment_id: exp_adnsid_scale_trio_sequencing
    name: Scale trio sequencing to the calculated discovery-power threshold
    description: >-
      Expand pooled clinical and research parent-offspring trio sequencing
      toward the ~350,000-trio sample size calculated to give 80% power to
      detect a 10-fold de novo protein-truncating-variant enrichment for an
      average gene, and re-run gene-level enrichment testing.
  - experiment_id: exp_adnsid_penetrance_biobank
    name: Biobank penetrance test for low-enrichment candidate genes
    description: >-
      For candidate genes showing lower-than-expected de novo PTV enrichment,
      measure PTV frequency in unselected adult population biobanks to
      distinguish reduced penetrance from limited statistical power.
  evidence:
  - reference: PMID:33057194
    reference_title: "Evidence for 28 genetic disorders discovered by combining healthcare and research data."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Modelling suggests that more than 1,000 genes associated with
      developmental disorders have not yet been described, many of which are
      likely to be less penetrant than the currently known genes.
    explanation: >-
      Quantifies the size and expected properties of the undiscovered gene
      set.
  - reference: PMID:33057194
    reference_title: "Evidence for 28 genetic disorders discovered by combining healthcare and research data."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      We calculated that a sample size of ~350,000 parent-offspring trios
      would be needed to have 80% power to detect a 10-fold enrichment of de
      novo PTVs for an average gene.
    explanation: >-
      A modeled power calculation for an average gene and specified enrichment, not a guarantee of completing
      the gene list.

    directness: INDIRECT
- discussion_id: adnsid_critical_window_translational_validity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Which outcomes remain reversible at different ages in each gene-associated disorder, and how do mouse
    restoration experiments translate to humans?
  attaches_to:
  - pathophysiology#Altered Development and Function of Neural Circuits
  rationale: >-
    Earlier SYNGAP1 mouse studies found developmental restrictions for particular outcomes, while later
    adult restoration rescued remote memory and selected epileptiform phenotypes. Reversibility is endpoint-
    and model-dependent. These findings support further study of treatment timing rather than a class-wide
    prohibition on adult molecular therapy.
  proposed_experiments:
  - experiment_id: exp_adnsid_adult_rescue_chromatin_module
    name: Adult-rescue test in chromatin-module AD-NSID mouse models
    description: >-
      Repeat the conditional adult-restoration experiment in mouse models of
      chromatin-module AD-NSID genes (e.g. Gatad2b, Zbtb18) to test whether
      the critical-window property generalises beyond synaptic genes or is
      specific to the SYNGAP1 spine-maturation mechanism.
  - experiment_id: exp_adnsid_organoid_window_mapping
    name: Human cortical organoid staged-correction window mapping
    description: >-
      Use human iPSC-derived cortical organoids carrying an AD-NSID variant
      with an inducible correction system, applying correction at staged
      timepoints, to map the equivalent plasticity window on a human rather
      than murine developmental timetable.
  - experiment_id: exp_adnsid_partial_rescue_endpoints
    name: Compare age-dependent rescue across distinct endpoints
    description: Compare memory, adaptive behaviors and seizure-related outcomes using the same restoration schedule, without assuming that all cognitive endpoints share one closure time.
  evidence:
  - reference: PMID:23141534
    reference_title: "Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Inducing SYNGAP1 mutations after critical developmental windows closed
      had minimal impact on spine synapse function, whereas repairing these
      pathogenic mutations in adulthood did not improve behavior and
      cognition.
    explanation: >-
      Earlier endpoint-specific mouse findings must be interpreted alongside subsequent adult-rescue experiments.

  - reference: PMID:31025938
    reference_title: Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: genetic reversal ofSyngap1pathogenicity in adult mice reverses deficits in remote memory
    explanation: Adult genetic restoration improved remote contextual memory in mice; this is endpoint-specific preclinical evidence and does not establish human therapeutic efficacy.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- discussion_id: adnsid_entity_boundary
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is autosomal dominant non-syndromic intellectual disability a coherent
    disease entity, or an ascertainment bin that should be dissolved into
    per-gene entries?
  attaches_to:
  - pathophysiology#Impaired Intellectual and Adaptive Function
  rationale: >-
    This category combines an inheritance pattern with the absence of a recognizable syndrome at ascertainment.
    It does not define one mechanism, complete penetrance, an exclusively de novo origin or a uniform
    trajectory. Several historical members now have gene-specific clinical descriptions. The existing
    subtype identities and historical context are retained while a future Grouping migration remains an
    explicit project-level scope decision.
  evidence:
  - reference: PMID:26989088
    reference_title: "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SYNGAP1 encephalopathy is characterised by early neurodevelopmental
      delay typically preceding the onset of a relatively recognisable
      epilepsy comprising generalised seizures (absences, myoclonic jerks) and
      frequent triggers.
    explanation: >-
      The flagship member of the class redescribed as a recognisable syndrome,
      the core argument for dissolving the category.
  - reference: PMID:23020937
    reference_title: "Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After exclusion of copy-number variants, de-novo point mutations and
      small indels are associated with severe, sporadic non-syndromic
      intellectual disability, accounting for 45-55% of patients with high
      locus heterogeneity.
    explanation: >-
      The counter-argument: the class does describe a real, quantified, shared
      genetic architecture even if its members are mechanistically diverse.

- discussion_id: adnsid_population_prevalence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What is the population prevalence of AD-NSID under an explicit clinical and molecular case definition?
  rationale: Published all-cause intellectual-disability prevalence and modeled birth prevalence of de novo developmental disorders describe different populations. Neither is a measured prevalence of AD-NSID. The DDD birth model includes recognizable syndromes and other dominant developmental disorders, while AD-NSID can also be inherited; the DDD estimate is therefore not an upper bound for this entire category.
  evidence:
  - reference: PMID:21236634
    reference_title: 'Prevalence of intellectual disability: a meta-analysis of population-based studies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The prevalence of intellectual disability across all 52 studies included in the meta-analysis was 10.37/1000 population.
    explanation: Provides the all-cause ID denominator; supports the order of magnitude but not an AD-NSID-specific rate.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  - reference: PMID:28135719
    reference_title: Prevalence and architecture of de novo mutations in developmental disorders.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age.
    explanation: Mutation-rate modeling estimates parental-age-dependent birth prevalence of broader de novo developmental disorders, not AD-NSID prevalence.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  attaches_to: []
notes: 'This existing class-level entry is retained pending a deliberate migration to a Grouping or further gene-specific entries. Its shared diagnostic and counseling context does not imply a single mechanism, complete penetrance, a static course, brain-exclusive manifestations or one treatment status. The gene list and graph are representative; subtype-level ubiquitin-proteasome and N-terminal acetylation mechanisms are described without asserting a universal downstream sequence. Broader developmental-disorder gene-discovery models do not estimate the number of remaining AD-NSID genes.

  Series enumeration (issue 12226). MONDO asserts 26 classes as direct subclasses of MONDO:0015802. Five already have a home in this knowledge base and are deliberately not duplicated here: MONDO:0014599 (MRD34) and MONDO:0030918 (MRD52, ASH1L) are standalone entries under those names; MONDO:0032485 (IDD61) is the `disease_term` of `MED13_Syndrome`; MONDO:0032919 (IDD62) is the `disease_term` of `DLG4-Related_Synaptopathy`; and MONDO:0032939 (MRD63, with macrocephaly) is carried as the MRD63 `has_subtypes` row on `TRIO-Related_Neurodevelopmental_Disorder`. Of the remaining 21, eighteen are now `has_subtypes` rows on this entry. Three are dispositioned elsewhere, and the reasons are recorded rather than left implicit.

  MONDO:0033492 `Coffin-Siris syndrome 6` was declined for this entry and added as a subtype row on `Coffin_Siris_Syndrome` instead. MONDO''s own textual definition reads `any Coffin-Siris syndrome in which the cause of the disease is a mutation in the ARID2 gene`, ClinGen curates ARID2 against Coffin-Siris syndrome (MONDO:0015452), and that entry already carries ARID2 in its `genetic:` block. MONDO nevertheless asserts the class under this non-syndromic parent rather than under Coffin-Siris syndrome, which is a defect in MONDO rather than a curation choice available here.

  MONDO:0014580 `intellectual disability, autosomal dominant 33` (DPP6) was declined: ClinGen classifies the DPP6 gene-disease relationship as Disputed. It is recorded as a `genetic:` entry with `relationship_type: DISPUTED` so the disposition is queryable rather than only narrated.

  MONDO:0013266 `neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language` (MEF2C) was declined as a subtype row and proposed instead as a standalone entry, recorded in `stubs/Neurodevelopmental_Disorder_With_Hypotonia_Stereotypic_Hand_Movements_And_Impaired_Language.yaml`. MEF2C has its own GeneReviews chapter, `MEF2C-Related Disorder`, which this knowledge base treats as evidence that a concept carries enough independent clinical content to be a disease entry rather than a row; searching the committed Bookshelf index by gene symbol and by disease label found no dedicated chapter for any other gene-defined class in this set. The index does carry a Coffin-Siris syndrome chapter, but that is for the umbrella entity rather than for the ARID2-defined class. Note also that the MEF2C chapter is titled for the gene rather than for the non-syndromic intellectual disability concept.

  What the subtype rows do and do not claim. Each row asserts that MONDO files this class under this entry and names this gene as its cause, with the ClinGen classification and the defining series recorded. It does not assert that the phenotype is non-syndromic; several rows record evidence that it is not. See the adnsid_clingen_disease_concept discussion, which collects that observation across the whole set. Speech, hypotonia, walking delay, autistic behavior and hyperactivity remain without causal edges because the sources establish phenotype associations but do not resolve a common mechanism across this heterogeneous category.'
animal_models:
- name: Adult-restorable Syngap1 haploinsufficiency mouse
  species: Mouse
  genotype: Syngap1 heterozygous Lox-Stop allele with inducible Cre-ER
  description: Tamoxifen-triggered restoration of endogenous SynGAP in adult mice rescued remote contextual memory and selected seizure and electrophysiological outcomes. Locomotor hyperactivity persisted, and earlier working-memory experiments found no rescue. These are outcome-specific preclinical findings, not evidence of a human treatment effect.
  modeled_mechanisms:
  - target: Altered Development and Function of Neural Circuits
    relationship: RESCUES
    description: Adult restoration reverses selected functional outcomes despite developmental haploinsufficiency.
    limitations: The model does not demonstrate reversal of every developmental abnormality or rescue of all cognitive outcomes.
    evidence:
    - reference: PMID:31025938
      reference_title: Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: genetic reversal ofSyngap1pathogenicity in adult mice reverses deficits in remote memory
      explanation: Adult genetic restoration improved remote contextual memory in mice; this is endpoint-specific preclinical evidence and does not establish human therapeutic efficacy.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  evidence:
  - reference: PMID:31025938
    reference_title: Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Adult restoration of SynGAP protein improved behavioral and electrophysiological measures of memory and seizure.
    explanation: Genetic restoration tests adult functional reversibility in mice; it does not establish the efficacy or delivery of a human therapy.
    quote_role: PRIMARY_RESULT
    directness: DIRECT

📚

References & Deep Research

References

PMID:26503795

Genetic studies in intellectual disability and related disorders.

No top-level findings curated for this source.

PMID:26748517

Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK547654/?report=reader

Intellectual Disability - StatPearls - NCBI Bookshelf

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: Autosomal Dominant Non-Syndromic Intellectual Disability · 2026-07-31T04:47:31Z · View source

De novo curation of MONDO:0015802 (autosomal dominant non-syndromic intellectual disability) as a genetically heterogeneous umbrella entity. Deep research provider: Edison/Falcon (research/Autosomal_Dominant_Non-Syndromic_Intellectual_Disability-deep-research-falcon.md; 542s runtime, 37 citations, 1 artifact). NEC preflight passed: the MONDO gene/OMIM/synonym anchors match the intended entity, and the curated parents match the MONDO is_a axis (MONDO:0000509 non-syndromic intellectual disability, MONDO:0100172 intellectual disability autosomal dominant). No GeneReviews chapter exists at this class level - gene-specific chapters exist for SYNGAP1 and STXBP1 but not for MONDO:0015802. Curated a 12-node pathograph spanning three convergent mechanism modules (synaptic transmission and plasticity, chromatin and transcriptional regulation, cytoskeletal/Rho-GTPase control of neuronal morphogenesis) converging on critical-window cortical circuit formation, with 10 causal genes: SYNGAP1, STXBP1, ZBTB18, GRIN2B, GATAD2B, MED13L, TRIO, CAMK2A, DLG4, KMT5B. The last three were added specifically to anchor the entry to the Open Targets gene set for this MONDO ID rather than to the general de-novo-ID literature. The unstable syndromic/non-syndromic boundary is modeled explicitly as a mechanistic_hypothesis with status EMERGING plus a CONTROVERSY discussion rather than asserted as fact; gene records that have migrated toward syndromic status (MED13L, TRIO, KMT5B) carry PARTIAL evidence with explicit caveats. An internal red-team review pass corrected the prevalence_class band to ABOVE_1_IN_1000, TRIO variant_origin to GERMLINE, five evidence_source misclassifications, one REFUTE-to-PARTIAL calibration, and a duplicated tissue-scale GO term on a molecular-scale node; it also split a bundled pathophysiology node into atomic Premature Dendritic Spine Maturation and Cortical Hyperexcitability nodes so the antiseizure-drug target_mechanisms edge attaches to the excitability half only. Two phenotype frequency bands that could not be reconciled across cited sources were deliberately omitted rather than guessed. Validation: just validate passes (schema, ontology terms, and references); reference validation was independently confirmed live by a deliberate-corruption probe; compliance 93.4 percent, weighted 93.7 percent.

Falcon ▸

Autosomal Dominant Non-Syndromic Intellectual Disability: Disease Characteristics Report

Edison Scientific Literature 37 citations 2026-07-31T00:25:40.556864

Autosomal Dominant Non-Syndromic Intellectual Disability: Disease Characteristics Report

Executive summary and scope

Autosomal dominant non-syndromic intellectual disability (AD-NSID) is not one uniform disorder. It is an umbrella for genetically heterogeneous neurodevelopmental disorders in which a heterozygous pathogenic variant causes intellectual and adaptive-function impairment as the principal phenotype, without a consistently recognizable congenital-malformation or multisystem syndrome. The preferred umbrella identifier is MONDO:0015802. It should be kept distinct from broader autosomal dominant intellectual disability (MONDO:0100172) and from numbered, gene-specific OMIM/MONDO entities. “Non-syndromic,” “nonspecific,” “isolated,” and “autosomal dominant mental retardation” are historical or alternative terms; however, “non-syndromic” is provisional because deeper phenotyping often identifies speech, behavioral, epileptic, growth, or subtle dysmorphic features. Open Targets currently associates MONDO:0015802 with genes including TLK2, ASH1L, STAG1, CLTC, CAMK2A, CIC, NAA15, TRIP12, KMT5B, TRIO, SET, and DLG4. This is a representative—not exhaustive—list and changes as gene–disease validity is reassessed. (OpenTargets Search: autosomal dominant intellectual disability)

Most evidence is aggregated from disease databases, gene-discovery studies, and mixed DD/ID sequencing cohorts, not from a single disease-specific EHR registry. Consequently, epidemiologic and phenotype frequencies reported for general ID/DD must not be interpreted as exact frequencies for MONDO:0015802.

Domain	Current evidence	Suggested ontology/identifier
Scope / definition	Autosomal dominant non-syndromic intellectual disability is best treated as a heterogeneous umbrella disorder rather than a single uniform entity. Open Targets maps autosomal dominant non-syndromic intellectual disability to MONDO:0015802 and lists representative associated genes including TLK2, ASH1L, STAG1, CLTC, CAMK2A, CIC, NAA15, TRIP12, KMT5B, TRIO, SET, DLG4; broader autosomal dominant ID is separated as MONDO:0100172. NSID denotes ID as the principal/isolated phenotype, though many reported “non-syndromic” cases may later accrue additional neurodevelopmental features (OpenTargets Search: autosomal dominant intellectual disability, maia2021intellectualdisabilitygenomics pages 1-2).	MONDO:0015802; related umbrella: MONDO:0100172
Disease level vs patient level evidence	Available evidence is mainly aggregated from disease/gene discovery studies, sequencing cohorts, and reviews; this is not primarily an EHR-derived single-disease registry. Most current knowledge comes from heterogeneous DD/ID/NDD cohorts in which AD de novo etiologies are overrepresented (li2024triowholeexomesequencing pages 1-2, ko2023genomewidesequencingmodalities pages 2-4, maia2021intellectualdisabilitygenomics pages 1-2).	Evidence type: aggregated disease/gene-level resource
Cardinal phenotype: intellectual disability	ID is defined by impaired intellectual functioning and adaptive behavior; overall ID prevalence is commonly cited at 1–3% worldwide, with GDD/ID together affecting nearly 2% of the pediatric population. Severity can range mild to profound; severe/profound forms are more often monogenic (maia2021intellectualdisabilitygenomics pages 1-2, ko2023genomewidesequencingmodalities pages 1-2, liaci2021neuronalcytoskeletonin pages 1-2).	HPO: Intellectual disability HP:0001249; Global developmental delay HP:0001263
Common associated neurodevelopmental phenotypes	Across DD/ID cohorts and mechanism reviews, common co-phenotypes include developmental delay, speech/language delay, seizures/epilepsy, autism/behavioral abnormalities, microcephaly, and dysmorphic features; these often increase diagnostic yield even when the target label is “non-syndromic” (li2024triowholeexomesequencing pages 1-2, ko2023genomewidesequencingmodalities pages 2-4, wayhelova2024exomesequencingimproves pages 1-2, kim2024diagnosticyieldof pages 1-2).	HPO: Developmental delay HP:0001263; Speech delay HP:0000750; Seizure HP:0001250; Autism HP:0000717; Behavioral abnormality HP:0000708; Microcephaly HP:0000252; Facial dysmorphism HP:0001999
Representative causal genes: synaptic / excitability	Representative AD genes linked in umbrella resources or cohort literature include GRIN1, DLG4, CAMK2A, TRIO, NRXN1, STXBP1, DYRK1A, KIF1A, GNB1; these converge on synapse formation/function, neuronal signaling, and plasticity (OpenTargets Search: autosomal dominant intellectual disability, vas2023regulatorydenovo pages 1-2, ford2023dendriticspineand pages 1-2).	HGNC gene symbols; GO: synapse organization GO:0050808; regulation of synaptic plasticity GO:0048167
Representative causal genes: chromatin / transcription / cohesin	Representative AD genes include ASH1L, KMT5B, STAG1, CIC, TLK2, ARID1B, KANSL1, WDR5 and related chromatin modifiers highlighted as strong ASD/ID susceptibility factors affecting dendritic spine and synapse biology (OpenTargets Search: autosomal dominant intellectual disability, vas2023regulatorydenovo pages 1-2, ford2023dendriticspineand pages 1-2).	HGNC gene symbols; GO: chromatin organization GO:0006325; regulation of transcription by RNA polymerase II GO:0006357
Representative causal genes: cytoskeleton / trafficking / neuronal morphogenesis	Reviews emphasize convergence of many ID genes on cytoskeleton dynamics and Rho GTPase-regulated neuronal migration, neuritogenesis, and synaptic plasticity; examples include TRIO, KIF1A, CLTC and Rho-pathway-related genes in broader ID biology (liaci2021neuronalcytoskeletonin pages 1-2).	GO: actin cytoskeleton organization GO:0030036; microtubule cytoskeleton organization GO:0000226; neuron projection development GO:0031175
Variant classes / molecular lesion types	Relevant pathogenic mechanisms include coding missense, nonsense, frameshift, splice, CNVs, small structural variants, and increasingly regulatory de novo mutations in fetal-brain enhancers. Vas et al. showed regulatory DNMs enriched in fetal brain-specific enhancers, with recurrent enhancer clusters linked to CSMD1, OLFM1, POU3F3 (vas2023regulatorydenovo pages 1-2, kim2024diagnosticyieldof pages 1-2).	Variant classes per ACMG/AMP; regulatory regions / enhancers
Inheritance / de novo contribution	AD ID is often caused by de novo variants, especially in moderate/severe disease. In a Finnish ID cohort, 75% of variants in known ID genes were de novo/suspected de novo, including 64% autosomal dominant and 11% X-linked; only 25% were inherited (jarvela2021exomesequencingreveals pages 1-2). Trio-WES in unexplained DD/ID also concluded that de novo variants in AD genes are major contributors, especially in non-consanguineous families (li2024triowholeexomesequencing pages 1-2).	Inheritance: autosomal dominant; de novo germline origin
Mosaicism / recurrence risk	Apparent de novo AD findings do not guarantee negligible recurrence risk. In a trio genome-wide study of 500 families, 12 cases of apparent mosaicism were identified, including 9 parental and 3 proband mosaic cases; empirical recurrence for a child with a de novo dominant condition is often cited as ~1%, but parental gonadal mosaicism can raise risk substantially (cook2021somaticmosaicismdetected pages 1-2).	Counseling concept: parental/gonadal mosaicism; somatic mosaicism
Anatomy / organ systems	Primary affected organ/system is the central nervous system, especially cortical and hippocampal circuits supporting cognition, learning, and adaptive behavior. Reviews also note involvement of excitation/inhibition balance and, in some genetic subgroups, broader multisystem findings despite a nominally nonsyndromic label (liaci2021neuronalcytoskeletonin pages 1-2, ford2023dendriticspineand pages 1-2).	UBERON: brain UBERON:0000955; cerebral cortex UBERON:0000956; hippocampus UBERON:0002421
Cells / subcellular processes	Mechanistic evidence highlights neurons, especially pyramidal neurons, dendrites, dendritic spines, and synapses; abnormal neuronal migration, neuritogenesis, and synaptic plasticity are recurrent themes. Subcellular emphasis includes chromatin, actin/microtubule cytoskeleton, and synaptic compartments (liaci2021neuronalcytoskeletonin pages 1-2, ford2023dendriticspineand pages 1-2).	CL: neuron CL:0000540; pyramidal neuron CL:0000598; GO CC: dendrite GO:0030425; dendritic spine GO:0043197; synapse GO:0045202; nucleus GO:0005634
Pathophysiology / causal chain	Upstream lesions include de novo coding or regulatory variants affecting chromatin regulation, transcription, enhancer activity, cytoskeleton dynamics, trafficking, and synaptic proteins. Downstream consequences include altered neuronal migration/neuritogenesis, abnormal dendritic spine and synapse morphogenesis, impaired network formation, excitation/inhibition imbalance, and finally impaired cognition/adaptive behavior (liaci2021neuronalcytoskeletonin pages 1-2, vas2023regulatorydenovo pages 1-2, ford2023dendriticspineand pages 1-2).	GO: neuron migration GO:0001764; axonogenesis GO:0007409; dendrite morphogenesis GO:0048813; learning or memory GO:0007611
Diagnostic workflow	Current evidence supports trio exome sequencing as first-tier for unexplained DD/ID/NDD, with genome sequencing used early or after nondiagnostic CMA/exome, particularly where structural, intronic, or regulatory variants are suspected. Standard pre-genomic workup often includes history/exam, CMA, Fragile X or targeted testing when indicated, and phenotype-guided metabolic testing (ko2023genomewidesequencingmodalities pages 1-2, wayhelova2024exomesequencingimproves pages 1-2, wigby2024evidencereviewand pages 1-2, kim2024diagnosticyieldof pages 1-2).	ACMG-aligned genome-wide testing strategy
Recent diagnostic yield data (2023–2024 priority)	Recent cohorts report: trio-WES 49.7% (86/173) in unexplained DD/ID; syndromic 57.8% vs non-syndromic 47.2% (li2024triowholeexomesequencing pages 1-2). Trio-ES in severe pediatric NDDs 48.9% (44/90), with 53.2% of causative variants novel (wayhelova2024exomesequencingimproves pages 1-2). Singleton WES in undiagnosed rare pediatric disease 43% (25/58) and clinical utility/actionability 76% (slaba2024diagnosticefficacyand pages 1-2). Trio-WGS after prior chromosome analysis/CMA/CES gave an additional 19.2% (10/52) diagnoses, 8/10 due to AD de novo variants (kim2024diagnosticyieldof pages 1-2). First-line GS review found mean diagnostic yield 45% for first-line GS and management changes 24–100% depending on cohort (wigby2024evidencereviewand pages 1-2).	Diagnostic modalities: WES, WGS, CMA
Real-world implementation	Real-world implementation now centers on clinical genetics and pediatric neurology pathways using trio-based ES/GS, ACMG-guided variant classification, and phenotype-driven reanalysis. ES/GS findings influence surveillance, reproductive counseling, and personalized management even when no disease-specific drug exists (wayhelova2024exomesequencingimproves pages 1-2, wigby2024evidencereviewand pages 1-2, slaba2024diagnosticefficacyand pages 1-2).	ACMG/AMP variant classification framework
Management / treatment	There is no single disease-specific pharmacotherapy for the umbrella disorder. Care is supportive and phenotype-directed: developmental therapies, speech/language therapy, educational support, behavioral management, seizure treatment when present, surveillance based on the molecular diagnosis, and genetic counseling. Reviews note that no pharmacological therapies are currently available for ID broadly, although pathway-based therapeutic opportunities are being explored (liaci2021neuronalcytoskeletonin pages 1-2, slaba2024diagnosticefficacyand pages 1-2).	MAXO: genetic counseling; developmental therapy; speech therapy; educational intervention; seizure management
Prevention / family planning	Primary prevention is generally not available for de novo monogenic disease; practical prevention focuses on genetic counseling, discussion of recurrence including mosaicism, and reproductive options after molecular diagnosis. Earlier genomic diagnosis can shorten the diagnostic odyssey and inform family planning (kim2024diagnosticyieldof pages 1-2, slaba2024diagnosticefficacyand pages 1-2, cook2021somaticmosaicismdetected pages 1-2).	MAXO: genetic counseling; reproductive counseling
Model systems / mechanistic platforms	Evidence includes animal and neuronal model studies summarized in reviews, especially mouse models of chromatin modifiers (ARID1B, KANSL1, WDR5, ZMIZ1) and systems-biology approaches emphasizing convergent neuronal network defects. These models are useful for studying dendritic spine, synapse, and developmental circuitry abnormalities (liaci2021neuronalcytoskeletonin pages 1-2, ford2023dendriticspineand pages 1-2).	Model categories: mouse models; neuronal cultures; systems biology
Evidence limitations	Disease boundaries are porous: “non-syndromic” cases may later show additional features; many data come from mixed DD/ID/NDD cohorts rather than pure MONDO:0015802 cohorts; gene lists change rapidly; penetrance/expressivity are often incompletely quantified; and few disorder-specific natural history or treatment trials exist (maia2021intellectualdisabilitygenomics pages 1-2, wayhelova2024exomesequencingimproves pages 1-2, slaba2024diagnosticefficacyand pages 1-2).	Curation note: maintain umbrella-vs-gene-specific distinction

Table: This table compacts the most actionable current evidence for autosomal dominant non-syndromic intellectual disability into a knowledge-base-ready format. It emphasizes scope, representative mechanisms and genes, ontology suggestions, modern diagnostic practice, and key evidence limitations.

1. Disease information

ID is defined by significant limitations in both intellectual functioning and adaptive behavior—conceptual, social, and practical skills—with onset during the developmental period. Global developmental delay (GDD) is used in young children, generally under five years, when standardized intellectual assessment is not yet reliable. The older IQ-only definition is insufficient; adaptive impairment is essential. ID overall affects approximately 1–3% of the population, while GDD/ID together affect nearly 2% of children. These figures cover all etiologies, not specifically AD-NSID. Mild ID represents approximately 85% of ID, moderate 10%, severe 3.5%, and profound 1.5% in commonly cited aggregate classifications. (maia2021intellectualdisabilitygenomics pages 1-2, ko2023genomewidesequencingmodalities pages 1-2, liaci2021neuronalcytoskeletonin pages 1-2)

Key identifiers and terminology

MONDO: MONDO:0015802, autosomal dominant non-syndromic intellectual disability.
Related MONDO: MONDO:0100172, intellectual disability, autosomal dominant.
MeSH: Intellectual Disability is the applicable broad concept; there is no uniquely specific MeSH descriptor for the AD-NSID umbrella.
ICD-10: F70–F79 classify intellectual disabilities by severity; they do not encode AD-NSID etiology.
ICD-11: 6A00, disorders of intellectual development, with severity extensions; again, inheritance is not encoded.
OMIM/Orphanet: individual gene-defined disorders generally have separate entries; no single OMIM number adequately represents the full umbrella.
Synonyms: autosomal dominant nonsyndromic ID; autosomal dominant non-syndromic mental retardation; isolated autosomal dominant intellectual disability; nonspecific autosomal dominant ID.

2. Etiology, risk, protection, and gene–environment interaction

Genetic causes

The defining cause is a germline heterozygous pathogenic variant. Moderate-to-severe cases are frequently de novo; familial transmission is more readily observed in mild disease because affected adults may reproduce. A 2024 review estimated that more than 400 genes have been associated with autosomal-dominant ID, while broader ID databases contain well over 1,500 established genes. (hou2024a10yearreview pages 5-7, wayhelova2024exomesequencingimproves pages 1-2)

Variant classes include missense, nonsense, frameshift, splice-altering and in-frame variants; exon-level or larger CNVs; balanced/complex structural rearrangements; and regulatory variants. Mechanisms differ by gene and allele: haploinsufficiency/loss of function, dominant-negative effects, and gain of function are all possible. Therefore, a gene cannot be assigned one universal molecular mechanism without allele-specific evidence.

The Finnish exome study of 39 ID families found pathogenic/likely pathogenic variants in 25/39 (64%). Among variants in known ID genes, 75% were de novo or suspected de novo—64% autosomal dominant and 11% X-linked—whereas 25% were inherited. This mixed syndromic/non-syndromic cohort supports the dominant de novo contribution but is not a prevalence study of AD-NSID. The abstract states: “de novo variants were the most common variants underlying ID in the studied Finnish population.” Published March 12, 2021; DOI: https://doi.org/10.1007/s00439-021-02268-1. (jarvela2021exomesequencingreveals pages 1-2)

Regulatory and chromosomal causes

De Vas et al. sequenced 21 ID trios and analyzed another 30 exome-negative probands. Regulatory de novo variants were enriched in fetal-brain-specific enhancers, including recurrent enhancer clusters linked to CSMD1, OLFM1, and POU3F3. Luciferase assays showed allele-specific activity for most tested variants, and CRISPR mutation/epigenome editing altered putative target-gene expression. Their exact conclusion was that these results “provide new evidence to indicate that DNMs in fetal brain-specific enhancers play an essential role in the aetiology of ID.” This is primary genomic, in-vitro reporter, and CRISPR functional evidence, but the small cohort does not establish clinical penetrance for each regulatory variant. Published February 28, 2023; DOI: https://doi.org/10.26508/lsa.202201843. (vas2023regulatorydenovo pages 1-2)

Large CNVs explain approximately 10–14% of ID overall, mostly de novo, but many produce syndromic phenotypes and should not automatically be labeled AD-NSID. (maia2021intellectualdisabilitygenomics pages 1-2)

Environmental, infectious, and lifestyle factors

No toxin, pathogen, diet, exercise pattern, smoking exposure, or occupational factor is established as a cause of a genetically confirmed AD-NSID disorder. Prenatal infection, hypoxic–ischemic injury, prematurity complications, neonatal meningitis, toxins, severe malnutrition, and other acquired insults are important alternative or additive causes of DD/ID, not causes of Mendelian inheritance. They may worsen developmental outcome in an affected child, but quantitative AD-NSID-specific gene–environment interaction data are unavailable. (liaci2021neuronalcytoskeletonin pages 1-2)

No validated genetic or environmental protective factor prevents expression after a highly penetrant pathogenic variant. Favorable modifiers may exist, but none is sufficiently validated for clinical annotation. Early enriched education, communication support, and rehabilitation improve function rather than biologically preventing the genotype.

3. Phenotypes and quality-of-life effects

The cardinal phenotype is developmental-onset impairment of cognition and adaptive functioning. Severity ranges from mild learning disability to profound dependence. Onset is congenital/developmental but recognition usually occurs in infancy or childhood through delayed milestones, speech delay, school difficulty, or impaired adaptive skills. The disorder is generally chronic and lifelong, not relapsing-remitting. Skills may continue to develop slowly; true neurodegeneration or loss of milestones should trigger evaluation for a different or additional diagnosis.

Phenotype	Typical characteristics	Suggested HPO term
Intellectual disability	Universal by definition; mild to profound; lifelong	HP:0001249
Global developmental delay	Common presenting label in children under five	HP:0001263
Delayed speech/language	Frequent across AD-ID genes; severity variable	HP:0000750
Motor developmental delay	Variable; often less severe than language/cognitive delay	HP:0001270
Impaired adaptive functioning	Conceptual, social, and practical limitations	HP:0011446, Abnormality of higher mental function, plus domain-specific terms
Behavioral abnormality	Autism, attention problems, anxiety, aggression, or stereotypy may occur but are not defining	HP:0000708; HP:0000717 for autism
Seizures/epilepsy	Gene-dependent rather than universal; may shift classification toward a syndromic/developmental epileptic encephalopathy	HP:0001250
Hypotonia	Variable, often early childhood	HP:0001252
Microcephaly or macrocephaly	Gene-dependent; not required	HP:0000252 / HP:0000256
Subtle facial dysmorphism	May emerge with systematic examination and challenges a strict “non-syndromic” designation	HP:0001999

Quality-of-life impact is dominated by communication limitations, educational needs, reduced independence, social participation barriers, caregiver burden, and need for lifelong support. Gene-specific QoL, EQ-5D, SF-36, survival, and phenotype-frequency datasets are generally absent. A 2024 consensus analysis found that phenotype descriptions in novel Mendelian disorder reports were superficial or deficient in more than 87% of publications across prioritized domains, illustrating why exact frequencies, adulthood outcomes, sleep, pain, and QoL remain uncertain.

4. Genetic and molecular information

Representative gene architecture

The following mechanistic groups are useful for curation; they are not an exhaustive diagnostic panel:

Chromatin, transcription, and cohesin: ASH1L, KMT5B, STAG1, CIC, SET, TLK2, NAA15, TRIP12; broader AD-ID genes include ARID1B and other chromatin regulators.
Synapse and excitability: CAMK2A, DLG4, GRIN1, GNB1 and gene-specific disorders involving STXBP1 or NRXN1.
Rho-GTPase/cytoskeletal development: TRIO and related neuronal morphogenesis pathways.
Vesicle trafficking/transport: CLTC, KIF1A, DYNC1H1.

Open Targets supports the association of the first set with MONDO:0015802 but does not, by itself, establish allele-level pathogenicity. Each variant requires ClinGen/ClinVar review, ACMG/AMP classification, segregation analysis, population frequency evaluation, and mechanism compatibility. (OpenTargets Search: autosomal dominant intellectual disability)

Pathogenic variants and classification

Pathogenic/likely pathogenic variants are ordinarily absent or extremely rare in population databases such as gnomAD, although gene-specific reduced penetrance can complicate interpretation. A 2024 trio-WES study filtered variants at minor allele frequency ≤0.01, but the threshold for a severe de novo dominant disorder is usually much lower and should be set using disease prevalence, penetrance, and allelic heterogeneity. A VUS does not establish diagnosis and must not guide predictive testing or irreversible reproductive decisions. (li2024triowholeexomesequencing pages 2-3)

Most causal variants are constitutional germline variants. Postzygotic mosaicism in the proband can attenuate severity; parental somatic/gonadal mosaicism can make an apparently de novo variant recurrent. In 500 genome-wide-sequenced families, Cook et al. identified 12 apparent mosaic cases: nine parental and three proband; six were not recognized as mosaic by Sanger sequencing. The authors concluded that genome-wide detection “can permit more accurate genetic counseling.” Published 2021; DOI: https://doi.org/10.1101/mcs.a006125. (cook2021somaticmosaicismdetected pages 1-2)

No consistently validated modifier gene, protective allele, or umbrella-specific episignature exists. Some individual chromatin disorders have blood DNA-methylation signatures, but those results should be recorded under the specific gene-defined disorder rather than generalized to AD-NSID.

5. Environmental information

Environmental exposures, lifestyle factors, and infectious agents are not primary etiologies once a causal AD variant is established. Their clinical relevance is principally differential diagnosis, prevention of additional brain injury, and optimization of general health. There is no AD-NSID-specific evidence that smoking, alcohol use by the affected person, diet, or exercise changes penetrance. Prenatal alcohol or teratogen exposure may create a blended phenotype. Routine immunization is appropriate but does not prevent the genetic disorder.

6. Mechanism and pathophysiology

Integrated causal chain

Upstream genetic lesion: a coding, splice, CNV, structural, or fetal-brain regulatory variant alters dosage or function of an AD-ID gene.
Molecular dysregulation: disturbed chromatin remodeling/transcription, enhancer activity, RNA/protein regulation, Rho-GTPase signaling, microtubule/actin dynamics, vesicle transport, glutamatergic signaling, or postsynaptic scaffolding.
Cellular effects: altered neural progenitor programs, neuronal migration, neurite extension, dendritic arborization, spine morphogenesis, synapse formation and plasticity.
Circuit effects: inefficient cortical/hippocampal connectivity and, in some genes, excitation–inhibition imbalance.
Clinical manifestation: impaired learning, memory, language, executive function, and adaptive behavior.

The cytoskeleton review describes this hierarchy from molecular defect to “cell compartment and functions, circuits, cognition, and behavior.” It identifies cytoskeletal disruption affecting neuronal migration, neuritogenesis, and synaptic plasticity, and notes convergence on Rho-GTPase signaling. Published June 7, 2021; DOI: https://doi.org/10.3390/ijms22116167. (liaci2021neuronalcytoskeletonin pages 1-2)

Chromatin modifiers can also act upstream of synaptic pathology. Animal models and human postmortem evidence show abnormal dendritic-spine/synapse morphogenesis and plasticity; ARID1B, KANSL1, and WDR5 are highlighted examples. This evidence is mechanistically informative but is not specific to every MONDO:0015802 gene. Published January 19, 2023; DOI: https://doi.org/10.3389/fnmol.2022.1048713. (ford2023dendriticspineand pages 1-2)

Suggested GO biological-process terms: chromatin organization (GO:0006325); regulation of transcription by RNA polymerase II (GO:0006357); nervous system development (GO:0007399); neuron migration (GO:0001764); neuron projection development (GO:0031175); axonogenesis (GO:0007409); dendrite morphogenesis (GO:0048813); synapse organization (GO:0050808); regulation of synaptic plasticity (GO:0048167); actin cytoskeleton organization (GO:0030036); learning or memory (GO:0007611).

Suggested cell types: neuron (CL:0000540), pyramidal neuron (CL:0000598), excitatory neuron and inhibitory interneuron where gene-specific evidence exists, neural stem/progenitor cell for prenatal chromatin/enhancer mechanisms. No immune-cell or inflammatory mechanism is consistently implicated in the umbrella disorder.

No reproducible umbrella-level metabolomic, lipidomic, proteomic, or circulating biomarker signature exists. WGS plus regulatory epigenomics and functional CRISPR assays represent the most relevant recent multi-omic advance. (vas2023regulatorydenovo pages 1-2)

7. Anatomical structures affected

The central nervous system is primary, especially cerebral cortex and hippocampal networks involved in cognition and memory. Cerebellar involvement may occur in individual genotypes. Peripheral organs are not obligatorily involved; consistent congenital or multisystem abnormalities should prompt a gene-specific syndromic diagnosis.

Suggested annotations are brain (UBERON:0000955), cerebral cortex (UBERON:0000956), hippocampus (UBERON:0002421), nervous tissue, neuron (CL:0000540), pyramidal neuron (CL:0000598), nucleus (GO:0005634), chromatin, cytoskeleton, dendrite (GO:0030425), dendritic spine (GO:0043197), and synapse (GO:0045202). Effects are bilateral and network-level; there is no characteristic lateralization. (liaci2021neuronalcytoskeletonin pages 1-2, ford2023dendriticspineand pages 1-2)

8. Temporal development

The biological lesion is present from conception or arises early postzygotically. Vulnerability is greatest during prenatal neurogenesis, neuronal migration, circuit assembly, and early-childhood synaptic maturation. Clinical onset is insidious and developmental rather than acute. The course is usually stable/nondegenerative but lifelong; developmental gains occur at a slower rate and may plateau. There are no validated early/intermediate/end-stage categories and no expected remission. Early childhood is the principal intervention window because communication systems, adaptive skills, and educational supports can be introduced during maximal developmental plasticity.

9. Inheritance and population

Inheritance is autosomal dominant. An affected heterozygous parent generally has a 50% transmission probability per pregnancy, although expression may vary. Many moderate/severe cases are de novo, so family history is often negative. In the 2024 trio-WES cohort, 95.4% had no family history of epilepsy or DD/ID, emphasizing that a negative pedigree does not exclude dominant disease. (li2024triowholeexomesequencing pages 2-3)

Penetrance is high for many severe de novo loss-of-function disorders but gene- and allele-specific. Expressivity can vary widely. Anticipation is not a general feature; repeat-expansion disorders belong in the differential rather than the core AD-NSID category. Consanguinity is not a risk factor for AD-NSID, though it raises the probability of an alternative recessive diagnosis. Founder effects and carrier frequencies are variant-specific; there is no meaningful aggregate carrier frequency because affected heterozygotes are not asymptomatic “carriers.”

For a confirmed de novo variant absent from parental blood, counseling commonly starts with an empirical recurrence risk near 1%, reflecting possible gonadal mosaicism. If a parent is mosaic, recurrence can be substantially higher and depends on germ-cell involvement; Cook et al. explain a theoretical range from approximately 1–2% to as high as 50%. Deep sequencing of multiple parental tissues or paternal sperm can refine risk in selected families. (cook2021somaticmosaicismdetected pages 1-2)

There is no reliable incidence or prevalence specifically for MONDO:0015802, no established ethnic concentration, geographic endemicity, or robust sex ratio. Autosomal inheritance predicts broadly similar biological risk in males and females; ascertainment may differ because males are more often referred for neurodevelopmental assessment.

10. Diagnostics

Clinical assessment

Assessment should include prenatal/perinatal and three-generation history; growth and dysmorphology examination; formal developmental, cognitive, language, and adaptive testing; hearing and vision evaluation; neurologic examination; and autism/behavioral screening. EEG is indicated for seizures or suspicious episodes, MRI for abnormal neurologic examination, regression, focal signs, abnormal head growth, or a genotype-specific indication. Routine biopsy is not useful. Metabolic testing should be phenotype-directed, particularly for regression, episodic decompensation, organomegaly, movement disorder, or unusual biochemical findings.

Current genetic-testing algorithm

Trio ES or GS early/first tier, with CNV calling and ACMG/AMP interpretation.
If ES is used, ensure adequate CNV detection; add CMA where platform/payer practice requires it or CNV sensitivity is insufficient.
Use Fragile X testing, repeat-expansion assays, methylation testing, mitochondrial testing, or single-gene testing when clinically indicated because standard ES may miss these mechanisms.
For nondiagnostic ES, perform periodic reanalysis, then GS to detect structural, deep-intronic, regulatory, repeat, low-level mosaic, or poorly covered variants.
RNA sequencing or methylation studies may resolve splice variants or gene-specific episignatures, but are not universal diagnostic tests.

Recent implementation data are strong:

Li et al., November 2024: trio-WES diagnosed 86/173 (49.7%) unexplained DD/ID cases. SNVs accounted for 54/173 (31.2%) and CNVs for 36/173 (20.8%); 22 SNVs were novel. Yield was 57.8% in syndromic versus 47.2% in non-syndromic DD/ID. Exact abstract conclusion: “De novo variants in autosomal dominant genes are significant contributors to DD/ID.” DOI: https://doi.org/10.1038/s41598-024-79431-x. (li2024triowholeexomesequencing pages 1-2)
Wayhelova et al., February 2024: trio-based ES yielded 44/90 (48.9%) diagnoses in severe pediatric NDD/MCA; 25/47 (53.2%) causative variants were novel, and ES detected intragenic CNVs through a 6-Mb duplication. DOI: https://doi.org/10.1186/s13023-024-03056-6. (wayhelova2024exomesequencingimproves pages 1-2)
Kim et al., August 2, 2024: after chromosome analysis, CMA, and clinical exome were nondiagnostic, trio-WGS solved an additional 10/52 (19.2%); 8/10 were AD de novo diagnoses. Reasons included small structural variants, uncovered/new genes, low variant allele fraction, coverage, and interpretation. DOI: https://doi.org/10.3390/diagnostics14151680. (kim2024diagnosticyieldof pages 1-2)
Wigby et al., February 2024: across 71 GS studies and more than 13,000 patients, unweighted mean yield was 45% for first-line GS, 33% after prior testing, and 33% in exome-negative cohorts; reported management changes ranged 24–100%. DOI: https://doi.org/10.1038/s41525-024-00396-x. (wigby2024evidencereviewand pages 1-2)
Slaba et al., November 2024: singleton WES diagnosed 25/58 (43%) undiagnosed pediatric patients; 76% of diagnosed cases had at least one management change. DOI: https://doi.org/10.1038/s41598-024-79872-4. (slaba2024diagnosticefficacyand pages 1-2)

Differential diagnosis includes syndromic AD-ID, X-linked or recessive ID, chromosomal disorders, Fragile X, imprinting disorders, developmental epileptic encephalopathy, autism without ID, cerebral palsy/perinatal injury, fetal alcohol spectrum disorder, congenital infection, metabolic disease, hypothyroidism, hearing/vision impairment, and neurodegenerative disorders. Clinical phenotype alone often cannot reliably distinguish them.

Population newborn screening is not available. After finding a familial variant, cascade testing, prenatal diagnosis, and preimplantation genetic testing are technically possible. Predictive testing of asymptomatic minors requires careful consideration because onset is developmental and penetrance may be allele-specific.

11. Outcome and prognosis

No umbrella-specific 5-year survival, life expectancy, or disease-specific mortality rate is available. In genuinely non-syndromic ID without epilepsy, severe motor impairment, swallowing dysfunction, or organ disease, life expectancy may approach that of the general population, but this cannot be assumed for every genotype. Morbidity is chiefly lifelong cognitive, communication, adaptive, educational, vocational, and social disability.

Major prognostic factors are severity of early developmental impairment, language acquisition, epilepsy, autism/behavioral comorbidity, motor and feeding ability, access to communication and educational services, and the specific molecular diagnosis. There is no validated molecular prognostic biomarker across AD-NSID. Recovery to fully typical cognition is uncommon, but meaningful functional gains are expected with individualized support. Regression, new neurologic signs, or unexpectedly rapid deterioration warrants reassessment for seizures, medication effects, psychiatric illness, sleep disorder, or an alternative/blended diagnosis.

12. Treatment and current applications

There is no approved disease-modifying pharmacotherapy, gene therapy, RNA therapy, cell therapy, immunotherapy, or surgery for the MONDO:0015802 umbrella. The 2021 mechanistic review states that “no pharmacological therapies are currently available” for ID broadly. Molecular diagnosis nevertheless changes surveillance, avoids unnecessary testing, informs recurrence counseling, and occasionally identifies a genotype-specific comorbidity or treatment. (liaci2021neuronalcytoskeletonin pages 1-2, slaba2024diagnosticefficacyand pages 1-2)

Standard multidisciplinary management

Individualized early developmental intervention, special education, and behavioral supports.
Speech-language therapy and augmentative/alternative communication.
Occupational and physical therapy for adaptive, sensory, fine-motor, gross-motor, or hypotonia-related needs.
Standard evidence-based treatment for epilepsy, ADHD, anxiety, sleep disturbance, constipation, feeding problems, and other comorbidities.
Hearing, vision, dental, nutritional, sleep, and safeguarding assessment.
Transition planning, supported decision-making, vocational support, respite, and caregiver mental-health support.

Suggested MAXO annotations include genetic counseling, developmental assessment, neuropsychological assessment, speech-language therapy, occupational therapy, physical therapy, educational intervention, augmentative communication, EEG, brain MRI, genomic sequencing, and seizure management. Precise MAXO IDs should be verified against the current ontology release before database ingestion.

No clinical trial retrieved was a disease-modifying trial specifically for AD-NSID. Relevant ID-wide studies largely concern behavioral, communication, lifestyle, or comorbidity interventions—for example written-language intervention (NCT05851937) and metformin for antipsychotic-associated weight gain (NCT05744479)—and should not be represented as treatments for the underlying genetic disease.

Research directions include restoring gene dosage, allele-specific silencing for gain-of-function alleles, ASOs, CRISPR-based correction, and pathway modulation of chromatin, Rho-GTPase/cytoskeletal, or synaptic defects. These remain gene- and variant-specific, largely preclinical concepts; the same intervention could be harmful if applied across opposite loss- and gain-of-function mechanisms.

13. Prevention

Primary prevention by lifestyle change or vaccination is not applicable. Prevention is principally reproductive and complication-focused:

Preconception and postdiagnostic genetic counseling.
Parental testing with consideration of low-level mosaicism.
Prenatal testing by CVS/amniocentesis or PGT-M when a familial pathogenic variant is known.
Early developmental surveillance of at-risk children.
Prevention of secondary harm through seizure control, communication support, safe feeding, sleep care, sensory screening, vaccination, and avoidance of additional neurotoxic exposures.

Noninvasive prenatal screening does not comprehensively detect heterogeneous single-gene AD-NSID. Prenatal diagnosis should not be based on a VUS.

14. Other species and natural disease

There is no recognized naturally occurring veterinary disease that is directly equivalent to the heterogeneous human AD-NSID umbrella. Orthologous genes are widely conserved in mammals, zebrafish, Drosophila, and C. elegans, and variants may cause learning, behavior, synaptic, or developmental phenotypes. These are comparative models rather than zoonotic disease. There is no infectious transmission, cross-species transmission, or zoonotic potential. Gene-, species-, NCBI Taxon-, NCBI Gene-, and VBO-level entries should be curated separately for each causal gene/model.

15. Model organisms

Available systems include constitutive or conditional knockout/heterozygous mice, variant knock-in mice, zebrafish, Drosophila, cultured primary neurons, patient-derived iPSCs, induced neurons, and cerebral organoids. Chromatin-modifier models involving ARID1B, KANSL1, WDR5, and related genes reproduce aspects of dendritic arborization, spine morphology, synaptic signaling, learning, or behavior. Cytoskeletal models test neuronal migration, neuritogenesis, Rho-GTPase signaling, and network plasticity. Regulatory-variant studies combine human WGS with luciferase assays and CRISPR epigenome editing. (liaci2021neuronalcytoskeletonin pages 1-2, vas2023regulatorydenovo pages 1-2, ford2023dendriticspineand pages 1-2)

Model limitations are substantial: human adaptive behavior cannot be directly modeled; heterozygous null animals may not mimic a human dominant-negative or gain-of-function allele; developmental timing and cortical architecture differ across species; and behavioral assays have limited construct validity. The preferred model is therefore variant-specific and should demonstrate directionally correct molecular dysfunction before therapeutic testing.

Evidence-quality conclusions

The strongest current evidence concerns the high contribution of de novo AD variants, the diagnostic effectiveness of trio ES/GS, and convergence on prenatal gene regulation, cytoskeletal development, and synaptic function. The weakest areas are disease-specific epidemiology, phenotype frequencies, adult natural history, QoL, penetrance, modifier genes, and treatment outcomes. A knowledge base should consequently retain MONDO:0015802 as an umbrella, attach variants and mechanisms to the relevant gene-specific disease whenever possible, and label statistics derived from mixed DD/ID cohorts as indirect rather than AD-NSID-specific evidence.

References

(OpenTargets Search: autosomal dominant intellectual disability): Open Targets Query (autosomal dominant intellectual disability, 32 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(maia2021intellectualdisabilitygenomics pages 1-2): Nuno Maia, Maria João Nabais Sá, Manuel Melo-Pires, Arjan P. M. de Brouwer, and Paula Jorge. Intellectual disability genomics: current state, pitfalls and future challenges. BMC Genomics, Dec 2021. URL: https://doi.org/10.1186/s12864-021-08227-4, doi:10.1186/s12864-021-08227-4. This article has 125 citations and is from a peer-reviewed journal.
(li2024triowholeexomesequencing pages 1-2): Chengyan Li, You Wang, Cizheng Zeng, Binglong Huang, Yinhui Chen, Chupeng Xue, Ling Liu, Shiwen Rong, and Yongwen Lin. Trio-whole exome sequencing reveals the importance of de novo variants in children with intellectual disability and developmental delay. Scientific Reports, Nov 2024. URL: https://doi.org/10.1038/s41598-024-79431-x, doi:10.1038/s41598-024-79431-x. This article has 22 citations and is from a peer-reviewed journal.
(ko2023genomewidesequencingmodalities pages 2-4): Mary Hsin-Ju Ko and Hui-Ju Chen. Genome-wide sequencing modalities for children with unexplained global developmental delay and intellectual disabilities—a narrative review. Mar 2023. URL: https://doi.org/10.3390/children10030501, doi:10.3390/children10030501. This article has 14 citations.
(ko2023genomewidesequencingmodalities pages 1-2): Mary Hsin-Ju Ko and Hui-Ju Chen. Genome-wide sequencing modalities for children with unexplained global developmental delay and intellectual disabilities—a narrative review. Mar 2023. URL: https://doi.org/10.3390/children10030501, doi:10.3390/children10030501. This article has 14 citations.
(liaci2021neuronalcytoskeletonin pages 1-2): Carla Liaci, Mattia Camera, Giovanni Caslini, Simona Rando, Salvatore Contino, Valentino Romano, and G. Merlo. Neuronal cytoskeleton in intellectual disability: from systems biology and modeling to therapeutic opportunities. International Journal of Molecular Sciences, Jun 2021. URL: https://doi.org/10.3390/ijms22116167, doi:10.3390/ijms22116167. This article has 36 citations.
(wayhelova2024exomesequencingimproves pages 1-2): Marketa Wayhelova, Vladimira Vallova, Petr Broz, Aneta Mikulasova, Jan Smetana, Hana Dynkova Filkova, Dominika Machackova, Kristina Handzusova, Renata Gaillyova, and Petr Kuglik. Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders. Orphanet Journal of Rare Diseases, Feb 2024. URL: https://doi.org/10.1186/s13023-024-03056-6, doi:10.1186/s13023-024-03056-6. This article has 18 citations and is from a peer-reviewed journal.
(kim2024diagnosticyieldof pages 1-2): Jaewon Kim, Jaewoong Lee, Myungshin Kim, and Dae-Hyun Jang. Diagnostic yield of trio whole-genome sequencing in children with undiagnosed developmental delay or congenital anomaly: a prospective cohort study. Diagnostics, 14:1680, Aug 2024. URL: https://doi.org/10.3390/diagnostics14151680, doi:10.3390/diagnostics14151680. This article has 6 citations.
(vas2023regulatorydenovo pages 1-2): Matias G De Vas, Fanny Boulet, Shweta S Joshi, Myles G Garstang, Tahir N Khan, Goutham Atla, David Parry, David Moore, Inês Cebola, Shuchen Zhang, Wei Cui, Anne K Lampe, Wayne W Lam, Jorge Ferrer, Madapura M Pradeepa, and Santosh S Atanur. Regulatory de novo mutations underlying intellectual disability. Life Science Alliance, 6:e202201843, Feb 2023. URL: https://doi.org/10.26508/lsa.202201843, doi:10.26508/lsa.202201843. This article has 7 citations and is from a peer-reviewed journal.
(ford2023dendriticspineand pages 1-2): Thomas James L. Ford, Byeong Tak Jeon, Hyunkyoung Lee, and Woo-Yang Kim. Dendritic spine and synapse pathology in chromatin modifier-associated autism spectrum disorders and intellectual disability. Frontiers in Molecular Neuroscience, Jan 2023. URL: https://doi.org/10.3389/fnmol.2022.1048713, doi:10.3389/fnmol.2022.1048713. This article has 30 citations.
(jarvela2021exomesequencingreveals pages 1-2): Irma Järvelä, Tuomo Määttä, Anushree Acharya, Juha Leppälä, Shalini N. Jhangiani, Maria Arvio, Auli Siren, Minna Kankuri-Tammilehto, Hannaleena Kokkonen, Maarit Palomäki, Teppo Varilo, Mary Fang, Trevor D. Hadley, Angad Jolly, Tarja Linnankivi, Ritva Paetau, Anni Saarela, Reetta Kälviäinen, Jan Olme, Liz M. Nouel-Saied, Diana M. Cornejo-Sanchez, Lorida Llaci, James R. Lupski, Jennifer E. Posey, Suzanne M. Leal, and Isabelle Schrauwen. Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (id) in the founder population of finland. Human Genetics, 140:1011-1029, Mar 2021. URL: https://doi.org/10.1007/s00439-021-02268-1, doi:10.1007/s00439-021-02268-1. This article has 55 citations and is from a peer-reviewed journal.
(cook2021somaticmosaicismdetected pages 1-2): Courtney B. Cook, Linlea Armstrong, Cornelius F. Boerkoel, Lorne A. Clarke, Christèle du Souich, Michelle K. Demos, William T. Gibson, Harinder Gill, Elena Lopez, Millan S. Patel, Kathryn Selby, Ziad Abu-Sharar, Alison M. Elliott, and Jan M. Friedman. Somatic mosaicism detected by genome-wide sequencing in 500 parent–child trios with suspected genetic disease: clinical and genetic counseling implications. Molecular Case Studies, 7:a006125, Oct 2021. URL: https://doi.org/10.1101/mcs.a006125, doi:10.1101/mcs.a006125. This article has 25 citations.
(wigby2024evidencereviewand pages 1-2): Kristen M. Wigby, Deanna Brockman, Gregory Costain, Caitlin Hale, Stacie L. Taylor, John Belmont, David Bick, David Dimmock, Susan Fernbach, John Greally, Vaidehi Jobanputra, Shashikant Kulkarni, Elizabeth Spiteri, and Ryan J. Taft. Evidence review and considerations for use of first line genome sequencing to diagnose rare genetic disorders. npj Genomic Medicine, Feb 2024. URL: https://doi.org/10.1038/s41525-024-00396-x, doi:10.1038/s41525-024-00396-x. This article has 26 citations and is from a peer-reviewed journal.
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(li2024triowholeexomesequencing pages 2-3): Chengyan Li, You Wang, Cizheng Zeng, Binglong Huang, Yinhui Chen, Chupeng Xue, Ling Liu, Shiwen Rong, and Yongwen Lin. Trio-whole exome sequencing reveals the importance of de novo variants in children with intellectual disability and developmental delay. Scientific Reports, Nov 2024. URL: https://doi.org/10.1038/s41598-024-79431-x, doi:10.1038/s41598-024-79431-x. This article has 22 citations and is from a peer-reviewed journal.

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Autosomal Dominant Non-Syndromic Intellectual Disability: Disease Characteristics Report

Executive summary and scope

1. Disease information

2. Etiology, risk, protection, and gene–environment interaction

Genetic causes

Regulatory and chromosomal causes

Environmental, infectious, and lifestyle factors

3. Phenotypes and quality-of-life effects

4. Genetic and molecular information

Representative gene architecture

Pathogenic variants and classification

5. Environmental information

6. Mechanism and pathophysiology

Integrated causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical assessment

Current genetic-testing algorithm

11. Outcome and prognosis

12. Treatment and current applications

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14. Other species and natural disease

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