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Mappings

MONDO

MONDO:0030918 intellectual disability, autosomal dominant 52

MONDO:0030918 is the MRD52 concept, xrefed to OMIM:617796 and carrying the RO:0004003 causal-gene relationship to HGNC:19088 (ASH1L).

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Inheritance

1

Autosomal dominant inheritance HP:0000006

The disorder is autosomal dominant with variable expressivity. Many established truncating variants are de novo, but maternal transmission of p.Lys827* with mild cognitive findings has been reported. Haploinsufficiency is a supported mechanism; reported missense alleles are not all proven to act by it.

Autosomal dominant inheritance Penetrance: UNKNOWN Expressivity: VARIABLE

Show evidence (3 references)

PMID:38674358 SUPPORT Human Clinical

"Heterozygous pathogenic variants in ASHL1 have been implicated in an autosomal dominant neurodevelopmental disorder (NDD)."

States the autosomal dominant, heterozygous inheritance mode. The gene symbol is misspelled "ASHL1" in the source sentence and is quoted as printed.

PMID:38674358 SUPPORT Human Clinical

"haploinsufficiency is believed to be at least one disease mechanism"

The source supports haploinsufficiency as at least one mechanism. Variable clinical expression and unknown penetrance are separate observations, not consequences encoded by this quote.

PMID:39902220 SUPPORT Human Clinical

"Cosegregation analysis revealed that the variant was passed down from the mother (Figure 1A). Sanger sequencing verified the presence or absence of this mutation in the family members (Figure 1B)."

The report states maternal transmission of p.Lys827*; the mother had similar cognitive symptoms. The full trio was not exome-sequenced.

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Discussions and Knowledge Gaps

8

How does reduced ASH1L function alter promoter H3K4me3 in the relevant neuronal systems?

KNOWLEDGE GAP OPEN gap_mrd52_which_histone_mark_carries_the_disease

Attached to

pathophysiology#Reduced ASH1L Histone Methyltransferase Activity pathophysiology#Loss of Activating Chromatin Marks at Neurodevelopmental Gene Promoters

Biochemical evidence establishes H3K36 substrate specificity, while severe mouse PFC knockdown lowers H3K4me3 without changing bulk H3K36me2/me3. Human-neuron work discusses H3K4me3 deposition by the interacting MLL complex. The remaining gap is the indirect route and disease-relevant chromatin context, not equal evidence that ASH1L directly catalyzes both marks.

Proposed experiments

Separation-of-function ASH1L alleles in neurons

exp_mrd52_separation_of_function_ash1l_alleles

Compare matched ASH1L dosage reduction and catalytic inactivation in isogenic human neurons, measuring H3K36me2, promoter H3K4me3, associated chromatin complexes and transcription. Rescue experiments should separate catalytic output from indirect chromatin regulation.

Show evidence (2 references)

PMID:21239497 SUPPORT In Vitro

"In addition, we show that human ASH1L specifically methylates histone H3 Lys-36."

Establishes direct catalytic specificity.

PMID:35210569 SUPPORT INDIRECT Other

"However, H3K36me2 presence will lead to upregulation of H3K36me3 by SET2 54, and H3K4me3 marks are deposited by the ASH1L interactor - MLL complex 55."

The authors distinguish secondary marks and an interacting H3K4 methyltransferase; this is contextual mechanistic interpretation.

Are ASH1L missense variants genuinely associated with a more severe and more autism-weighted phenotype than truncating variants, and if so does that mean they act by something other than simple haploinsufficiency?

KNOWLEDGE GAP OPEN gap_mrd52_missense_versus_truncating_severity

Attached to

pathophysiology#Heterozygous ASH1L Loss of Function pathophysiology#Reduced ASH1L Histone Methyltransferase Activity

Small published case series suggested greater severity with missense alleles, but ascertainment, variable pathogenicity and allele-specific effects prevent inferring dominant-negative or gain-of-function behavior from clinical severity alone. The 2024 registry excluded its three missense-VUS participants; its literature table nevertheless includes earlier reported missense cases. Functional results in ASH1L-associated Tourette cohorts cannot automatically establish the mechanism of different MRD52 alleles.

Proposed experiments

Functional assay of reported ASH1L missense alleles

exp_mrd52_missense_allele_functional_assay

Express reported missense alleles alongside wild type and null in a neuronal system, and test both catalytic output and whether the missense protein interferes with the wild-type allele, to distinguish haploinsufficiency from a dominant-negative effect.

Show evidence (2 references)

PMID:34373061 SUPPORT Human Clinical

"We found that patients with missense mutations in ASH1L appeared to present with more severe phenotypes and a higher likelihood of ASD than those with truncating mutations."

States the genotype-phenotype claim this gap is about.

PMID:38674358 SUPPORT Other

"However, additional functional studies are needed to understand the mechanism of disease for missense variants [11]"

The review explicitly leaves the MRD52 missense mechanism unresolved; it does not establish a uniform null-versus-missense severity relationship.

How do dosage, seizure subtype and rescue effects translate from distinct Ash1l mouse models to human epilepsy?

HUMAN MODEL MISMATCH OPEN mismatch_mrd52_model_genotype_and_seizure_semiology

Attached to

pathophysiology#Cortical Excitation-Inhibition Imbalance phenotypes#Seizures phenotypes#Absence Seizures phenotypes#Focal Motor Seizures phenotypes#Myoclonic Seizures phenotypes#Febrile Seizures

Severe juvenile PFC knockdown and heterozygous gene-trap models both support hyperexcitability, but differ in dosage, mortality and rescue. Combined diazepam/chemogenetic inhibition rescued seizures without social or anxiety rescue in the severe model; pyramidal inhibition alone improved social behavior and absence-like seizures in the heterozygous model. Human absence seizures are explicitly reported, so absence semiology is shared. Human focal motor, myoclonic and febrile seizures have no demonstrated subtype-specific circuit in these experiments. PTZ-provoked convulsions are not spontaneous generalized convulsive seizures.

Proposed experiments

Longitudinal seizure phenotyping of genotype-matched Ash1l heterozygotes

exp_mrd52_heterozygous_model_seizure_characterization

Perform long-term video-EEG across development in heterozygous Ash1l mice on more than one genetic background, classifying seizure types against the human semiologies, and test whether the GABA-enhancing rescue that works in the severe knockdown also works at heterozygous dose.

Show evidence (2 references)

PMID:34782621 SUPPORT Model Organism

"Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors."

The rescue result, and its own limit - the same intervention does not touch the social or anxiety phenotype, so even within the model it addresses one arm only.

PMID:39766886 SUPPORT Model Organism

"Epileptiform discharges were found on electroencephalograms (EEGs) of Ash1l+/GT mice, indicating absence-like seizures."

Establishes the semiology of the genotype-matched model, which is the half of the mismatch that dose-matching does not fix.

Which mechanisms explain the case-scoped neurologic findings?

KNOWLEDGE GAP OPEN gap_mrd52_neurologic_attribution

Attached to

phenotypes#Attention Deficit Hyperactivity Disorder phenotypes#Speech Delay phenotypes#Hypotonia phenotypes#Motor Delay phenotypes#Receptive Language Impairment phenotypes#Hyperactivity phenotypes#Depression phenotypes#Delayed CNS Myelination phenotypes#Loss of Acquired Spoken Language

The reviewed sources do not isolate a cellular or circuit mechanism for these individual human outcomes. Qualified genetic causation of anxiety, repetitive traits and memory deficits is represented separately. Delayed CNS myelination is an imaging finding in a missense case; the homozygous neural-deletion myelination phenotype is experimental support for ASH1L involvement, but the cellular route and translation to this allele remain unresolved. Specific speech, motor, tone and affective findings are not explained merely by naming a generic developmental program.

Which mechanisms explain the case-scoped gait findings?

KNOWLEDGE GAP OPEN gap_mrd52_gait_attribution

Attached to

phenotypes#Gait Disturbance phenotypes#Gait Ataxia phenotypes#Dysmetria phenotypes#Incoordination phenotypes#Internal Tibial Torsion

The clinical motor findings do not demonstrate a cerebellar or neuromuscular lesion. BGR 2 has additional unconfirmed biallelic TNR missense VUS and a TSHZ3 VUS. BGR 3 has stiff gait with tibial torsion and other VUS. Neither coexistence nor broad developmental-gene dysregulation proves a particular causal route.

Which mechanisms explain the case-scoped extraneural findings?

KNOWLEDGE GAP OPEN gap_mrd52_extraneural_attribution

Attached to

phenotypes#Gastrointestinal Disturbance phenotypes#Facial Dysmorphism phenotypes#Ocular Abnormality phenotypes#Genital Malformation phenotypes#Sensorineural Hearing Impairment phenotypes#Hearing Impairment phenotypes#Scoliosis phenotypes#Pectus Carinatum phenotypes#Pectus Excavatum phenotypes#Penile Torsion phenotypes#Cryptorchidism phenotypes#Cervical Vertebral Fusion phenotypes#Hyperopia phenotypes#Strabismus phenotypes#Nystagmus phenotypes#Astigmatism phenotypes#Gastroesophageal Reflux phenotypes#Vomiting phenotypes#Hypothyroidism phenotypes#Smooth Philtrum phenotypes#Hypertelorism phenotypes#Dolichocephaly phenotypes#Lumbar Hyperlordosis phenotypes#Scapular Winging

The reviewed human cases establish these observations but do not identify their organ-specific ASH1L mechanisms. A shortened-nasal-bone phenotype in homozygous mouse models does not establish the causes of diverse human ocular, genital, skeletal or facial findings. The separate hypothalamic feeding/growth hypothesis is represented with HYPOTHETICAL confidence. POU4F3/ATP2B2 VUS complicate BGR 3 hearing attribution; several individual skeletal findings come from a missense case of unknown inheritance. Reflux and vomiting coexist without a source-established causal direction.

Which mechanisms explain the case-scoped sleep findings?

KNOWLEDGE GAP OPEN gap_mrd52_sleep_attribution

Attached to

phenotypes#Sleep Disturbance phenotypes#Sleep Apnea phenotypes#Excessive Daytime Somnolence phenotypes#Sleepwalking

The sources describe sleep symptoms but do not establish an ASH1L-specific sleep-circuit mechanism or causal links among these manifestations. Apnea and daytime sleepiness were reported in different cases; an apnea-to-somnolence arrow would conflate cohorts.

How should discrepant clinical summaries and isolated supplemental findings be interpreted?

KNOWLEDGE GAP OPEN scope_mrd52_clinical_tables

Attached to

phenotypes#Gastrointestinal Disturbance phenotypes#Hearing Impairment phenotypes#Facial Dysmorphism phenotypes#Sleep Disturbance

Cordova’s labelled Supplemental Table 1 contains additional case-scoped findings: congenital cardiac lesions in the Homsy and Faundes cases, constipation, hyperacusis, precocious puberty, joint hypermobility, hydronephrosis, inguinal hernia, optic-disc pseudopapilledema, and detailed facial components. These are retained as clinical leads rather than assigned frequencies or developmental mechanisms; original full reports for those observations were not accessible in this review. The Stessman supplement was read directly: unspecified nocturnal incontinence is not assumed to be gastrointestinal disease or urinary enuresis, and bedtime difficulty is not equated with insomnia. Its patient 11282 narrative says no other medical problems while Table 21 records bloating/gas, so those gastrointestinal details remain discrepant. Unlabelled draft worksheets in the Cordova workbook were not treated as finalized data.

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Pathophysiology

11

Heterozygous ASH1L Loss of Function

Heterozygous truncating or deletion alleles can reduce ASH1L function and cause the dominant neurodevelopmental disorder. Missense alleles require variant-specific interpretation; their effects are not assumed to equal haploinsufficiency.

ASH1L hgnc:19088

Downstream

Reduced ASH1L Histone Methyltransferase Activity Predicted truncation/deletion reduces functional enzyme dosage; the effect of every clinical allele has not been directly assayed.

Impaired Craniofacial Development Experimental loss of Ash1l impairs craniofacial development, with a proposed neural-crest route in the neural conditional model. Translation from homozygous model dosage to human heterozygous dysmorphism is unresolved.

Anxiety Provisional translation of the mouse finding that Ash1l haploinsufficiency causally produces anxiety and repetitive behavior. The intermediate circuit is unresolved; mouse grooming is an analogue of the compulsive component, not proof of human obsessional thoughts.

Obsessive-Compulsive Traits Provisional translation of the mouse finding that Ash1l haploinsufficiency causally produces anxiety and repetitive behavior. The intermediate circuit is unresolved; mouse grooming is an analogue of the compulsive component, not proof of human obsessional thoughts.

Memory Impairment Provisional translation of memory deficits following neural Ash1l deletion. Homozygous neural deletion affects recognition memory, whereas the heterozygous gene-trap study found spatial-memory impairment with preserved object recognition; a single human memory substrate is unresolved.

Proposed Hypothalamic Circuit Dysfunction Hypothetical translation from homozygous neural deletion and global-null phenotypes; loss of one ASH1L copy has not been shown to impair human hypothalamic circuits.

Show evidence (3 references)

PMID:38674358 SUPPORT Human Clinical

"Heterozygous pathogenic variants in ASHL1 have been implicated in an autosomal dominant neurodevelopmental disorder (NDD)."

Establishes heterozygous ASH1L variants as the cause. The gene symbol is misspelled in the source sentence and is quoted as printed.

PMID:28191889 SUPPORT Human Clinical

"Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease."

The large targeted-sequencing study that delineated ASH1L as a neurodevelopmental-disorder gene with a syndromic presentation.

PMID:29753921 SUPPORT Human Clinical

"Our report provides further evidence to support loss-of-function alterations of ASH1L as causative for an emergent neurodevelopmental syndrome characterized by MCA, intellectual disability, and behavioral problems, and further delineates this genetic disorder."

The original clinical report directly supports LoF causation; detailed downstream routes remain incompletely resolved.

Reduced ASH1L Histone Methyltransferase Activity

Mechanism confidence: Provisional

ASH1L is an H3K36-specific histone methyltransferase. Loss of functional dosage is predicted to reduce ASH1L-dependent catalytic output. The decrease in promoter H3K4me3 observed after severe mouse PFC knockdown is an associated chromatin consequence, not proof of direct H3K4 catalysis by ASH1L.

histone H3K36 methyltransferase activity GO:0046975 ↓ DECREASED

Downstream

Loss of Activating Chromatin Marks at Neurodevelopmental Gene Promoters Provisional indirect route from loss of ASH1L function to lower promoter H3K4me3. The severe PFC-knockdown study found unchanged bulk H3K36me2/me3; it does not show ASH1L directly depositing H3K4me3.

Show evidence (1 reference)

PMID:21239497 SUPPORT In Vitro

"In addition, we show that human ASH1L specifically methylates histone H3 Lys-36."

Primary biochemical substrate-specificity evidence distinguishes direct H3K36 catalysis from an indirect change in H3K4me3.

Loss of Activating Chromatin Marks at Neurodevelopmental Gene Promoters

Mechanism confidence: Provisional

Severe juvenile PFC Ash1l knockdown reduces H3K4me3 occupancy at selected synaptic-gene promoters. Bulk H3K36me2/me3 was unchanged in that experiment. Lower H3K4me3 in idiopathic-ASD postmortem PFC is contextual human evidence, not a measurement in genetically confirmed ASH1L patients.

neuron CL:0000540

Downstream

Downregulation of Synaptic and Neurodevelopmental Gene Programs The authors link reduced promoter H3K4me3 to transcriptional loss of selected synaptic genes in mouse PFC; this is a proposed chromatin-to-transcription relation rather than proof that all affected genes use the same route.

Show evidence (1 reference)

PMID:34782621 SUPPORT Model Organism

"These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters."

Directly links reduced promoter H3K4me3 occupancy to the downregulated synaptic gene set, in mouse prefrontal cortex.

Downregulation of Synaptic and Neurodevelopmental Gene Programs

Mechanism confidence: Provisional

ASH1L loss dysregulates neurodevelopmental and synaptic transcription in distinct experimental systems. Selected genes decrease in severe PFC knockdown, haploinsufficient gene-trap mice and homozygous neural conditional deletion; these datasets are not equivalent to one uniform human transcriptional defect.

neuron CL:0000540

regulation of transcription by RNA polymerase II GO:0006357 ↓ DECREASED

Downstream

Synaptic Pruning Failure In the haploinsufficient model, reduced EphA7 signaling mediates pruning failure; ephrin-A5 supplementation rescues pruning and discrimination.

Cortical Excitation-Inhibition Imbalance Reduced synaptic-gene expression is proposed to depress inhibition and increase excitation in PFC; synaptic and intrinsic contributions differ between experimental manipulations.

Disrupted Cortical Neuron Specification and Lamination The authors propose reduced developmental-gene expression, including Emx2, as a route to delayed cortical lamination in homozygous deletion. No corresponding human cellular lesion has been established.

Intellectual Disability Provisional translation of the authors’ hypothesis that reduced developmental-gene expression disrupts brain development and contributes to ASD/ID. Intervening human circuitry is unresolved, and homozygous neural deletion is more severe than typical human dosage.

Autism Provisional translation of the authors’ hypothesis that reduced developmental-gene expression disrupts brain development and contributes to ASD/ID. Intervening human circuitry is unresolved, and homozygous neural deletion is more severe than typical human dosage.

Reduced Neuronal Arborization Reduced NTRK2/TrkB expression is proposed to contribute to impaired arborization; incomplete rescue and altered isoform expression indicate other pathways may contribute.

Pyramidal Neuron Hyperexcitability The severe-knockdown study also proposes downregulated ion-channel, transporter and ATPase genes as contributors to intrinsic excitability, independent of the synaptic E/I route.

Show evidence (2 references)

PMID:34782621 SUPPORT Model Organism

"Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy."

Establishes that the transcriptional consequence of ASH1L loss falls specifically on autism, intellectual-disability and epilepsy risk genes.

PMID:34145365 SUPPORT Model Organism

"Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development."

Independent model-organism support for ASH1L acting through transcriptional regulation during neural development.

Synaptic Pruning Failure

Mechanism confidence: Provisional

Developmental synapse elimination fails and excess synapses persist. In haploinsufficient mice this is traced to loss of Eph receptor A7 expression through EZH2-mediated H3K27me3 accumulation in its gene body, and restoring EphA7 signalling with its ligand ephrin-A5 restores pruning. This node captures the single concept of the pruning deficit.

neuron CL:0000540

synapse pruning GO:0098883 ↓ DECREASED

Animal models

Ash1l heterozygous knockout mouse (EphA7 pruning model) Mouse recapitulates Excess synapses persist because developmental pruning fails, and the responsible gene, Eph receptor A7, is identified together with the repressive-mark mechanism silencing it.

Downstream

Autism Provisional human translation of the mouse pruning hypothesis. EphA7 rescue demonstrates pruning and discrimination effects; it does not prove every human behavioral feature arises from pruning failure.

Show evidence (2 references)

PMID:35081333 SUPPORT Model Organism

"Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period."

Establishes failed synapse pruning as the cellular mechanism in Ash1l-deficient neurons.

PMID:35081333 SUPPORT Model Organism

"Specifically, Eph receptor A7 is downregulated in Ash1l+/- mice through accumulating EZH2-mediated H3K27me3 in its gene body."

Identifies the specific gene, and the repressive-mark mechanism, connecting ASH1L haploinsufficiency to the pruning deficit.

Cortical Excitation-Inhibition Imbalance

Mechanism confidence: Provisional

Mouse PFC experiments show diminished GABAergic inhibition and enhanced glutamatergic transmission after Ash1l loss. The resulting synaptic excitation-inhibition imbalance is a proposed contributor to human epilepsy and autistic features, with model-specific dosage and rescue differences.

GABAergic neuron CL:0000617

gamma-aminobutyric acid signaling pathway GO:0007214 ↓ DECREASED

Downstream

Pyramidal Neuron Hyperexcitability The synaptic shift increases excitatory drive onto PFC pyramidal neurons. Intrinsic excitability changes are an additional contribution, not a consequence established solely by E/I imbalance.

Show evidence (1 reference)

PMID:34782621 SUPPORT Model Organism

"Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality."

Direct electrophysiological demonstration of the imbalance and its link to seizures, in a prefrontal knockdown model.

Pyramidal Neuron Hyperexcitability

Mechanism confidence: Provisional

Cortical pyramidal neurons become hyperexcitable through altered intrinsic properties as well as the synaptic shift. This node captures the single concept of network hyperexcitability and conforms to the shared epilepsy final common pathway.

pyramidal neuron CL:0000598

action potential GO:0001508 ↑ INCREASED

Animal models

Ash1l gene-trap haploinsufficient mouse Mouse recapitulates Whole-cell recording in prefrontal cortex demonstrates increased pyramidal excitability arising from intrinsic property changes plus enhanced glutamatergic and diminished GABAergic transmission, in a heterozygous animal matching the human genotype.

Downstream

Seizures Provisional clinical translation of the heterozygous gene-trap rescue experiment. PFC inhibition improved social behavior and abolished absence-like seizures; this does not demonstrate a single circuit for all human seizure semiologies.

Absence Seizures Provisional clinical translation of the heterozygous gene-trap rescue experiment. PFC inhibition improved social behavior and abolished absence-like seizures; this does not demonstrate a single circuit for all human seizure semiologies.

Autism Provisional clinical translation of the heterozygous gene-trap rescue experiment. PFC inhibition improved social behavior and abolished absence-like seizures; this does not demonstrate a single circuit for all human seizure semiologies.

Show evidence (1 reference)

PMID:39766886 SUPPORT Model Organism

"Whole-cell patch-clamp recordings showed that Ash1l haploinsufficiency increased the excitability of pyramidal neurons in the PFC by altering intrinsic neuronal properties, enhancing glutamatergic synaptic transmission, and diminishing GABAergic synaptic inhibition."

Establishes pyramidal hyperexcitability in the model that matches the human heterozygous genotype, and separates the intrinsic from the synaptic contribution.

Disrupted Cortical Neuron Specification and Lamination

Mechanism confidence: Provisional

Homozygous germline or cortex-specific Ash1l deletion alters cortical neuron specification and lamination in mice. SATB2-positive projection neurons are ectopically placed and show altered differentiation trajectories. This is an experimental developmental mechanism, not an observed lesion in human ASH1L patients.

cortical projection neuron CL:0000598

cerebral cortex neuron differentiation GO:0021895 ⚠ ABNORMAL

Animal models

Cortex-specific Ash1l conditional knockout mouse Mouse recapitulates Cortical Ash1l deletion produces excess and ectopically placed SATB2-expressing projection neurons with an altered differentiation trajectory, establishing a requirement for ASH1L in projection neuron specification.

Show evidence (1 reference)

PMID:38943682 SUPPORT Model Organism

"Birthdating revealed generation of ectopically placed deep layer neurons that express SATB2"

Demonstrates misspecified, ectopically positioned cortical projection neurons after cortical Ash1l deletion.

Impaired Craniofacial Development

Mechanism confidence: Provisional

Ash1l-null embryos and neural-lineage conditional knockout mice have shortened nasal bones. The neural conditional study proposes abnormal development of NESTIN-positive neural-crest derivatives as a cause. This experimental route does not establish the causes of the heterogeneous human genital, skeletal and facial findings.

Animal models

Cortex-specific Ash1l conditional knockout mouse Mouse partially recapitulates The germline null dies perinatally and has shortened nasal bones, demonstrating a requirement for Ash1l in craniofacial development outside the brain.

Show evidence (1 reference)

PMID:38943682 SUPPORT Model Organism

"Notably, Ash1l-/- exhibited shortened nasal bones (n = 31, P = 0.017)."

A specific craniofacial phenotype in the germline-null mouse; other human organ anomalies are not inferred.

Reduced Neuronal Arborization

Mechanism confidence: Provisional

Acute ASH1L knockdown in stem-cell-derived human cortical excitatory neurons reduces neurite length and branching. Reduced NTRK2 expression and antagonistic PRC2 activity are implicated; EZH2 inhibition partially rescues morphogenesis, while added BDNF does not. These are engineered immature neurons, not clinical neuropathology.

neuron CL:0000540

Downstream

Autism Provisional hypothesis that impaired neurite development compromises connectivity and contributes to autism in ASH1L patients; functional synapses were not yet mature in the experimental cultures.

Microcephaly Provisional arborization hypothesis for the reported postnatal microcephaly. The clinical report concerns a missense allele whereas the cellular experiment uses acute knockdown; gliogenesis and other explanations remain possible.

Show evidence (1 reference)

PMID:35210569 SUPPORT In Vitro

"Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis."

Direct experimental finding after acute knockdown in human stem-cell-derived neurons.

Proposed Hypothalamic Circuit Dysfunction

Mechanism confidence: Hypothetical

The neural Ash1l-null mouse study proposes that impaired development of hypothalamic circuits could disturb feeding behavior and early postnatal growth. This hypothesis was motivated by neonatal survival and growth findings; hypothalamic pathology and a corresponding human lesion were not demonstrated.

Downstream

Feeding Difficulties The authors propose hypothalamic dysfunction as a possible explanation for feeding behavior and postnatal growth; no patient-specific causal attribution is established. Human growth delay was reported in a missense case, further limiting dosage and allele translation.

Growth Delay The authors propose hypothalamic dysfunction as a possible explanation for feeding behavior and postnatal growth; no patient-specific causal attribution is established. Human growth delay was reported in a missense case, further limiting dosage and allele translation.

Show evidence (1 reference)

PMID:34145365 SUPPORT INDIRECT Model Organism

"suggest that Ash1L might also play important roles in establishing neural circuits in the developing hypothalamus, which is critical for normal feeding behaviors and early postnatal growth 28."

The authors propose a hypothalamic-development route, explicitly requiring further testing in patients.

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Pathograph

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

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Phenotypes

55

Digestive 4

Gastrointestinal Disturbance Abnormality of the gastrointestinal tract HP:0011024

The 2024 discussion and Table 1 report gastrointestinal disturbances in 6/8 assessed probands, but the labelled supplementary table places unspecified nighttime incontinence among gastrointestinal findings. The original Stessman narrative explicitly reports no gastrointestinal disturbance in that patient. This imperfect aggregate is preserved as a source report without assigning a gastrointestinal frequency band.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

The 2024 synthesis reports a broad gastrointestinal category. Its pooled 6/8 count is not assigned a frequency because the underlying table includes an ambiguously classified incontinence observation; specific reflux and vomiting are independently documented.

Feeding Difficulties FREQUENT HP:0011968

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

4/8 = 50% maps to the FREQUENT band (30-79%), on a denominator of eight. The denominator is feature-specific and subject to ascertainment and reporting bias.

Gastroesophageal Reflux HP:0002020

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"febrile seizures beginning at age 3, ASD, attention deficit hyperactivity disorder (ADHD), obsessive behaviors, gastroesophageal reflux disease, and astigmatism."

This is a specific gastroesophageal reflux diagnosis, separate from the broad gastrointestinal count.

Vomiting HP:0002013

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"His neurodevelopmental phenotype is consistent with previous publications including ASD, ADHD, obsessive behaviors, feeding difficulties, and excessive reflux and vomiting during infancy."

Reports vomiting directly in the ASH1L frameshift proband; the co-occurrence with reflux does not independently establish its cause.

Ear 2

Sensorineural Hearing Impairment HP:0000407

BGR 3 also carried POU4F3 and ATP2B2 missense VUS in genes associated with hearing loss, so ASH1L-specific attribution is unresolved. The generic hearing count is 4/9 in the 2024 discussion versus 3/8 in Table 1; Supplemental Table 1 includes hyperacusis among hearing findings. Neither aggregate supplies a sensorineural-loss frequency.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic seizures); this proband’s epilepsy is Klonopin-resistant."

Reports actual bilateral sensorineural hearing loss in BGR 3; additional hearing-gene variants prevent unqualified causal attribution to ASH1L.

Hearing Impairment HP:0000365

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"She has ID, hearing deficits, hypothyroidism, hyperopia, astigmatism, normal growth, smooth filtrum, hypertelorism, and a low hairline."

The original ASH1L patient narrative supports this finding; this is a case observation without a population frequency.

Endocrine 1

Hypothyroidism HP:0000821

The original narrative and Table 21 both say hypothyroidism. Cordova’s later Supplemental Table 1 transcribes this as hyperthyroidism; that secondary transcription is not followed.

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"She has ID, hearing deficits, hypothyroidism, hyperopia, astigmatism, normal growth, smooth filtrum, hypertelorism, and a low hairline."

The original ASH1L patient narrative supports this finding; this is a case observation without a population frequency.

Eye 6

Ocular Abnormality FREQUENT Abnormality of the eye HP:0000478

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

6/10 = 60% maps to the FREQUENT band (30-79%), on a denominator of ten. The denominator is feature-specific and subject to ascertainment and reporting bias.

Hyperopia Hypermetropia HP:0000540

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"A smaller percentage of probands also have been reported with seizures, feeding difficulties, hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),..."

The clinical synthesis explicitly names this ocular finding. Its pooled 6/10 eye-abnormality count cannot establish a component-specific band.

Strabismus HP:0000486

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"A smaller percentage of probands also have been reported with seizures, feeding difficulties, hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),..."

The clinical synthesis explicitly names this ocular finding. Its pooled 6/10 eye-abnormality count cannot establish a component-specific band.

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"A smaller percentage of probands also have been reported with seizures, feeding difficulties, hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),..."

The clinical synthesis explicitly names this ocular finding. Its pooled 6/10 eye-abnormality count cannot establish a component-specific band.

Astigmatism HP:0000483

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"febrile seizures beginning at age 3, ASD, attention deficit hyperactivity disorder (ADHD), obsessive behaviors, gastroesophageal reflux disease, and astigmatism."

The BGR 1 narrative establishes this refractive abnormality directly.

Hypertelorism HP:0000316

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"She has ID, hearing deficits, hypothyroidism, hyperopia, astigmatism, normal growth, smooth filtrum, hypertelorism, and a low hairline."

The original ASH1L patient narrative supports this finding; this is a case observation without a population frequency.

Genitourinary 3

Genital Malformation FREQUENT Abnormality of the genital system HP:0000078

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

5/9 = 56% maps to the FREQUENT band (30-79%), on a denominator of nine. The denominator is feature-specific and subject to ascertainment and reporting bias.

Penile Torsion Torsion of the penis HP:0030263

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"In addition to DD/ID and ASD, genital and urinary malformations (such as penile torsion and cryptorchidism) and sleep disorders have also been reported."

The clinical synthesis explicitly names this component. The 5/9 genital-malformation tally is not its frequency.

Cryptorchidism HP:0000028

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"In addition to DD/ID and ASD, genital and urinary malformations (such as penile torsion and cryptorchidism) and sleep disorders have also been reported."

The clinical synthesis explicitly names this component. The 5/9 genital-malformation tally is not its frequency.

Head and Neck 4

Facial Dysmorphism Abnormal facial shape HP:0001999

The 2024 discussion gives 9/13 (69%) whereas its published Table 1 gives 8/10 (80%); these cross frequency-enum boundaries, so no band is assigned. BGR 1 and BGR 2 were systematically assessed and nondysmorphic. The literature has no consistent facial gestalt.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

9/13 = 69% maps to the FREQUENT band (30-79%). The same paper notes that in most published probands it is unclear whether dysmorphology was assessed and negative or simply not assessed, so this figure is likely inflated. The denominator is feature-specific and subject to ascertainment and reporting bias.

Microcephaly HP:0000252

A finding in this missense case does not establish penetrance in truncating-variant carriers. The source’s growth failure is not equated with undernutrition, and delayed myelination is not permanent hypomyelination.

Show evidence (1 reference)

PMID:28394464 SUPPORT Human Clinical

"We identified a novel mutation in ASH1L in a patient with severe intellectual disability, growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities."

The original case-report abstract supports the finding. Brain white-matter localization of delayed myelination is also reported in the later clinical synthesis. The missense mechanism is unestablished.

Smooth Philtrum HP:0000319

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"She has ID, hearing deficits, hypothyroidism, hyperopia, astigmatism, normal growth, smooth filtrum, hypertelorism, and a low hairline."

The original ASH1L patient narrative supports this finding; this is a case observation without a population frequency.

Dolichocephaly HP:0000268

Missense pathogenicity and mechanism require separate evaluation; these findings are retained as case-scoped observations.

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"His phenotype showed dolicocephaly, normal weight and height, lumbar hyperlordosis, winged scapulae."

The original narrative documents the sign in the p.Arg2391His missense case of unknown inheritance. It does not establish a LoF-specific phenotype or a muscular cause.

Limbs 2

Internal Tibial Torsion HP:0034372

BGR 3 also carried MED12, POU4F3 and ATP2B2 VUS; the report did not resolve their contributions.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"The proband also has a stiff gait with left internal tibial torsion and is now walking without assistance."

Reports a specific orthopedic finding; coexistence does not demonstrate that torsion explains the full gait disorder.

Scapular Winging HP:0003691

Missense pathogenicity and mechanism require separate evaluation; these findings are retained as case-scoped observations.

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"His phenotype showed dolicocephaly, normal weight and height, lumbar hyperlordosis, winged scapulae."

The original narrative documents the sign in the p.Arg2391His missense case of unknown inheritance. It does not establish a LoF-specific phenotype or a muscular cause.

Musculoskeletal 6

Hypotonia FREQUENT HP:0001252

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent. The 2024 discussion gives 4/7 (57%) and its published Table 1 gives 4/8 (50%); both fall in FREQUENT. The discrepancy is retained rather than choosing a reconstructed denominator.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

4/7 = 57% maps to the FREQUENT band (30-79%), on a denominator of seven. The denominator is feature-specific and subject to ascertainment and reporting bias.

Scoliosis OCCASIONAL HP:0002650

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"other less common phenotypes include hearing impairments (4/9, 44%), pectus carinatum/excavatum (2/7, 29%), and scoliosis (2/7, 29%)"

2/7 = 29% maps to the OCCASIONAL band (5-29%), on a denominator of seven. The denominator is feature-specific and subject to ascertainment and reporting bias.

Pectus Carinatum HP:0000768

The pooled pectus carinatum/excavatum figure of 2/7 is not a carinatum-specific frequency. The labelled Supplemental Table 1 attributes carinatum to the de Ligt p.Ala724Ser case and excavatum to the Shen frameshift case; missense pathogenicity and mechanism require separate evaluation.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"A smaller percentage of probands also have been reported with seizures, feeding difficulties, hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),..."

The published clinical synthesis explicitly lists carinatum and excavatum as distinct reported findings. The pooled frequency is not transferred to either component.

Pectus Excavatum HP:0000767

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"A smaller percentage of probands also have been reported with seizures, feeding difficulties, hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),..."

The clinical synthesis lists excavatum separately from carinatum; the 2/7 combined pectus tally is not a subtype frequency.

Cervical Vertebral Fusion Fused cervical vertebrae HP:0002949

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"A smaller percentage of probands also have been reported with seizures, feeding difficulties, hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),..."

The source explicitly lists cervical spinal fusion, with case attribution checked in its labelled Supplemental Table 1.

Lumbar Hyperlordosis HP:0002938

Missense pathogenicity and mechanism require separate evaluation; these findings are retained as case-scoped observations.

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"His phenotype showed dolicocephaly, normal weight and height, lumbar hyperlordosis, winged scapulae."

The original narrative documents the sign in the p.Arg2391His missense case of unknown inheritance. It does not establish a LoF-specific phenotype or a muscular cause.

Nervous System 26

Intellectual Disability HP:0001249

The 2024 summary reports ID or developmental delay in 15/16 assessed probands; this combined denominator does not establish an intellectual-disability-only frequency. Borderline test scores in some reports are not equated with a formal ID diagnosis.

Show evidence (2 references)

PMID:34373061 SUPPORT Human Clinical

"Here, we present twin sisters exhibiting mild intellectual disability and seizures."

The ASH1L twin report establishes mild intellectual disability independently of the combined ID/DD tally.

PMID:28394464 SUPPORT Human Clinical

"We identified a novel mutation in ASH1L in a patient with severe intellectual disability, growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities."

Severe ID was reported in the p.Ala2786Pro missense case; its mechanism is not assumed to match truncating alleles.

Attention Deficit Hyperactivity Disorder HP:0007018

The 6/7 (86%) summary combines ADHD with hyperactivity and cannot supply an ADHD-specific frequency.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"His neurodevelopmental phenotype is consistent with previous publications including ASD, ADHD, obsessive behaviors, feeding difficulties, and excessive reflux and vomiting during infancy."

BGR 2 has an explicitly reported ADHD diagnosis, independent of the pooled ADHD-or-hyperactivity count.

Obsessive-Compulsive Traits VERY_FREQUENT HP:0008770

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (2 references)

PMID:38674358 SUPPORT Human Clinical

"His neurodevelopmental phenotype is consistent with previous publications including ASD, ADHD, obsessive behaviors, feeding difficulties, and excessive reflux and vomiting during infancy."

The registry narrative specifies obsessive behaviors, supporting the broader obsessive-compulsive-trait term rather than compulsions alone.

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

4/5 = 80% falls at the lower edge of the VERY_FREQUENT band (80-99%), on a denominator of only five assessed probands. The denominator is feature-specific and subject to ascertainment and reporting bias.

Autism FREQUENT HP:0000717

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

6/10 = 60% maps to the FREQUENT band (30-79%), on a denominator of ten assessed probands. The denominator is feature-specific and subject to ascertainment and reporting bias.

Sleep Disturbance FREQUENT HP:0002360

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

6/9 = 67% maps to the FREQUENT band (30-79%), on a denominator of nine. The denominator is feature-specific and subject to ascertainment and reporting bias.

Speech Delay FREQUENT Delayed speech and language development HP:0000750

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

6/10 = 60% maps to the FREQUENT band (30-79%), on a denominator of ten. The denominator is feature-specific and subject to ascertainment and reporting bias.

Seizures FREQUENT HP:0001250

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

6/11 = 55% maps to the FREQUENT band (30-79%), on a denominator of eleven. The denominator is feature-specific and subject to ascertainment and reporting bias.

Motor Delay FREQUENT HP:0001270

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8, 75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems (6/10,..."

6/12 = 50% maps to the FREQUENT band (30-79%), on a denominator of twelve. The denominator is feature-specific and subject to ascertainment and reporting bias.

Gait Disturbance FREQUENT HP:0001288

The reported proportion comes from selected published cases plus three registry participants, among those assessed or described for this feature. It is not population prevalence or penetrance; unreported findings were not counted as absent. BGR 2 also carried research-only biallelic TNR missense VUS and a TSHZ3 VUS. BGR 3 carried MED12, POU4F3 and ATP2B2 VUS. Their contributions remain uncertain; an ataxic-gait frequency cannot be inferred from the combined 2/4 abnormal-gait count.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"and abnormal gait (2/4, 50%)"

2/4 = 50% maps to the FREQUENT band (30-79%), but on a denominator of only four probands - the weakest estimate in this set. The denominator is feature-specific and subject to ascertainment and reporting bias.

Depression HP:0000716

The pooled mood/anxiety-or-depression count of 2/4 cannot establish a depression-specific frequency.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"This proband also has features which have not been previously reported, including depression (diagnosed at age 11) and mixed receptive language disorder (diagnosed at age 7)."

This is a specific depression diagnosis in BGR 1, not the broader pooled mood-disorder count.

Gait Ataxia HP:0002066

BGR 2 also carried unconfirmed research biallelic TNR missense VUS and a TSHZ3 VUS; their contributions to the motor phenotype remain unresolved. No cerebellar lesion is inferred from these signs.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"In addition, the proband displays dysmetria and an abnormal, ataxic gait with difficulty coordinating motion and balance."

Direct BGR 2 clinical description; the separate components are not used to infer a cerebellar mechanism.

Dysmetria HP:0001310

BGR 2 also carried unconfirmed research biallelic TNR missense VUS and a TSHZ3 VUS; their contributions to the motor phenotype remain unresolved. No cerebellar lesion is inferred from these signs.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"In addition, the proband displays dysmetria and an abnormal, ataxic gait with difficulty coordinating motion and balance."

Direct BGR 2 clinical description; the separate components are not used to infer a cerebellar mechanism.

Incoordination HP:0002311

BGR 2 also carried unconfirmed research biallelic TNR missense VUS and a TSHZ3 VUS; their contributions to the motor phenotype remain unresolved. No cerebellar lesion is inferred from these signs.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"In addition, the proband displays dysmetria and an abnormal, ataxic gait with difficulty coordinating motion and balance."

Direct BGR 2 clinical description; the separate components are not used to infer a cerebellar mechanism.

Receptive Language Impairment Receptive language delay HP:0010863

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"This proband also has features which have not been previously reported, including depression (diagnosed at age 11) and mixed receptive language disorder (diagnosed at age 7)."

The clinical diagnosis supports the receptive-language component. No severity or frequency is inferred.

Febrile Seizures Febrile seizure (within the age range of 3 months to 6 years) HP:0002373

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"febrile seizures beginning at age 3, ASD, attention deficit hyperactivity disorder (ADHD), obsessive behaviors, gastroesophageal reflux disease, and astigmatism."

The age and febrile trigger support this specific seizure term; simple versus complex is not reported.

Absence Seizures Generalized non-motor (absence) seizure HP:0002121

BGR 3 also carried a MED12 VUS, as well as POU4F3 and ATP2B2 VUS; their contributions were unresolved. A mouse absence-like phenotype is not evidence that all human seizure types share an identical circuit.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic seizures); this proband’s epilepsy is Klonopin-resistant."

This human case explicitly supplies the seizure subtype. No particular focus, awareness state, or generalized onset is inferred beyond the stated semiology.

Focal Motor Seizures HP:0011153

BGR 3 also carried a MED12 VUS, as well as POU4F3 and ATP2B2 VUS; their contributions were unresolved. A mouse absence-like phenotype is not evidence that all human seizure types share an identical circuit.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic seizures); this proband’s epilepsy is Klonopin-resistant."

This human case explicitly supplies the seizure subtype. No particular focus, awareness state, or generalized onset is inferred beyond the stated semiology.

Myoclonic Seizures HP:0032794

BGR 3 also carried a MED12 VUS, as well as POU4F3 and ATP2B2 VUS; their contributions were unresolved. A mouse absence-like phenotype is not evidence that all human seizure types share an identical circuit.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic seizures); this proband’s epilepsy is Klonopin-resistant."

This human case explicitly supplies the seizure subtype. No particular focus, awareness state, or generalized onset is inferred beyond the stated semiology.

Delayed CNS Myelination HP:0002188

A finding in this missense case does not establish penetrance in truncating-variant carriers. The source’s growth failure is not equated with undernutrition, and delayed myelination is not permanent hypomyelination.

Show evidence (1 reference)

PMID:28394464 SUPPORT Human Clinical

"We identified a novel mutation in ASH1L in a patient with severe intellectual disability, growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities."

The original case-report abstract supports the finding. Brain white-matter localization of delayed myelination is also reported in the later clinical synthesis. The missense mechanism is unestablished.

Memory Impairment HP:0002354

Additional ACTL6B, COQ8A, DPP6 and SETD1B VUS were reported. Structural predictions in this paper are computational, not a functional assay of the patient’s enzyme.

Show evidence (1 reference)

PMID:39902220 SUPPORT Human Clinical

"Additionally, it is reported that the proband has mild ID with poor learning abilities and poor memory."

The human case establishes memory difficulty; it does not establish a particular memory-system defect.

Sleep Apnea HP:0010535

Show evidence (1 reference)

PMID:29753921 SUPPORT Human Clinical

"Here, we identified a novel de novo frame-shift variant, c.2422_2423delAAinsT which predicts p.(Lys808TyrfsTer40), in ASH1L in a patient with multiple congenital anomalies (MCA), fine motor developmental delay, learning difficulties, attention deficit hyperactivity disorder, sleep apnea, and scoliosis."

The original abstract directly reports sleep apnea. Without the original full clinical narrative, the curated binding remains at the supported apnea level.

Anxiety HP:0000739

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"Consistent with previous probands, most BGR participants reported ID/DD, ASD, obsessive behaviors, speech and motor delays, seizures, ADHD, gastrointestinal disturbances, and/or anxiety."

The registry summary reports anxiety; no anxiety-disorder subtype or frequency is assigned.

Hyperactivity HP:0000752

This patient carried the p.Arg2391His missense variant of unknown inheritance. Pathogenicity and mechanism are less secure than for established LoF alleles; no frequency is transferred from the combined ADHD/hyperactivity tally.

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"After a regular psychomotor development, he showed at 3 years a regression in the verbal speech, and some behavioral changes, such as hyperactivity and tendency to isolation."

The source explicitly reports hyperactivity, separately from an ADHD diagnosis.

Excessive Daytime Somnolence HP:0001262

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"Patient has a history of sleep problems including excessive daytime sleepiness and unusually frequent naps during the day."

The original frameshift-case narrative supports daytime somnolence; no sleep-disorder mechanism is established.

Sleepwalking HP:0025236

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"Patient has a history of sleep problems including sleepwalking, difficulty going to bed, long or frequent daytime naps, and incontinence at night."

The original narrative supports sleepwalking. Bedtime difficulty is not upgraded to insomnia, and unspecified nocturnal incontinence is not assumed to be urinary enuresis.

Loss of Acquired Spoken Language HP:6001483

The p.Arg2391His missense variant was of unknown inheritance; a mechanism equivalent to LoF is not established.

Show evidence (1 reference)

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf SUPPORT Human Clinical

"After a regular psychomotor development, he showed at 3 years a regression in the verbal speech, and some behavioral changes, such as hyperactivity and tendency to isolation."

The original narrative supports regression of acquired verbal language, without implying complete mutism.

Growth 1

Growth Delay HP:0001510

A finding in this missense case does not establish penetrance in truncating-variant carriers. The source’s growth failure is not equated with undernutrition, and delayed myelination is not permanent hypomyelination.

Show evidence (1 reference)

PMID:28394464 SUPPORT Human Clinical

"We identified a novel mutation in ASH1L in a patient with severe intellectual disability, growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities."

The original case-report abstract supports the finding. Brain white-matter localization of delayed myelination is also reported in the later clinical synthesis. The missense mechanism is unestablished.

🧬

Genetic Associations

1

ASH1L

Gene: ASH1L hgnc:19088 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:38674358 SUPPORT Human Clinical

"relationship to syndromic complex neurodevelopmental disorder was classified as Definitive."

Records the ClinGen Definitive gene-disease validity classification for ASH1L.

PMID:39902220 SUPPORT Human Clinical

"A review of reported ASH1L nonsense mutations to explore genotype-phenotype correlations suggested that these variants typically result in a loss of function."

Supports loss of function as the mechanism of the nonsense allele class.

💊

Medical Actions

2

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Seizures are managed with standard antiseizure medication. No agent has been shown to be preferentially effective in this disorder, and at least one reported proband's epilepsy was resistant to clonazepam, so treatment is empirical.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic seizures); this proband’s epilepsy is Klonopin-resistant."

The reported epilepsy was resistant to clonazepam (Klonopin). This case supports the need for individualized seizure management, not a preferred medication or demonstrated efficacy.

Developmental and Behavioral Support

Action: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Management is otherwise supportive and multidisciplinary: developmental, speech and language, and behavioural intervention for the intellectual disability, autism, ADHD and compulsive behaviours, together with surveillance for the sleep, gastrointestinal, ocular, hearing and musculoskeletal features that make up the syndromic phenotype. This is standard neurodevelopmental care rather than a disease-specific protocol.

Show evidence (1 reference)

PMID:39902220 SUPPORT INDIRECT Other

"The primary interventions for managing mild ID include a variety of therapeutic approaches, such as educational support and behavioral therapies (32)."

The clinical paper summarizes supportive management of ID generally; this is not an ASH1L-specific trial.

🔬

Diagnosis

1

Exome or Genome Sequencing

The diagnosis is molecular: identification of a heterozygous loss-of-function ASH1L variant, usually de novo, on trio exome or genome sequencing performed for developmental delay, autism or epilepsy. There is no biochemical or imaging marker. Interpretation is complicated in practice by the frequency with which additional variants of uncertain significance are found alongside the ASH1L variant.

Show evidence (1 reference)

PMID:38674358 SUPPORT Human Clinical

"ASH1L variants were first implicated in human disease in 2012 through a large sequencing study in persons with severe ID."

Establishes sequencing as the route by which the disorder is identified.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

The 2024 clinical synthesis reports feature-specific denominators, including 16 assessed for combined ID/DD; this is not a reliable total case count. Many variants in sequencing cohorts lack detailed clinical descriptions. No population prevalence or penetrance is inferred.

Show evidence (2 references)

PMID:38674358 SUPPORT Human Clinical

"ID/DD is the most frequent phenotype (15/16, 94%)"

Sixteen is the denominator assessed for the combined ID/DD phenotype, not a proven count of all affected individuals.

PMID:34782621 SUPPORT Other

"Over 100 loss-of-function (LOF) mutations in the coding regions of ASH1L have been discovered"

Establishes the much larger variant count from sequencing cohorts, against which the small clinically described cohort should be read. Evidence source is OTHER because this is the paper's summary of the genetic literature.

🐁

Animal Models

3

Ash1l gene-trap haploinsufficient mouse

A heterozygous gene-trap knockout, and the model whose genotype most closely matches human patients. It shows social deficits, increased self-grooming and cognitive impairment, absence-like epileptiform discharge on EEG, increased susceptibility to chemically provoked convulsive seizures, and prefrontal pyramidal hyperexcitability.

Species

Mouse

Genotype

Ash1l+/GT (targeted gene-trap knockout, heterozygous)

Publication

PMID:39766886

Pathograph links

Pyramidal Neuron Hyperexcitability recapitulates fidelity: moderate Whole-cell recording in prefrontal cortex demonstrates increased pyramidal excitability arising from intrinsic property changes plus enhanced glutamatergic and diminished GABAergic transmission, in a heterozygous animal matching the human genotype.

Limitations: Measured only in prefrontal cortex; the human seizure semiologies include focal motor and myoclonic seizures whose generators are not necessarily prefrontal, and no human electrophysiological or tissue correlate exists.

Readouts

Prefrontal pyramidal neuron excitability

Whole-cell patch-clamp recording of prefrontal pyramidal neurons in Ash1l+/GT versus wild-type mice.

Direction: INCREASED

Interpretation: Increased excitability with the excitatory-inhibitory shift is the direct electrophysiological correlate of this node.

Show evidence (1 reference)

PMID:39766886 SUPPORT Model Organism

"Whole-cell patch-clamp recordings showed that Ash1l haploinsufficiency increased the excitability of pyramidal neurons in the PFC by altering intrinsic neuronal properties, enhancing glutamatergic synaptic transmission, and diminishing GABAergic synaptic inhibition."

Reports the electrophysiological measurement behind this readout.

Show evidence (1 reference)

PMID:39766886 SUPPORT Model Organism

"Chemogenetic inhibition of pyramidal neurons in the PFC of Ash1l+/GT mice ameliorated autism-like social deficits and abolished absence-like seizures."

Reversing the excitability abnormality abolishes the seizure phenotype, which is what makes this model informative for the node rather than merely correlated with it.

Show evidence (1 reference)

PMID:39766886 SUPPORT Model Organism

"Ash1l+/GT mice displayed social deficits, increased self-grooming, and cognitive impairments."

Establishes the behavioural phenotype of the haploinsufficient model.

Ash1l heterozygous knockout mouse (EphA7 pruning model)

Haploinsufficient mice show anxiety, repetitive behaviour and altered social behaviour with intact learning but impaired discrimination. Neuronal Ash1l deletion produces excess synapses through a pruning deficit, traced to silencing of Eph receptor A7 by EZH2-deposited H3K27me3; supplying the EphA7 ligand ephrin-A5 restores pruning and rescues the discrimination deficit.

Species

Mouse

Genotype

Ash1l+/- germline heterozygous knockout, and neuron-specific Ash1l deletion

Publication

PMID:35081333

Pathograph links

Synaptic Pruning Failure recapitulates fidelity: moderate Excess synapses persist because developmental pruning fails, and the responsible gene, Eph receptor A7, is identified together with the repressive-mark mechanism silencing it.

Limitations: Synapse counts and pruning have not been measured in human ASH1L patients or tissue, and the pruning defect is most evident post-learning in a specific paradigm; the EPHA7 route is one identified mechanism, not necessarily the only one.

Readouts

Synapse number after learning

Synapse quantification in Ash1l-deleted neurons, particularly in the post-learning period.

Direction: INCREASED

Interpretation: Excess synapses are the direct cellular readout of the pruning failure.

Show evidence (1 reference)

PMID:35081333 SUPPORT Model Organism

"Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period."

Reports the synapse-number measurement behind this readout.

Discrimination performance after ephrin-A5 supplementation

Behavioural discrimination testing in Ash1l+/- mice given the EphA7 ligand ephrin-A5, against untreated mutants.

Direction: RESTORED

Interpretation: Rescue by reactivating the specific downstream receptor is what makes the EPHA7 route causal rather than correlative.

Show evidence (1 reference)

PMID:35081333 SUPPORT Model Organism

"Importantly, increasing activation of EphA7 in Ash1l+/- mice by supplying its ligand, ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits."

Reports the rescue experiment behind this readout.

Show evidence (1 reference)

PMID:35081333 SUPPORT Model Organism

"Specifically, Eph receptor A7 is downregulated in Ash1l+/- mice through accumulating EZH2-mediated H3K27me3 in its gene body."

Supports treating this model as informative for the pruning node by naming the responsible gene and chromatin mechanism.

Show evidence (1 reference)

PMID:35081333 SUPPORT Model Organism

"Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for ASD, resulting from synapse pruning deficits."

States the model's central conclusion connecting haploinsufficiency to the pruning mechanism.

Cortex-specific Ash1l conditional knockout mouse

Tamoxifen-induced cortical deletion from E10.5 misspecifies cortical projection neurons: SATB2-expressing neurons increase in number, spread through the cortical plate, and appear ectopically in deep layers, with an altered differentiation trajectory on single-cell RNA sequencing. The germline null is present at expected proportions at E18.5 but absent at birth, and has shortened nasal bones.

Species

Mouse

Genotype

Ash1l exon 4 conditional deletion (p.V1693Afs*2), Emx1-Cre-ERT2 induced at E10.5; and Ash1l germline null

Publication

PMID:38943682

Pathograph links

Disrupted Cortical Neuron Specification and Lamination recapitulates fidelity: moderate Cortical Ash1l deletion produces excess and ectopically placed SATB2-expressing projection neurons with an altered differentiation trajectory, establishing a requirement for ASH1L in projection neuron specification.

Limitations: This is a homozygous conditional deletion, not the usual human heterozygous dosage. The reviewed human cases do not establish an equivalent cortical lamination lesion; delayed white-matter myelination in one missense case is a different finding.

Readouts

Laminar distribution of SATB2-expressing neurons

Immunohistochemistry for SATB2 with EdU birthdating in conditional knockout versus control cortex.

Direction: ALTERED

Interpretation: Deep-layer neurons ectopically expressing an upper-layer marker are the structural readout of misspecification.

Show evidence (1 reference)

PMID:38943682 SUPPORT Model Organism

"Birthdating revealed generation of ectopically placed deep layer neurons that express SATB2"

Reports the birthdating measurement behind this readout.

Show evidence (1 reference)

PMID:38943682 SUPPORT Model Organism

"In the cortical-specific knockout model, SATB2 neurons showed increased numbers (n = 6/genotype, P = 0.0001) and were distributed through the cortical plate."

Supports treating this model as informative for the cortical patterning node.

Impaired Craniofacial Development partially recapitulates fidelity: low The germline null dies perinatally and has shortened nasal bones, demonstrating a requirement for Ash1l in craniofacial development outside the brain.

Limitations: The mouse finding is a specific craniofacial measurement in homozygous nulls; the human extraneural phenotype is dominated by genital and musculoskeletal anomalies with no consistent facial gestalt, and human heterozygotes survive. The two do not correspond feature for feature.

Readouts

Nasal bone length

Skeletal measurement in Ash1l germline null embryos versus controls.

Direction: DECREASED

Interpretation: A quantified craniofacial skeletal defect outside the nervous system.

Show evidence (1 reference)

PMID:38943682 SUPPORT Model Organism

"Notably, Ash1l-/- exhibited shortened nasal bones (n = 31, P = 0.017)."

Reports the craniofacial measurement behind this readout.

Show evidence (1 reference)

PMID:38943682 SUPPORT Model Organism

"This study underscores the essential role of Ash1l in postnatal survival and normal craniofacial development."

Supports an extraneural developmental requirement while the specific features differ from the human phenotype.

Show evidence (1 reference)

PMID:38943682 SUPPORT Model Organism

"In the cortical-specific knockout model, SATB2 neurons showed increased numbers (n = 6/genotype, P = 0.0001) and were distributed through the cortical plate."

Establishes the cortical patterning phenotype that makes this model informative.

{ }

Source YAML

click to show

name: Intellectual Disability Autosomal Dominant 52
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
disease_term:
  preferred_term: intellectual disability, autosomal dominant 52
  term:
    id: MONDO:0030918
    label: intellectual disability, autosomal dominant 52
synonyms:
- MRD52
- mental retardation, autosomal dominant 52
- autosomal dominant mental retardation 52
- autosomal dominant intellectual disability 52
- ASH1L-related syndromic complex neurodevelopmental disorder
- ASH1L-related neurodevelopmental disorder
description: |-
  ASH1L-related neurodevelopmental disorder (MRD52) is caused by heterozygous pathogenic ASH1L variants, particularly loss-of-function alleles. Intellectual disability, autism, speech and motor delays, behavioral differences and seizures occur variably, with ocular, genital, skeletal, gastrointestinal and sleep findings in some individuals. Average cognition in a registry participant and mild inherited disease demonstrate that the historical intellectual-disability name does not describe every presentation. Missense pathogenicity and mechanism require variant-specific assessment.

  ASH1L directly methylates H3K36. Experimental loss also changes transcription and, in severe mouse prefrontal knockdown, promoter H3K4me3. These observations do not establish direct H3K4 catalysis. Proposed routes include EphA7-dependent synaptic pruning, altered cortical excitation-inhibition, developmental-gene dysregulation and reduced neuronal arborization. Clinical translation is qualified because acute human-neuron knockdown, heterozygous gene-trap mice, severe focal mouse knockdown and homozygous developmental deletions are distinct systems. Their causal findings are preserved without assigning every human manifestation to a common developmental intermediate.
parents:
- Neurodevelopmental Disorder
- Epilepsy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0030918
      label: intellectual disability, autosomal dominant 52
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO:0030918 is the MRD52 concept, xrefed to OMIM:617796 and carrying the
      RO:0004003 causal-gene relationship to HGNC:19088 (ASH1L).
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: The disorder is autosomal dominant with variable expressivity. Many established truncating
    variants are de novo, but maternal transmission of p.Lys827* with mild cognitive findings has been
    reported. Haploinsufficiency is a supported mechanism; reported missense alleles are not all proven
    to act by it.
  penetrance: UNKNOWN
  expressivity: VARIABLE
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Heterozygous pathogenic variants in ASHL1 have been implicated in an autosomal dominant neurodevelopmental
      disorder (NDD).
    explanation: States the autosomal dominant, heterozygous inheritance mode. The gene symbol is misspelled
      "ASHL1" in the source sentence and is quoted as printed.
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: haploinsufficiency is believed to be at least one disease mechanism
    explanation: The source supports haploinsufficiency as at least one mechanism. Variable clinical expression
      and unknown penetrance are separate observations, not consequences encoded by this quote.
  - reference: PMID:39902220
    reference_title: Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cosegregation analysis revealed that the variant was passed down from the mother (Figure
      1A). Sanger sequencing verified the presence or absence of this mutation in the family members (Figure
      1B).
    explanation: The report states maternal transmission of p.Lys827*; the mother had similar cognitive
      symptoms. The full trio was not exome-sequenced.
pathophysiology:
- name: Heterozygous ASH1L Loss of Function
  description: Heterozygous truncating or deletion alleles can reduce ASH1L function and cause the dominant
    neurodevelopmental disorder. Missense alleles require variant-specific interpretation; their effects
    are not assumed to equal haploinsufficiency.
  role: trigger
  biological_scale: MOLECULAR
  gene:
    preferred_term: ASH1L
    term:
      id: hgnc:19088
      label: ASH1L
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Heterozygous pathogenic variants in ASHL1 have been implicated in an autosomal dominant neurodevelopmental
      disorder (NDD).
    explanation: Establishes heterozygous ASH1L variants as the cause. The gene symbol is misspelled in
      the source sentence and is quoted as printed.
  - reference: PMID:28191889
    reference_title: Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism
      and developmental-disability biases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic
      forms of disease.
    explanation: The large targeted-sequencing study that delineated ASH1L as a neurodevelopmental-disorder
      gene with a syndromic presentation.
  - reference: PMID:29753921
    reference_title: De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our report provides further evidence to support loss-of-function alterations of ASH1L as
      causative for an emergent neurodevelopmental syndrome characterized by MCA, intellectual disability,
      and behavioral problems, and further delineates this genetic disorder.
    explanation: The original clinical report directly supports LoF causation; detailed downstream routes
      remain incompletely resolved.
  downstream:
  - target: Reduced ASH1L Histone Methyltransferase Activity
    causal_link_type: DIRECT
    description: Predicted truncation/deletion reduces functional enzyme dosage; the effect of every clinical
      allele has not been directly assayed.
    evidence:
    - reference: PMID:38674358
      reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
        Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: haploinsufficiency is believed to be at least one disease mechanism
      explanation: Human genetic and model evidence supports reduced functional dosage; enzyme loss is
        not individually measured for every variant.
      directness: INDIRECT
  - target: Impaired Craniofacial Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Experimental loss of Ash1l impairs craniofacial development, with a proposed neural-crest
      route in the neural conditional model. Translation from homozygous model dosage to human heterozygous
      dysmorphism is unresolved.
    evidence:
    - reference: PMID:34145365
      reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
        behaviors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Since, in our animal model, Ash1L is also deleted in the NESTIN + neural crest stem cells
        (NCSCs) that develop into craniofacial skeletal tissues 29, it is possible that the observed craniofacial
        deformity is caused by aberrant craniofacial skeletal formation from the Ash1L-deleted NCSCs.
      explanation: The authors propose a neural-crest substrate for the measured nasal-bone defect; no
        genital or general skeletal fanout is claimed.
      directness: INDIRECT
  - target: Anxiety
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional translation of the mouse finding that Ash1l haploinsufficiency causally produces
      anxiety and repetitive behavior. The intermediate circuit is unresolved; mouse grooming is an analogue
      of the compulsive component, not proof of human obsessional thoughts.
    evidence:
    - reference: PMID:35081333
      reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links
        Eph receptor gene to autism spectrum disorder.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior,
        including repetitive behavior, and alters social behavior.
      explanation: This source establishes causal effects of gene dosage in mice. Human expression and
        individual behavioral components remain a qualified extrapolation.
      directness: INDIRECT
  - target: Obsessive-Compulsive Traits
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional translation of the mouse finding that Ash1l haploinsufficiency causally produces
      anxiety and repetitive behavior. The intermediate circuit is unresolved; mouse grooming is an analogue
      of the compulsive component, not proof of human obsessional thoughts.
    evidence:
    - reference: PMID:35081333
      reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links
        Eph receptor gene to autism spectrum disorder.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior,
        including repetitive behavior, and alters social behavior.
      explanation: This source establishes causal effects of gene dosage in mice. Human expression and
        individual behavioral components remain a qualified extrapolation.
      directness: INDIRECT
  - target: Memory Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional translation of memory deficits following neural Ash1l deletion. Homozygous
      neural deletion affects recognition memory, whereas the heterozygous gene-trap study found spatial-memory
      impairment with preserved object recognition; a single human memory substrate is unresolved.
    evidence:
    - reference: PMID:34145365
      reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
        behaviors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple
        developmental defects, core autistic-like behaviors, and impaired cognitive memory.
      explanation: Gene deletion causally produces memory impairment in this model; the human LoF case
        provides the clinical finding, with additional VUS caveats.
      directness: INDIRECT
  - target: Proposed Hypothalamic Circuit Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypothetical translation from homozygous neural deletion and global-null phenotypes;
      loss of one ASH1L copy has not been shown to impair human hypothalamic circuits.
    evidence:
    - reference: PMID:34145365
      reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
        behaviors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: suggest that Ash1L might also play important roles in establishing neural circuits in the
        developing hypothalamus, which is critical for normal feeding behaviors and early postnatal growth
        28.
      explanation: The authors propose a hypothalamic-development route, explicitly requiring further
        testing in patients.
      directness: INDIRECT
- name: Reduced ASH1L Histone Methyltransferase Activity
  description: ASH1L is an H3K36-specific histone methyltransferase. Loss of functional dosage is predicted
    to reduce ASH1L-dependent catalytic output. The decrease in promoter H3K4me3 observed after severe
    mouse PFC knockdown is an associated chromatin consequence, not proof of direct H3K4 catalysis by
    ASH1L.
  role: mediator
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: histone H3K36 methyltransferase activity
    term:
      id: GO:0046975
      label: histone H3K36 methyltransferase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:21239497
    reference_title: Crystal structure of the human histone methyltransferase ASH1L catalytic domain and
      its implications for the regulatory mechanism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In addition, we show that human ASH1L specifically methylates histone H3 Lys-36.
    explanation: Primary biochemical substrate-specificity evidence distinguishes direct H3K36 catalysis
      from an indirect change in H3K4me3.
  downstream:
  - target: Loss of Activating Chromatin Marks at Neurodevelopmental Gene Promoters
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional indirect route from loss of ASH1L function to lower promoter H3K4me3. The
      severe PFC-knockdown study found unchanged bulk H3K36me2/me3; it does not show ASH1L directly depositing
      H3K4me3.
    evidence:
    - reference: PMID:34782621
      reference_title: Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic
        aberrations and seizures.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These downregulated genes are enriched in excitatory and inhibitory synaptic function and
        have decreased H3K4me3 occupancy at their promoters.
      explanation: The measured promoter change follows ASH1L depletion; catalytic and chromatin intermediates
        are unresolved.
      directness: INDIRECT
  mechanism_confidence: PROVISIONAL
- name: Loss of Activating Chromatin Marks at Neurodevelopmental Gene Promoters
  description: Severe juvenile PFC Ash1l knockdown reduces H3K4me3 occupancy at selected synaptic-gene
    promoters. Bulk H3K36me2/me3 was unchanged in that experiment. Lower H3K4me3 in idiopathic-ASD postmortem
    PFC is contextual human evidence, not a measurement in genetically confirmed ASH1L patients.
  role: mediator
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:34782621
    reference_title: Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations
      and seizures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These downregulated genes are enriched in excitatory and inhibitory synaptic function and
      have decreased H3K4me3 occupancy at their promoters.
    explanation: Directly links reduced promoter H3K4me3 occupancy to the downregulated synaptic gene
      set, in mouse prefrontal cortex.
  downstream:
  - target: Downregulation of Synaptic and Neurodevelopmental Gene Programs
    causal_link_type: DIRECT
    description: The authors link reduced promoter H3K4me3 to transcriptional loss of selected synaptic
      genes in mouse PFC; this is a proposed chromatin-to-transcription relation rather than proof that
      all affected genes use the same route.
    evidence:
    - reference: PMID:34782621
      reference_title: Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic
        aberrations and seizures.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These data have linked the Ash1L deficiency-induced transcriptional loss of synaptic genes
        to H3K4me3 reduction in PFC.
      explanation: ChIP and expression data support the proposed relation in severe PFC knockdown.
      directness: INDIRECT
  mechanism_confidence: PROVISIONAL
- name: Downregulation of Synaptic and Neurodevelopmental Gene Programs
  description: ASH1L loss dysregulates neurodevelopmental and synaptic transcription in distinct experimental
    systems. Selected genes decrease in severe PFC knockdown, haploinsufficient gene-trap mice and homozygous
    neural conditional deletion; these datasets are not equivalent to one uniform human transcriptional
    defect.
  role: central_effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  evidence:
  - reference: PMID:34782621
    reference_title: Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations
      and seizures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated
      with ASD, intellectual disability (ID) and epilepsy.
    explanation: Establishes that the transcriptional consequence of ASH1L loss falls specifically on
      autism, intellectual-disability and epilepsy risk genes.
  - reference: PMID:34145365
    reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
      behaviors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during
      neural cell development.
    explanation: Independent model-organism support for ASH1L acting through transcriptional regulation
      during neural development.
  downstream:
  - target: Synaptic Pruning Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: In the haploinsufficient model, reduced EphA7 signaling mediates pruning failure; ephrin-A5
      supplementation rescues pruning and discrimination.
    evidence:
    - reference: PMID:35081333
      reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links
        Eph receptor gene to autism spectrum disorder.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Importantly, increasing activation of EphA7 in Ash1l+/- mice by supplying its ligand, ephrin-A5,
        strongly promotes synapse pruning and rescues discrimination deficits.
      explanation: The rescue supports the EphA7 route, not a general loss of learning ability.
  - target: Cortical Excitation-Inhibition Imbalance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced synaptic-gene expression is proposed to depress inhibition and increase excitation
      in PFC; synaptic and intrinsic contributions differ between experimental manipulations.
    evidence:
    - reference: PMID:39766886
      reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
        and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The significantly elevated eAP, sAP, increased frequency of sEPSC, and reduced amplitude
        and frequency of sIPSC in pyramidal neurons of Ash1l+/GT mice indicated Ash1l haploinsufficiency
        altered intrinsic neuronal properties and disrupted synaptic excitation and inhibition, leading
        to a subsequent neural hyperexcitability in the PFC.
      explanation: The haploinsufficient model supports the functional route; gene-expression causation
        is inferred in combination with physiological changes.
      directness: INDIRECT
  - target: Disrupted Cortical Neuron Specification and Lamination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors propose reduced developmental-gene expression, including Emx2, as a route
      to delayed cortical lamination in homozygous deletion. No corresponding human cellular lesion has
      been established.
    evidence:
    - reference: PMID:34145365
      reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
        behaviors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: |-
        Of note, loss of Emx2 was reported to impair the neuronal migration in the developing mouse cortex 30, which might cause the delayed cor- tical lamination observed in the Ash1L-KO developing cortex (Fig. 2b, c).
      explanation: This is the authors’ model-specific causal hypothesis, not a demonstrated human lamination
        defect.
      directness: INDIRECT
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional translation of the authors’ hypothesis that reduced developmental-gene expression
      disrupts brain development and contributes to ASD/ID. Intervening human circuitry is unresolved,
      and homozygous neural deletion is more severe than typical human dosage.
    evidence:
    - reference: PMID:34145365
      reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
        behaviors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: suggesting that ASH1L might function as a master epigenetic regulator to facilitate the
        expression of FOXG1 and other critical genes for normal brain development, while mutations of
        ASH1L lead to mis-regulation of gene expression, disturbance of the normal brain developmental
        program, and brain functional abnormalities of ASD/ID.
      explanation: The source explicitly proposes this transcriptional route to ASD/ID; uncertainty about
        the intervening circuitry does not remove that qualified causal hypothesis.
      directness: INDIRECT
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional translation of the authors’ hypothesis that reduced developmental-gene expression
      disrupts brain development and contributes to ASD/ID. Intervening human circuitry is unresolved,
      and homozygous neural deletion is more severe than typical human dosage.
    evidence:
    - reference: PMID:34145365
      reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
        behaviors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: suggesting that ASH1L might function as a master epigenetic regulator to facilitate the
        expression of FOXG1 and other critical genes for normal brain development, while mutations of
        ASH1L lead to mis-regulation of gene expression, disturbance of the normal brain developmental
        program, and brain functional abnormalities of ASD/ID.
      explanation: The source explicitly proposes this transcriptional route to ASD/ID; uncertainty about
        the intervening circuitry does not remove that qualified causal hypothesis.
      directness: INDIRECT
  - target: Reduced Neuronal Arborization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced NTRK2/TrkB expression is proposed to contribute to impaired arborization; incomplete
      rescue and altered isoform expression indicate other pathways may contribute.
    evidence:
    - reference: PMID:35210569
      reference_title: Counteracting epigenetic mechanisms regulate the structural development of neuronal
        circuitry in human neurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Therefore, we propose that the deficit in TrkB expression caused by ASH1L knockdown contributes
        to the defects in neuronal morphogenesis.
      explanation: The authors explicitly propose this transcription-to-morphogenesis route, with partial
        mechanistic resolution.
      directness: INDIRECT
  - target: Pyramidal Neuron Hyperexcitability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The severe-knockdown study also proposes downregulated ion-channel, transporter and ATPase
      genes as contributors to intrinsic excitability, independent of the synaptic E/I route.
    evidence:
    - reference: PMID:34782621
      reference_title: Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic
        aberrations and seizures.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: RNAseq analysis revealed that a number of genes encoding voltage-gated potassium channels
        and other ion channels, transporters and transporting ATPases were significantly downregulated
        by Ash1L deficiency (Supplementary Fig. 5f), which may underlie the elevated intrinsic excitability.
      explanation: The authors explicitly propose this intrinsic-excitability route; individual channel
        contributions remain unresolved.
      directness: INDIRECT
  mechanism_confidence: PROVISIONAL
- name: Synaptic Pruning Failure
  description: Developmental synapse elimination fails and excess synapses persist. In haploinsufficient
    mice this is traced to loss of Eph receptor A7 expression through EZH2-mediated H3K27me3 accumulation
    in its gene body, and restoring EphA7 signalling with its ligand ephrin-A5 restores pruning. This
    node captures the single concept of the pruning deficit.
  role: mediator
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: synapse pruning
    term:
      id: GO:0098883
      label: synapse pruning
    modifier: DECREASED
  evidence:
  - reference: PMID:35081333
    reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph
      receptor gene to autism spectrum disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse
      pruning deficits, especially during the post-learning period.
    explanation: Establishes failed synapse pruning as the cellular mechanism in Ash1l-deficient neurons.
  - reference: PMID:35081333
    reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph
      receptor gene to autism spectrum disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Specifically, Eph receptor A7 is downregulated in Ash1l+/- mice through accumulating EZH2-mediated
      H3K27me3 in its gene body.
    explanation: Identifies the specific gene, and the repressive-mark mechanism, connecting ASH1L haploinsufficiency
      to the pruning deficit.
  downstream:
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional human translation of the mouse pruning hypothesis. EphA7 rescue demonstrates
      pruning and discrimination effects; it does not prove every human behavioral feature arises from
      pruning failure.
    evidence:
    - reference: PMID:35081333
      reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links
        Eph receptor gene to autism spectrum disorder.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for
        ASD, resulting from synapse pruning deficits.
      explanation: The authors explicitly attribute ASD-like outcomes to pruning defects; the clinical
        translation remains provisional.
      directness: INDIRECT
  mechanism_confidence: PROVISIONAL
- name: Cortical Excitation-Inhibition Imbalance
  description: Mouse PFC experiments show diminished GABAergic inhibition and enhanced glutamatergic transmission
    after Ash1l loss. The resulting synaptic excitation-inhibition imbalance is a proposed contributor
    to human epilepsy and autistic features, with model-specific dosage and rescue differences.
  role: mediator
  biological_scale: CELLULAR
  conforms_to: epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance
  cell_types:
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: gamma-aminobutyric acid signaling pathway
    term:
      id: GO:0007214
      label: gamma-aminobutyric acid signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:34782621
    reference_title: Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations
      and seizures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced
      glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated
      with severe seizures and early mortality.
    explanation: Direct electrophysiological demonstration of the imbalance and its link to seizures,
      in a prefrontal knockdown model.
  downstream:
  - target: Pyramidal Neuron Hyperexcitability
    causal_link_type: DIRECT
    description: The synaptic shift increases excitatory drive onto PFC pyramidal neurons. Intrinsic excitability
      changes are an additional contribution, not a consequence established solely by E/I imbalance.
    evidence:
    - reference: PMID:39766886
      reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
        and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: |-
        These results demonstrated that Ash1l haploinsufficiency dampened pre- and post-synaptic GABAergic inhibition, and enhanced pre-synaptic glutamatergic excitation, which increased the excitability of pyramidal neurons in the PFC.
      explanation: The source states the synaptic contribution to pyramidal excitability.
  mechanism_confidence: PROVISIONAL
- name: Pyramidal Neuron Hyperexcitability
  description: Cortical pyramidal neurons become hyperexcitable through altered intrinsic properties as
    well as the synaptic shift. This node captures the single concept of network hyperexcitability and
    conforms to the shared epilepsy final common pathway.
  role: central_effector
  biological_scale: CELLULAR
  conforms_to: epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: action potential
    term:
      id: GO:0001508
      label: action potential
    modifier: INCREASED
  evidence:
  - reference: PMID:39766886
    reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
      and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Whole-cell patch-clamp recordings showed that Ash1l haploinsufficiency increased the excitability
      of pyramidal neurons in the PFC by altering intrinsic neuronal properties, enhancing glutamatergic
      synaptic transmission, and diminishing GABAergic synaptic inhibition.
    explanation: Establishes pyramidal hyperexcitability in the model that matches the human heterozygous
      genotype, and separates the intrinsic from the synaptic contribution.
  downstream:
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional clinical translation of the heterozygous gene-trap rescue experiment. PFC
      inhibition improved social behavior and abolished absence-like seizures; this does not demonstrate
      a single circuit for all human seizure semiologies.
    evidence:
    - reference: PMID:39766886
      reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
        and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These results demonstrated that Ash1l haploinsufficiency-induced autism-like social deficits
        and absence-like seizures could be mitigated by inhibition of pyramidal neuronal activity in the
        PFC.
      explanation: Chemogenetic rescue supports causal contribution of PFC excitability in this mouse
        model; applying it to the clinical phenotype remains indirect.
      directness: INDIRECT
  - target: Absence Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional clinical translation of the heterozygous gene-trap rescue experiment. PFC
      inhibition improved social behavior and abolished absence-like seizures; this does not demonstrate
      a single circuit for all human seizure semiologies.
    evidence:
    - reference: PMID:39766886
      reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
        and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These results demonstrated that Ash1l haploinsufficiency-induced autism-like social deficits
        and absence-like seizures could be mitigated by inhibition of pyramidal neuronal activity in the
        PFC.
      explanation: Chemogenetic rescue supports causal contribution of PFC excitability in this mouse
        model; applying it to the clinical phenotype remains indirect.
      directness: INDIRECT
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional clinical translation of the heterozygous gene-trap rescue experiment. PFC
      inhibition improved social behavior and abolished absence-like seizures; this does not demonstrate
      a single circuit for all human seizure semiologies.
    evidence:
    - reference: PMID:39766886
      reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
        and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These results demonstrated that Ash1l haploinsufficiency-induced autism-like social deficits
        and absence-like seizures could be mitigated by inhibition of pyramidal neuronal activity in the
        PFC.
      explanation: Chemogenetic rescue supports causal contribution of PFC excitability in this mouse
        model; applying it to the clinical phenotype remains indirect.
      directness: INDIRECT
  mechanism_confidence: PROVISIONAL
- name: Disrupted Cortical Neuron Specification and Lamination
  description: Homozygous germline or cortex-specific Ash1l deletion alters cortical neuron specification
    and lamination in mice. SATB2-positive projection neurons are ectopically placed and show altered
    differentiation trajectories. This is an experimental developmental mechanism, not an observed lesion
    in human ASH1L patients.
  role: mediator
  biological_scale: TISSUE
  cell_types:
  - preferred_term: cortical projection neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: cerebral cortex neuron differentiation
    term:
      id: GO:0021895
      label: cerebral cortex neuron differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38943682
    reference_title: Ash1l loss-of-function results in structural birth defects and altered cortical development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Birthdating revealed generation of ectopically placed deep layer neurons that express SATB2
    explanation: Demonstrates misspecified, ectopically positioned cortical projection neurons after cortical
      Ash1l deletion.
  mechanism_confidence: PROVISIONAL
- name: Impaired Craniofacial Development
  description: Ash1l-null embryos and neural-lineage conditional knockout mice have shortened nasal bones.
    The neural conditional study proposes abnormal development of NESTIN-positive neural-crest derivatives
    as a cause. This experimental route does not establish the causes of the heterogeneous human genital,
    skeletal and facial findings.
  role: mediator
  biological_scale: TISSUE
  evidence:
  - reference: PMID:38943682
    reference_title: Ash1l loss-of-function results in structural birth defects and altered cortical development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Notably, Ash1l-/- exhibited shortened nasal bones (n = 31, P = 0.017).
    explanation: A specific craniofacial phenotype in the germline-null mouse; other human organ anomalies
      are not inferred.
  mechanism_confidence: PROVISIONAL
- name: Reduced Neuronal Arborization
  description: Acute ASH1L knockdown in stem-cell-derived human cortical excitatory neurons reduces neurite
    length and branching. Reduced NTRK2 expression and antagonistic PRC2 activity are implicated; EZH2
    inhibition partially rescues morphogenesis, while added BDNF does not. These are engineered immature
    neurons, not clinical neuropathology.
  role: mediator
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:35210569
    reference_title: Counteracting epigenetic mechanisms regulate the structural development of neuronal
      circuitry in human neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding
      the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis.
    explanation: Direct experimental finding after acute knockdown in human stem-cell-derived neurons.
  downstream:
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional hypothesis that impaired neurite development compromises connectivity and
      contributes to autism in ASH1L patients; functional synapses were not yet mature in the experimental
      cultures.
    evidence:
    - reference: PMID:35210569
      reference_title: Counteracting epigenetic mechanisms regulate the structural development of neuronal
        circuitry in human neurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Defects in neuronal morphogenesis could potentially impair the establishment of neuronal
        connections which could contribute to the neurodevelopmental pathogenesis associated with ASD
        in patients with ASH1L mutations.
      explanation: This is the source’s explicitly qualified clinical hypothesis, not demonstrated human
        neuropathology.
      directness: INDIRECT
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Provisional arborization hypothesis for the reported postnatal microcephaly. The clinical
      report concerns a missense allele whereas the cellular experiment uses acute knockdown; gliogenesis
      and other explanations remain possible.
    evidence:
    - reference: PMID:35210569
      reference_title: Counteracting epigenetic mechanisms regulate the structural development of neuronal
        circuitry in human neurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Postnatal microcephaly could arise as a result of impaired neuronal arborization and/or
        a defect in the generation, proliferation or survival of glial cells or their precursor cells
        39, 84.
      explanation: The authors discuss this hypothesis in the context of the ASH1L microcephaly case;
        it is not a proof that this patient’s allele reduces arborization.
      directness: INDIRECT
- name: Proposed Hypothalamic Circuit Dysfunction
  description: The neural Ash1l-null mouse study proposes that impaired development of hypothalamic circuits
    could disturb feeding behavior and early postnatal growth. This hypothesis was motivated by neonatal
    survival and growth findings; hypothalamic pathology and a corresponding human lesion were not demonstrated.
  role: mediator
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:34145365
    reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
      behaviors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: suggest that Ash1L might also play important roles in establishing neural circuits in the
      developing hypothalamus, which is critical for normal feeding behaviors and early postnatal growth
      28.
    explanation: The authors propose a hypothalamic-development route, explicitly requiring further testing
      in patients.
    directness: INDIRECT
  downstream:
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors propose hypothalamic dysfunction as a possible explanation for feeding behavior
      and postnatal growth; no patient-specific causal attribution is established. Human growth delay
      was reported in a missense case, further limiting dosage and allele translation.
    evidence:
    - reference: PMID:34145365
      reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
        behaviors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: It will be interesting to examine whether ASH1L mutations could cause hypothalamus dysfunctions
        that affect normal feeding behaviors and postnatal growth in human patients.
      explanation: This is an explicitly proposed human-disease hypothesis from the model discussion,
        not a demonstrated patient mechanism.
      directness: INDIRECT
  - target: Growth Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors propose hypothalamic dysfunction as a possible explanation for feeding behavior
      and postnatal growth; no patient-specific causal attribution is established. Human growth delay
      was reported in a missense case, further limiting dosage and allele translation.
    evidence:
    - reference: PMID:34145365
      reference_title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like
        behaviors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: It will be interesting to examine whether ASH1L mutations could cause hypothalamus dysfunctions
        that affect normal feeding behaviors and postnatal growth in human patients.
      explanation: This is an explicitly proposed human-disease hypothesis from the model discussion,
        not a demonstrated patient mechanism.
      directness: INDIRECT
phenotypes:
- name: Intellectual Disability
  description: 'Intellectual disability ranges from mild to severe in reported ASH1L cases. It is not
    obligatory: BGR 2 had average measured cognition despite autism and other findings.'
  category: Nervous System
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:34373061
    reference_title: ASH1L mutation caused seizures and intellectual disability in twin sisters.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we present twin sisters exhibiting mild intellectual disability and seizures.
    explanation: The ASH1L twin report establishes mild intellectual disability independently of the combined
      ID/DD tally.
  - reference: PMID:28394464
    reference_title: Novel MCA/ID syndrome with ASH1L mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a novel mutation in ASH1L in a patient with severe intellectual disability,
      growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities.
    explanation: Severe ID was reported in the p.Ala2786Pro missense case; its mechanism is not assumed
      to match truncating alleles.
  notes: The 2024 summary reports ID or developmental delay in 15/16 assessed probands; this combined
    denominator does not establish an intellectual-disability-only frequency. Borderline test scores in
    some reports are not equated with a formal ID diagnosis.
- name: Attention Deficit Hyperactivity Disorder
  description: Clinical ADHD diagnoses were reported in the registry and in the Shen case.
  category: Nervous System
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His neurodevelopmental phenotype is consistent with previous publications including ASD,
      ADHD, obsessive behaviors, feeding difficulties, and excessive reflux and vomiting during infancy.
    explanation: BGR 2 has an explicitly reported ADHD diagnosis, independent of the pooled ADHD-or-hyperactivity
      count.
  notes: The 6/7 (86%) summary combines ADHD with hyperactivity and cannot supply an ADHD-specific frequency.
- name: Obsessive-Compulsive Traits
  description: Obsessive behaviors were reported in BGR 1 and BGR 2. The literature summary includes obsessive
    or compulsive traits, including trichotillomania, without establishing an obsessive-compulsive disorder
    diagnosis.
  category: Nervous System
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Obsessive-compulsive trait
    term:
      id: HP:0008770
      label: Obsessive-compulsive trait
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His neurodevelopmental phenotype is consistent with previous publications including ASD,
      ADHD, obsessive behaviors, feeding difficulties, and excessive reflux and vomiting during infancy.
    explanation: The registry narrative specifies obsessive behaviors, supporting the broader obsessive-compulsive-trait
      term rather than compulsions alone.
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 4/5 = 80% falls at the lower edge of the VERY_FREQUENT band (80-99%), on a denominator
      of only five assessed probands. The denominator is feature-specific and subject to ascertainment
      and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Autism
  description: Autism spectrum disorder is reported in a majority of probands assessed.
  category: Nervous System
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 6/10 = 60% maps to the FREQUENT band (30-79%), on a denominator of ten assessed probands.
      The denominator is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Gastrointestinal Disturbance
  description: Gastrointestinal symptoms include reported gastroesophageal reflux and vomiting; constipation
    is recorded in the clinical literature table.
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Abnormality of the gastrointestinal tract
    term:
      id: HP:0011024
      label: Abnormality of the gastrointestinal tract
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: The 2024 synthesis reports a broad gastrointestinal category. Its pooled 6/8 count is
      not assigned a frequency because the underlying table includes an ambiguously classified incontinence
      observation; specific reflux and vomiting are independently documented.
  notes: The 2024 discussion and Table 1 report gastrointestinal disturbances in 6/8 assessed probands,
    but the labelled supplementary table places unspecified nighttime incontinence among gastrointestinal
    findings. The original Stessman narrative explicitly reports no gastrointestinal disturbance in that
    patient. This imperfect aggregate is preserved as a source report without assigning a gastrointestinal
    frequency band.
- name: Facial Dysmorphism
  description: Variable facial dysmorphism is reported in a majority, but with no recognizable pattern;
    two systematically assessed registry probands were explicitly non-dysmorphic.
  category: Head and Neck
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 9/13 = 69% maps to the FREQUENT band (30-79%). The same paper notes that in most published
      probands it is unclear whether dysmorphology was assessed and negative or simply not assessed, so
      this figure is likely inflated. The denominator is feature-specific and subject to ascertainment
      and reporting bias.
  notes: The 2024 discussion gives 9/13 (69%) whereas its published Table 1 gives 8/10 (80%); these cross
    frequency-enum boundaries, so no band is assigned. BGR 1 and BGR 2 were systematically assessed and
    nondysmorphic. The literature has no consistent facial gestalt.
- name: Sleep Disturbance
  description: Sleep disorders are reported in a majority of probands assessed.
  category: Nervous System
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 6/9 = 67% maps to the FREQUENT band (30-79%), on a denominator of nine. The denominator
      is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Ocular Abnormality
  description: Hyperopia, astigmatism, strabismus and nystagmus are among the reported ocular findings.
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 6/10 = 60% maps to the FREQUENT band (30-79%), on a denominator of ten. The denominator
      is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Speech Delay
  description: Speech and language delay is common; one proband had mixed receptive language disorder.
  category: Nervous System
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 6/10 = 60% maps to the FREQUENT band (30-79%), on a denominator of ten. The denominator
      is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Hypotonia
  description: Hypotonia is reported in approximately half of assessed probands, with discrepant
    denominators in the 2024 source.
  category: Nervous System
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 4/7 = 57% maps to the FREQUENT band (30-79%), on a denominator of seven. The denominator
      is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent. The 2024 discussion gives 4/7 (57%) and its published
    Table 1 gives 4/8 (50%); both fall in FREQUENT. The discrepancy is retained rather than choosing a
    reconstructed denominator.
- name: Genital Malformation
  description: Genital malformations such as penile torsion and cryptorchidism are reported
    in over half of probands assessed. Most reported probands are male.
  category: Genitourinary
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of the genital system
    term:
      id: HP:0000078
      label: Abnormality of the genital system
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 5/9 = 56% maps to the FREQUENT band (30-79%), on a denominator of nine. The denominator
      is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Seizures
  description: Seizures occur in roughly half of probands, spanning febrile, focal motor, absence and
    myoclonic types; one reported proband's epilepsy was drug-resistant.
  category: Nervous System
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 6/11 = 55% maps to the FREQUENT band (30-79%), on a denominator of eleven. The denominator
      is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Motor Delay
  description: Motor delay is reported in half of probands assessed.
  category: Nervous System
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 6/12 = 50% maps to the FREQUENT band (30-79%), on a denominator of twelve. The denominator
      is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Feeding Difficulties
  description: Feeding difficulties in infancy are reported in half of probands assessed.
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%), with other common phenotypes being ADHD
      or hyperactivity (6/7, 86%), obsessive behaviors (4/5, 80%), gastrointestinal disturbances (6/8,
      75%), facial dysmorphisms (9/13, 69%), sleep disorders (6/9, 67%), ASD (6/10, 60%), ocular problems
      (6/10, 60%), hypotonia (4/7, 57%), genital malformations (5/9, 56%), speech delay (6/10, 60%), seizures
      (6/11, 55%), motor delay (6/12, 50%), feeding difficulties (4/8, 50%), mood disorders (2/4, 50%),
      and abnormal gait (2/4, 50%)
    explanation: 4/8 = 50% maps to the FREQUENT band (30-79%), on a denominator of eight. The denominator
      is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Gait Disturbance
  description: Abnormal gait was reported in BGR 2 (ataxic, with dysmetria and incoordination) and BGR
    3 (stiff, with internal tibial torsion). These are distinct presentations.
  category: Nervous System
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: and abnormal gait (2/4, 50%)
    explanation: 2/4 = 50% maps to the FREQUENT band (30-79%), but on a denominator of only four probands
      - the weakest estimate in this set. The denominator is feature-specific and subject to ascertainment
      and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent. BGR 2 also carried research-only biallelic TNR missense
    VUS and a TSHZ3 VUS. BGR 3 carried MED12, POU4F3 and ATP2B2 VUS. Their contributions remain uncertain;
    an ataxic-gait frequency cannot be inferred from the combined 2/4 abnormal-gait count.
- name: Sensorineural Hearing Impairment
  description: Mild bilateral sensorineural hearing loss was reported in BGR 3. Cordova’s case table also
    summarizes left-sided moderate sensorineural loss in the earlier Okamoto missense case.
  category: Auditory
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic
      seizures); this proband’s epilepsy is Klonopin-resistant.
    explanation: Reports actual bilateral sensorineural hearing loss in BGR 3; additional hearing-gene
      variants prevent unqualified causal attribution to ASH1L.
  notes: BGR 3 also carried POU4F3 and ATP2B2 missense VUS in genes associated with hearing loss, so ASH1L-specific
    attribution is unresolved. The generic hearing count is 4/9 in the 2024 discussion versus 3/8 in Table
    1; Supplemental Table 1 includes hyperacusis among hearing findings. Neither aggregate supplies a
    sensorineural-loss frequency.
- name: Scoliosis
  description: Scoliosis is among the less common musculoskeletal findings.
  category: Skeletal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: other less common phenotypes include hearing impairments (4/9, 44%), pectus carinatum/excavatum
      (2/7, 29%), and scoliosis (2/7, 29%)
    explanation: 2/7 = 29% maps to the OCCASIONAL band (5-29%), on a denominator of seven. The denominator
      is feature-specific and subject to ascertainment and reporting bias.
  notes: The reported proportion comes from selected published cases plus three registry participants,
    among those assessed or described for this feature. It is not population prevalence or penetrance;
    unreported findings were not counted as absent.
- name: Pectus Carinatum
  description: Pectus carinatum was reported in the earlier severe-ID missense case summarized by Cordova
    et al.
  category: Skeletal
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A smaller percentage of probands also have been reported with seizures, feeding difficulties,
      hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical
      spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),
      hearing impairments, and gastrointestinal disturbances [11,13,14,15,16].
    explanation: The published clinical synthesis explicitly lists carinatum and excavatum as distinct
      reported findings. The pooled frequency is not transferred to either component.
  notes: The pooled pectus carinatum/excavatum figure of 2/7 is not a carinatum-specific frequency. The
    labelled Supplemental Table 1 attributes carinatum to the de Ligt p.Ala724Ser case and excavatum to
    the Shen frameshift case; missense pathogenicity and mechanism require separate evaluation.
- name: Depression
  description: Depression was diagnosed at age 11 in BGR 1.
  category: Nervous System
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This proband also has features which have not been previously reported, including depression
      (diagnosed at age 11) and mixed receptive language disorder (diagnosed at age 7).
    explanation: This is a specific depression diagnosis in BGR 1, not the broader pooled mood-disorder
      count.
  notes: The pooled mood/anxiety-or-depression count of 2/4 cannot establish a depression-specific frequency.
- name: Pectus Excavatum
  description: Pectus excavatum is reported in the Shen frameshift case summarized in the 2024 clinical
    synthesis.
  category: Skeletal
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A smaller percentage of probands also have been reported with seizures, feeding difficulties,
      hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical
      spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),
      hearing impairments, and gastrointestinal disturbances [11,13,14,15,16].
    explanation: The clinical synthesis lists excavatum separately from carinatum; the 2/7 combined pectus
      tally is not a subtype frequency.
- name: Penile Torsion
  description: Penile Torsion is among the congenital genital findings in published ASH1L cases.
  category: Genitourinary
  phenotype_term:
    preferred_term: Torsion of the penis
    term:
      id: HP:0030263
      label: Torsion of the penis
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition to DD/ID and ASD, genital and urinary malformations (such as penile torsion and
      cryptorchidism) and sleep disorders have also been reported.
    explanation: The clinical synthesis explicitly names this component. The 5/9 genital-malformation
      tally is not its frequency.
- name: Cryptorchidism
  description: Cryptorchidism is among the congenital genital findings in published ASH1L cases.
  category: Genitourinary
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition to DD/ID and ASD, genital and urinary malformations (such as penile torsion and
      cryptorchidism) and sleep disorders have also been reported.
    explanation: The clinical synthesis explicitly names this component. The 5/9 genital-malformation
      tally is not its frequency.
- name: Cervical Vertebral Fusion
  description: Cervical spinal fusion was reported in the Okamoto missense case summarized by Cordova
    et al.; a particular vertebral level is not established here.
  category: Skeletal
  phenotype_term:
    preferred_term: Fused cervical vertebrae
    term:
      id: HP:0002949
      label: Fused cervical vertebrae
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A smaller percentage of probands also have been reported with seizures, feeding difficulties,
      hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical
      spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),
      hearing impairments, and gastrointestinal disturbances [11,13,14,15,16].
    explanation: The source explicitly lists cervical spinal fusion, with case attribution checked in
      its labelled Supplemental Table 1.
- name: Hyperopia
  description: Hyperopia is reported among the heterogeneous ocular findings; no frequency or universal
    association is inferred.
  category: Ophthalmological
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A smaller percentage of probands also have been reported with seizures, feeding difficulties,
      hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical
      spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),
      hearing impairments, and gastrointestinal disturbances [11,13,14,15,16].
    explanation: The clinical synthesis explicitly names this ocular finding. Its pooled 6/10 eye-abnormality
      count cannot establish a component-specific band.
- name: Strabismus
  description: Strabismus is reported among the heterogeneous ocular findings; no frequency or universal
    association is inferred.
  category: Ophthalmological
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A smaller percentage of probands also have been reported with seizures, feeding difficulties,
      hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical
      spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),
      hearing impairments, and gastrointestinal disturbances [11,13,14,15,16].
    explanation: The clinical synthesis explicitly names this ocular finding. Its pooled 6/10 eye-abnormality
      count cannot establish a component-specific band.
- name: Nystagmus
  description: Nystagmus is reported among the heterogeneous ocular findings; no frequency or universal
    association is inferred.
  category: Ophthalmological
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A smaller percentage of probands also have been reported with seizures, feeding difficulties,
      hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical
      spinal fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus),
      hearing impairments, and gastrointestinal disturbances [11,13,14,15,16].
    explanation: The clinical synthesis explicitly names this ocular finding. Its pooled 6/10 eye-abnormality
      count cannot establish a component-specific band.
- name: Astigmatism
  description: Astigmatism was reported in BGR 1 and in the Stessman frameshift case.
  category: Ophthalmological
  phenotype_term:
    preferred_term: Astigmatism
    term:
      id: HP:0000483
      label: Astigmatism
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: febrile seizures beginning at age 3, ASD, attention deficit hyperactivity disorder (ADHD),
      obsessive behaviors, gastroesophageal reflux disease, and astigmatism.
    explanation: The BGR 1 narrative establishes this refractive abnormality directly.
- name: Gastroesophageal Reflux
  description: Gastroesophageal reflux disease was reported in BGR 1; BGR 2 had excessive infantile reflux.
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: febrile seizures beginning at age 3, ASD, attention deficit hyperactivity disorder (ADHD),
      obsessive behaviors, gastroesophageal reflux disease, and astigmatism.
    explanation: This is a specific gastroesophageal reflux diagnosis, separate from the broad gastrointestinal
      count.
- name: Vomiting
  description: Excessive vomiting during infancy was reported in BGR 2.
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His neurodevelopmental phenotype is consistent with previous publications including ASD,
      ADHD, obsessive behaviors, feeding difficulties, and excessive reflux and vomiting during infancy.
    explanation: Reports vomiting directly in the ASH1L frameshift proband; the co-occurrence with reflux
      does not independently establish its cause.
- name: Gait Ataxia
  description: Gait ataxia was reported in BGR 2, alongside difficulty with balance.
  category: Nervous System
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, the proband displays dysmetria and an abnormal, ataxic gait with difficulty
      coordinating motion and balance.
    explanation: Direct BGR 2 clinical description; the separate components are not used to infer a cerebellar
      mechanism.
  notes: BGR 2 also carried unconfirmed research biallelic TNR missense VUS and a TSHZ3 VUS; their contributions
    to the motor phenotype remain unresolved. No cerebellar lesion is inferred from these signs.
- name: Dysmetria
  description: Dysmetria was reported in BGR 2, alongside difficulty with balance.
  category: Nervous System
  phenotype_term:
    preferred_term: Dysmetria
    term:
      id: HP:0001310
      label: Dysmetria
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, the proband displays dysmetria and an abnormal, ataxic gait with difficulty
      coordinating motion and balance.
    explanation: Direct BGR 2 clinical description; the separate components are not used to infer a cerebellar
      mechanism.
  notes: BGR 2 also carried unconfirmed research biallelic TNR missense VUS and a TSHZ3 VUS; their contributions
    to the motor phenotype remain unresolved. No cerebellar lesion is inferred from these signs.
- name: Incoordination
  description: Incoordination was reported in BGR 2, alongside difficulty with balance.
  category: Nervous System
  phenotype_term:
    preferred_term: Incoordination
    term:
      id: HP:0002311
      label: Incoordination
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, the proband displays dysmetria and an abnormal, ataxic gait with difficulty
      coordinating motion and balance.
    explanation: Direct BGR 2 clinical description; the separate components are not used to infer a cerebellar
      mechanism.
  notes: BGR 2 also carried unconfirmed research biallelic TNR missense VUS and a TSHZ3 VUS; their contributions
    to the motor phenotype remain unresolved. No cerebellar lesion is inferred from these signs.
- name: Internal Tibial Torsion
  description: Left internal tibial torsion accompanied the stiff gait of BGR 3.
  category: Skeletal
  phenotype_term:
    preferred_term: Internal tibial torsion
    term:
      id: HP:0034372
      label: Internal tibial torsion
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband also has a stiff gait with left internal tibial torsion and is now walking without
      assistance.
    explanation: Reports a specific orthopedic finding; coexistence does not demonstrate that torsion
      explains the full gait disorder.
  notes: BGR 3 also carried MED12, POU4F3 and ATP2B2 VUS; the report did not resolve their contributions.
- name: Receptive Language Impairment
  description: Mixed receptive language disorder was diagnosed at age 7 in BGR 1, beyond the earlier speech
    delay.
  category: Nervous System
  phenotype_term:
    preferred_term: Receptive language delay
    term:
      id: HP:0010863
      label: Receptive language delay
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This proband also has features which have not been previously reported, including depression
      (diagnosed at age 11) and mixed receptive language disorder (diagnosed at age 7).
    explanation: The clinical diagnosis supports the receptive-language component. No severity or frequency
      is inferred.
- name: Febrile Seizures
  description: Febrile seizures began at age 3 in BGR 1.
  category: Nervous System
  phenotype_term:
    preferred_term: Febrile seizure (within the age range of 3 months to 6 years)
    term:
      id: HP:0002373
      label: Febrile seizure (within the age range of 3 months to 6 years)
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: febrile seizures beginning at age 3, ASD, attention deficit hyperactivity disorder (ADHD),
      obsessive behaviors, gastroesophageal reflux disease, and astigmatism.
    explanation: The age and febrile trigger support this specific seizure term; simple versus complex
      is not reported.
- name: Absence Seizures
  description: Generalized non-motor (absence) seizure was reported in BGR 3, whose epilepsy was resistant
    to clonazepam.
  category: Nervous System
  phenotype_term:
    preferred_term: Generalized non-motor (absence) seizure
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic
      seizures); this proband’s epilepsy is Klonopin-resistant.
    explanation: This human case explicitly supplies the seizure subtype. No particular focus, awareness
      state, or generalized onset is inferred beyond the stated semiology.
  notes: BGR 3 also carried a MED12 VUS, as well as POU4F3 and ATP2B2 VUS; their contributions were unresolved.
    A mouse absence-like phenotype is not evidence that all human seizure types share an identical circuit.
- name: Focal Motor Seizures
  description: Focal motor seizure was reported in BGR 3, whose epilepsy was resistant to clonazepam.
  category: Nervous System
  phenotype_term:
    preferred_term: Focal motor seizure
    term:
      id: HP:0011153
      label: Focal motor seizure
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic
      seizures); this proband’s epilepsy is Klonopin-resistant.
    explanation: This human case explicitly supplies the seizure subtype. No particular focus, awareness
      state, or generalized onset is inferred beyond the stated semiology.
  notes: BGR 3 also carried a MED12 VUS, as well as POU4F3 and ATP2B2 VUS; their contributions were unresolved.
    A mouse absence-like phenotype is not evidence that all human seizure types share an identical circuit.
- name: Myoclonic Seizures
  description: Myoclonic seizure was reported in BGR 3, whose epilepsy was resistant to clonazepam.
  category: Nervous System
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic
      seizures); this proband’s epilepsy is Klonopin-resistant.
    explanation: This human case explicitly supplies the seizure subtype. No particular focus, awareness
      state, or generalized onset is inferred beyond the stated semiology.
  notes: BGR 3 also carried a MED12 VUS, as well as POU4F3 and ATP2B2 VUS; their contributions were unresolved.
    A mouse absence-like phenotype is not evidence that all human seizure types share an identical circuit.
- name: Microcephaly
  description: Microcephaly was reported in the Okamoto p.Ala2786Pro missense case.
  category: Nervous System
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:28394464
    reference_title: Novel MCA/ID syndrome with ASH1L mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a novel mutation in ASH1L in a patient with severe intellectual disability,
      growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities.
    explanation: The original case-report abstract supports the finding. Brain white-matter localization
      of delayed myelination is also reported in the later clinical synthesis. The missense mechanism
      is unestablished.
  notes: A finding in this missense case does not establish penetrance in truncating-variant carriers.
    The source’s growth failure is not equated with undernutrition, and delayed myelination is not permanent
    hypomyelination.
- name: Growth Delay
  description: Growth delay was reported in the Okamoto p.Ala2786Pro missense case.
  category: Growth
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:28394464
    reference_title: Novel MCA/ID syndrome with ASH1L mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a novel mutation in ASH1L in a patient with severe intellectual disability,
      growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities.
    explanation: The original case-report abstract supports the finding. Brain white-matter localization
      of delayed myelination is also reported in the later clinical synthesis. The missense mechanism
      is unestablished.
  notes: A finding in this missense case does not establish penetrance in truncating-variant carriers.
    The source’s growth failure is not equated with undernutrition, and delayed myelination is not permanent
    hypomyelination.
- name: Delayed CNS Myelination
  description: Delayed CNS myelination was reported in the Okamoto p.Ala2786Pro missense case.
  category: Nervous System
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: PMID:28394464
    reference_title: Novel MCA/ID syndrome with ASH1L mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a novel mutation in ASH1L in a patient with severe intellectual disability,
      growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities.
    explanation: The original case-report abstract supports the finding. Brain white-matter localization
      of delayed myelination is also reported in the later clinical synthesis. The missense mechanism
      is unestablished.
  notes: A finding in this missense case does not establish penetrance in truncating-variant carriers.
    The source’s growth failure is not equated with undernutrition, and delayed myelination is not permanent
    hypomyelination.
- name: Memory Impairment
  description: Poor memory was reported in a 23-year-old woman with mild ID and maternally inherited p.Lys827*.
  category: Nervous System
  phenotype_term:
    preferred_term: Memory impairment
    term:
      id: HP:0002354
      label: Memory impairment
  evidence:
  - reference: PMID:39902220
    reference_title: Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additionally, it is reported that the proband has mild ID with poor learning abilities and
      poor memory.
    explanation: The human case establishes memory difficulty; it does not establish a particular memory-system
      defect.
  notes: Additional ACTL6B, COQ8A, DPP6 and SETD1B VUS were reported. Structural predictions in this paper
    are computational, not a functional assay of the patient’s enzyme.
- name: Sleep Apnea
  description: Sleep apnea was reported in the Shen frameshift case; the 2024 clinical table calls it
    obstructive.
  category: Respiratory
  phenotype_term:
    preferred_term: Sleep apnea
    term:
      id: HP:0010535
      label: Sleep apnea
  evidence:
  - reference: PMID:29753921
    reference_title: De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we identified a novel de novo frame-shift variant, c.2422_2423delAAinsT which predicts
      p.(Lys808TyrfsTer40), in ASH1L in a patient with multiple congenital anomalies (MCA), fine motor
      developmental delay, learning difficulties, attention deficit hyperactivity disorder, sleep apnea,
      and scoliosis.
    explanation: The original abstract directly reports sleep apnea. Without the original full clinical
      narrative, the curated binding remains at the supported apnea level.
- name: Anxiety
  description: Anxiety was reported among BGR participants, but the combined anxiety/depression summary
    does not identify an anxiety-specific denominator.
  category: Nervous System
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Consistent with previous probands, most BGR participants reported ID/DD, ASD, obsessive behaviors,
      speech and motor delays, seizures, ADHD, gastrointestinal disturbances, and/or anxiety.
    explanation: The registry summary reports anxiety; no anxiety-disorder subtype or frequency is assigned.
- name: Hypothyroidism
  description: Hypothyroidism was reported in Stessman patient 1206-11D, a six-year-old girl with a de
    novo frameshift variant.
  category: Endocrine
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She has ID, hearing deficits, hypothyroidism, hyperopia, astigmatism, normal growth, smooth
      filtrum, hypertelorism, and a low hairline.
    explanation: The original ASH1L patient narrative supports this finding; this is a case observation
      without a population frequency.
  notes: The original narrative and Table 21 both say hypothyroidism. Cordova’s later Supplemental Table
    1 transcribes this as hyperthyroidism; that secondary transcription is not followed.
- name: Smooth Philtrum
  description: Smooth philtrum was reported in Stessman patient 1206-11D, a six-year-old girl with a de
    novo frameshift variant.
  category: Head and Neck
  phenotype_term:
    preferred_term: Smooth philtrum
    term:
      id: HP:0000319
      label: Smooth philtrum
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She has ID, hearing deficits, hypothyroidism, hyperopia, astigmatism, normal growth, smooth
      filtrum, hypertelorism, and a low hairline.
    explanation: The original ASH1L patient narrative supports this finding; this is a case observation
      without a population frequency.
- name: Hypertelorism
  description: Hypertelorism was reported in Stessman patient 1206-11D, a six-year-old girl with a de
    novo frameshift variant.
  category: Head and Neck
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She has ID, hearing deficits, hypothyroidism, hyperopia, astigmatism, normal growth, smooth
      filtrum, hypertelorism, and a low hairline.
    explanation: The original ASH1L patient narrative supports this finding; this is a case observation
      without a population frequency.
- name: Hearing Impairment
  description: Hearing impairment was reported in Stessman patient 1206-11D, a six-year-old girl with
    a de novo frameshift variant.
  category: Auditory
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She has ID, hearing deficits, hypothyroidism, hyperopia, astigmatism, normal growth, smooth
      filtrum, hypertelorism, and a low hairline.
    explanation: The original ASH1L patient narrative supports this finding; this is a case observation
      without a population frequency.
- name: Hyperactivity
  description: Hyperactivity accompanied verbal regression at age 3 in Stessman patient 3145.
  category: Nervous System
  phenotype_term:
    preferred_term: Hyperactivity
    term:
      id: HP:0000752
      label: Hyperactivity
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After a regular psychomotor development, he showed at 3 years a regression in the verbal
      speech, and some behavioral changes, such as hyperactivity and tendency to isolation.
    explanation: The source explicitly reports hyperactivity, separately from an ADHD diagnosis.
  notes: This patient carried the p.Arg2391His missense variant of unknown inheritance. Pathogenicity
    and mechanism are less secure than for established LoF alleles; no frequency is transferred from the
    combined ADHD/hyperactivity tally.
- name: Dolichocephaly
  description: Dolichocephaly was reported in Stessman patient 3145.
  category: Head and Neck
  phenotype_term:
    preferred_term: Dolichocephaly
    term:
      id: HP:0000268
      label: Dolichocephaly
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His phenotype showed dolicocephaly, normal weight and height, lumbar hyperlordosis, winged
      scapulae.
    explanation: The original narrative documents the sign in the p.Arg2391His missense case of unknown
      inheritance. It does not establish a LoF-specific phenotype or a muscular cause.
  notes: Missense pathogenicity and mechanism require separate evaluation; these findings are retained
    as case-scoped observations.
- name: Lumbar Hyperlordosis
  description: Lumbar hyperlordosis was reported in Stessman patient 3145.
  category: Skeletal
  phenotype_term:
    preferred_term: Lumbar hyperlordosis
    term:
      id: HP:0002938
      label: Lumbar hyperlordosis
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His phenotype showed dolicocephaly, normal weight and height, lumbar hyperlordosis, winged
      scapulae.
    explanation: The original narrative documents the sign in the p.Arg2391His missense case of unknown
      inheritance. It does not establish a LoF-specific phenotype or a muscular cause.
  notes: Missense pathogenicity and mechanism require separate evaluation; these findings are retained
    as case-scoped observations.
- name: Scapular Winging
  description: Scapular winging was reported in Stessman patient 3145.
  category: Skeletal
  phenotype_term:
    preferred_term: Scapular winging
    term:
      id: HP:0003691
      label: Scapular winging
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His phenotype showed dolicocephaly, normal weight and height, lumbar hyperlordosis, winged
      scapulae.
    explanation: The original narrative documents the sign in the p.Arg2391His missense case of unknown
      inheritance. It does not establish a LoF-specific phenotype or a muscular cause.
  notes: Missense pathogenicity and mechanism require separate evaluation; these findings are retained
    as case-scoped observations.
- name: Excessive Daytime Somnolence
  description: Excessive daytime sleepiness and frequent naps were reported in Stessman patient 11282.p1.
  category: Nervous System
  phenotype_term:
    preferred_term: Excessive daytime somnolence
    term:
      id: HP:0001262
      label: Excessive daytime somnolence
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient has a history of sleep problems including excessive daytime sleepiness and unusually
      frequent naps during the day.
    explanation: The original frameshift-case narrative supports daytime somnolence; no sleep-disorder
      mechanism is established.
- name: Sleepwalking
  description: Sleepwalking was reported in Stessman patient 13678.p1, who carried a de novo nonsense
    variant.
  category: Nervous System
  phenotype_term:
    preferred_term: Sleep walking
    term:
      id: HP:0025236
      label: Sleep walking
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient has a history of sleep problems including sleepwalking, difficulty going to bed,
      long or frequent daytime naps, and incontinence at night.
    explanation: The original narrative supports sleepwalking. Bedtime difficulty is not upgraded to insomnia,
      and unspecified nocturnal incontinence is not assumed to be urinary enuresis.
- name: Loss of Acquired Spoken Language
  description: Verbal speech regressed at age 3 in Stessman patient 3145 after initially regular psychomotor
    development.
  category: Nervous System
  phenotype_term:
    preferred_term: Loss of acquired spoken language
    term:
      id: HP:6001483
      label: Loss of acquired spoken language
  evidence:
  - reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    reference_title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After a regular psychomotor development, he showed at 3 years a regression in the verbal
      speech, and some behavioral changes, such as hyperactivity and tendency to isolation.
    explanation: The original narrative supports regression of acquired verbal language, without implying
      complete mutism.
  notes: The p.Arg2391His missense variant was of unknown inheritance; a mechanism equivalent to LoF is
    not established.
genetic:
- name: ASH1L
  gene_term:
    preferred_term: ASH1L
    term:
      id: hgnc:19088
      label: ASH1L
  relationship_type: CAUSATIVE
  notes: ASH1L (1q22) encodes a Trithorax-group histone methyltransferase. Pathogenic alleles reported
    with detailed phenotyping are predominantly loss-of-function (nonsense, frameshift, deletion); missense
    alleles have also been reported but their disease mechanism is unresolved. ClinGen's Intellectual
    Disability and Autism Gene Curation Expert Panel classified the gene-disease relationship as Definitive.
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: relationship to syndromic complex neurodevelopmental disorder was classified as Definitive.
    explanation: Records the ClinGen Definitive gene-disease validity classification for ASH1L.
  - reference: PMID:39902220
    reference_title: Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A review of reported ASH1L nonsense mutations to explore genotype-phenotype correlations
      suggested that these variants typically result in a loss of function.
    explanation: Supports loss of function as the mechanism of the nonsense allele class.
diagnosis:
- name: Exome or Genome Sequencing
  description: 'The diagnosis is molecular: identification of a heterozygous loss-of-function ASH1L variant,
    usually de novo, on trio exome or genome sequencing performed for developmental delay, autism or epilepsy.
    There is no biochemical or imaging marker. Interpretation is complicated in practice by the frequency
    with which additional variants of uncertain significance are found alongside the ASH1L variant.'
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ASH1L variants were first implicated in human disease in 2012 through a large sequencing
      study in persons with severe ID.
    explanation: Establishes sequencing as the route by which the disorder is identified.
treatments:
- name: Antiseizure Medication
  description: Seizures are managed with standard antiseizure medication. No agent has been shown to be
    preferentially effective in this disorder, and at least one reported proband's epilepsy was resistant
    to clonazepam, so treatment is empirical.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ASD, mild bilateral sensorineural hearing loss, and epilepsy (absence, focal motor, and myoclonic
      seizures); this proband’s epilepsy is Klonopin-resistant.
    explanation: The reported epilepsy was resistant to clonazepam (Klonopin). This case supports the
      need for individualized seizure management, not a preferred medication or demonstrated efficacy.
- name: Developmental and Behavioral Support
  description: 'Management is otherwise supportive and multidisciplinary: developmental, speech and language,
    and behavioural intervention for the intellectual disability, autism, ADHD and compulsive behaviours,
    together with surveillance for the sleep, gastrointestinal, ocular, hearing and musculoskeletal features
    that make up the syndromic phenotype. This is standard neurodevelopmental care rather than a disease-specific
    protocol.'
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:39902220
    reference_title: Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The primary interventions for managing mild ID include a variety of therapeutic approaches,
      such as educational support and behavioral therapies (32).
    explanation: The clinical paper summarizes supportive management of ID generally; this is not an ASH1L-specific
      trial.
    directness: INDIRECT
animal_models:
- name: Ash1l gene-trap haploinsufficient mouse
  species: Mouse
  genotype: Ash1l+/GT (targeted gene-trap knockout, heterozygous)
  publication: PMID:39766886
  description: A heterozygous gene-trap knockout, and the model whose genotype most closely matches human
    patients. It shows social deficits, increased self-grooming and cognitive impairment, absence-like
    epileptiform discharge on EEG, increased susceptibility to chemically provoked convulsive seizures,
    and prefrontal pyramidal hyperexcitability.
  evidence:
  - reference: PMID:39766886
    reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
      and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Ash1l+/GT mice displayed social deficits, increased self-grooming, and cognitive impairments.
    explanation: Establishes the behavioural phenotype of the haploinsufficient model.
  modeled_mechanisms:
  - target: Pyramidal Neuron Hyperexcitability
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Whole-cell recording in prefrontal cortex demonstrates increased pyramidal excitability
      arising from intrinsic property changes plus enhanced glutamatergic and diminished GABAergic transmission,
      in a heterozygous animal matching the human genotype.
    limitations: Measured only in prefrontal cortex; the human seizure semiologies include focal motor
      and myoclonic seizures whose generators are not necessarily prefrontal, and no human electrophysiological
      or tissue correlate exists.
    readouts:
    - name: Prefrontal pyramidal neuron excitability
      target: Pyramidal Neuron Hyperexcitability
      description: Whole-cell patch-clamp recording of prefrontal pyramidal neurons in Ash1l+/GT versus
        wild-type mice.
      direction: INCREASED
      interpretation: Increased excitability with the excitatory-inhibitory shift is the direct electrophysiological
        correlate of this node.
      evidence:
      - reference: PMID:39766886
        reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
          and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Whole-cell patch-clamp recordings showed that Ash1l haploinsufficiency increased the
          excitability of pyramidal neurons in the PFC by altering intrinsic neuronal properties, enhancing
          glutamatergic synaptic transmission, and diminishing GABAergic synaptic inhibition.
        explanation: Reports the electrophysiological measurement behind this readout.
    evidence:
    - reference: PMID:39766886
      reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
        and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Chemogenetic inhibition of pyramidal neurons in the PFC of Ash1l+/GT mice ameliorated autism-like
        social deficits and abolished absence-like seizures.
      explanation: Reversing the excitability abnormality abolishes the seizure phenotype, which is what
        makes this model informative for the node rather than merely correlated with it.
  - target: Seizures
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: The model has an electrographic seizure phenotype and increased susceptibility to provoked
      convulsive seizures.
    limitations: The spontaneous phenotype is absence-like epileptiform discharge, whereas the reported
      human semiologies are febrile, focal motor, absence and myoclonic seizures; convulsive seizures
      in the model appear only on pentylenetetrazole challenge. The model therefore reproduces a seizure
      tendency, not the human epilepsy.
    readouts:
    - name: Electroencephalographic epileptiform discharge
      target: Seizures
      description: EEG recording in Ash1l+/GT versus wild-type mice.
      direction: INCREASED
      interpretation: Spontaneous epileptiform discharge establishes an unprovoked seizure phenotype,
        of absence type.
      evidence:
      - reference: PMID:39766886
        reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
          and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Epileptiform discharges were found on electroencephalograms (EEGs) of Ash1l+/GT mice,
          indicating absence-like seizures.
        explanation: Reports the EEG measurement behind this readout.
    evidence:
    - reference: PMID:39766886
      reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
        and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Epileptiform discharges were found on electroencephalograms (EEGs) of Ash1l+/GT mice, indicating
        absence-like seizures.
      explanation: Supports the model as informative for a seizure tendency while naming the semiology
        mismatch that limits it.
- name: Ash1l heterozygous knockout mouse (EphA7 pruning model)
  species: Mouse
  genotype: Ash1l+/- germline heterozygous knockout, and neuron-specific Ash1l deletion
  publication: PMID:35081333
  description: Haploinsufficient mice show anxiety, repetitive behaviour and altered social behaviour
    with intact learning but impaired discrimination. Neuronal Ash1l deletion produces excess synapses
    through a pruning deficit, traced to silencing of Eph receptor A7 by EZH2-deposited H3K27me3; supplying
    the EphA7 ligand ephrin-A5 restores pruning and rescues the discrimination deficit.
  evidence:
  - reference: PMID:35081333
    reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph
      receptor gene to autism spectrum disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for ASD,
      resulting from synapse pruning deficits.
    explanation: States the model's central conclusion connecting haploinsufficiency to the pruning mechanism.
  modeled_mechanisms:
  - target: Synaptic Pruning Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Excess synapses persist because developmental pruning fails, and the responsible gene,
      Eph receptor A7, is identified together with the repressive-mark mechanism silencing it.
    limitations: Synapse counts and pruning have not been measured in human ASH1L patients or tissue,
      and the pruning defect is most evident post-learning in a specific paradigm; the EPHA7 route is
      one identified mechanism, not necessarily the only one.
    readouts:
    - name: Synapse number after learning
      target: Synaptic Pruning Failure
      description: Synapse quantification in Ash1l-deleted neurons, particularly in the post-learning
        period.
      direction: INCREASED
      interpretation: Excess synapses are the direct cellular readout of the pruning failure.
      evidence:
      - reference: PMID:35081333
        reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links
          Eph receptor gene to autism spectrum disorder.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse
          pruning deficits, especially during the post-learning period.
        explanation: Reports the synapse-number measurement behind this readout.
    - name: Discrimination performance after ephrin-A5 supplementation
      target: Synaptic Pruning Failure
      description: Behavioural discrimination testing in Ash1l+/- mice given the EphA7 ligand ephrin-A5,
        against untreated mutants.
      direction: RESTORED
      interpretation: Rescue by reactivating the specific downstream receptor is what makes the EPHA7
        route causal rather than correlative.
      evidence:
      - reference: PMID:35081333
        reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links
          Eph receptor gene to autism spectrum disorder.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Importantly, increasing activation of EphA7 in Ash1l+/- mice by supplying its ligand,
          ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits.
        explanation: Reports the rescue experiment behind this readout.
    evidence:
    - reference: PMID:35081333
      reference_title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links
        Eph receptor gene to autism spectrum disorder.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Specifically, Eph receptor A7 is downregulated in Ash1l+/- mice through accumulating EZH2-mediated
        H3K27me3 in its gene body.
      explanation: Supports treating this model as informative for the pruning node by naming the responsible
        gene and chromatin mechanism.
- name: Cortex-specific Ash1l conditional knockout mouse
  species: Mouse
  genotype: Ash1l exon 4 conditional deletion (p.V1693Afs*2), Emx1-Cre-ERT2 induced at E10.5; and Ash1l
    germline null
  publication: PMID:38943682
  description: 'Tamoxifen-induced cortical deletion from E10.5 misspecifies cortical projection neurons:
    SATB2-expressing neurons increase in number, spread through the cortical plate, and appear ectopically
    in deep layers, with an altered differentiation trajectory on single-cell RNA sequencing. The germline
    null is present at expected proportions at E18.5 but absent at birth, and has shortened nasal bones.'
  evidence:
  - reference: PMID:38943682
    reference_title: Ash1l loss-of-function results in structural birth defects and altered cortical development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In the cortical-specific knockout model, SATB2 neurons showed increased numbers (n = 6/genotype,
      P = 0.0001) and were distributed through the cortical plate.
    explanation: Establishes the cortical patterning phenotype that makes this model informative.
  modeled_mechanisms:
  - target: Disrupted Cortical Neuron Specification and Lamination
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Cortical Ash1l deletion produces excess and ectopically placed SATB2-expressing projection
      neurons with an altered differentiation trajectory, establishing a requirement for ASH1L in projection
      neuron specification.
    limitations: This is a homozygous conditional deletion, not the usual human heterozygous dosage. The
      reviewed human cases do not establish an equivalent cortical lamination lesion; delayed white-matter
      myelination in one missense case is a different finding.
    readouts:
    - name: Laminar distribution of SATB2-expressing neurons
      target: Disrupted Cortical Neuron Specification and Lamination
      description: Immunohistochemistry for SATB2 with EdU birthdating in conditional knockout versus
        control cortex.
      direction: ALTERED
      interpretation: Deep-layer neurons ectopically expressing an upper-layer marker are the structural
        readout of misspecification.
      evidence:
      - reference: PMID:38943682
        reference_title: Ash1l loss-of-function results in structural birth defects and altered cortical
          development.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Birthdating revealed generation of ectopically placed deep layer neurons that express
          SATB2
        explanation: Reports the birthdating measurement behind this readout.
    evidence:
    - reference: PMID:38943682
      reference_title: Ash1l loss-of-function results in structural birth defects and altered cortical
        development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In the cortical-specific knockout model, SATB2 neurons showed increased numbers (n = 6/genotype,
        P = 0.0001) and were distributed through the cortical plate.
      explanation: Supports treating this model as informative for the cortical patterning node.
  - target: Impaired Craniofacial Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: The germline null dies perinatally and has shortened nasal bones, demonstrating a requirement
      for Ash1l in craniofacial development outside the brain.
    limitations: The mouse finding is a specific craniofacial measurement in homozygous nulls; the human
      extraneural phenotype is dominated by genital and musculoskeletal anomalies with no consistent facial
      gestalt, and human heterozygotes survive. The two do not correspond feature for feature.
    readouts:
    - name: Nasal bone length
      target: Impaired Craniofacial Development
      description: Skeletal measurement in Ash1l germline null embryos versus controls.
      direction: DECREASED
      interpretation: A quantified craniofacial skeletal defect outside the nervous system.
      evidence:
      - reference: PMID:38943682
        reference_title: Ash1l loss-of-function results in structural birth defects and altered cortical
          development.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Notably, Ash1l-/- exhibited shortened nasal bones (n = 31, P = 0.017).
        explanation: Reports the craniofacial measurement behind this readout.
    evidence:
    - reference: PMID:38943682
      reference_title: Ash1l loss-of-function results in structural birth defects and altered cortical
        development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: This study underscores the essential role of Ash1l in postnatal survival and normal craniofacial
        development.
      explanation: Supports an extraneural developmental requirement while the specific features differ
        from the human phenotype.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: The 2024 clinical synthesis reports feature-specific denominators, including 16 assessed for
    combined ID/DD; this is not a reliable total case count. Many variants in sequencing cohorts lack
    detailed clinical descriptions. No population prevalence or penetrance is inferred.
  evidence:
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ID/DD is the most frequent phenotype (15/16, 94%)
    explanation: Sixteen is the denominator assessed for the combined ID/DD phenotype, not a proven count
      of all affected individuals.
  - reference: PMID:34782621
    reference_title: Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations
      and seizures.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Over 100 loss-of-function (LOF) mutations in the coding regions of ASH1L have been discovered
    explanation: Establishes the much larger variant count from sequencing cohorts, against which the
      small clinically described cohort should be read. Evidence source is OTHER because this is the paper's
      summary of the genetic literature.
datasets: []
discussions:
- discussion_id: gap_mrd52_which_histone_mark_carries_the_disease
  prompt: How does reduced ASH1L function alter promoter H3K4me3 in the relevant neuronal systems?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced ASH1L Histone Methyltransferase Activity
  - pathophysiology#Loss of Activating Chromatin Marks at Neurodevelopmental Gene Promoters
  rationale: Biochemical evidence establishes H3K36 substrate specificity, while severe mouse PFC knockdown
    lowers H3K4me3 without changing bulk H3K36me2/me3. Human-neuron work discusses H3K4me3 deposition
    by the interacting MLL complex. The remaining gap is the indirect route and disease-relevant chromatin
    context, not equal evidence that ASH1L directly catalyzes both marks.
  proposed_experiments:
  - experiment_id: exp_mrd52_separation_of_function_ash1l_alleles
    name: Separation-of-function ASH1L alleles in neurons
    description: Compare matched ASH1L dosage reduction and catalytic inactivation in isogenic human neurons,
      measuring H3K36me2, promoter H3K4me3, associated chromatin complexes and transcription. Rescue experiments
      should separate catalytic output from indirect chromatin regulation.
  evidence:
  - reference: PMID:21239497
    reference_title: Crystal structure of the human histone methyltransferase ASH1L catalytic domain and
      its implications for the regulatory mechanism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In addition, we show that human ASH1L specifically methylates histone H3 Lys-36.
    explanation: Establishes direct catalytic specificity.
  - reference: PMID:35210569
    reference_title: Counteracting epigenetic mechanisms regulate the structural development of neuronal
      circuitry in human neurons.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: However, H3K36me2 presence will lead to upregulation of H3K36me3 by SET2 54, and H3K4me3
      marks are deposited by the ASH1L interactor - MLL complex 55.
    explanation: The authors distinguish secondary marks and an interacting H3K4 methyltransferase; this
      is contextual mechanistic interpretation.
    directness: INDIRECT
- discussion_id: gap_mrd52_missense_versus_truncating_severity
  prompt: Are ASH1L missense variants genuinely associated with a more severe and more autism-weighted
    phenotype than truncating variants, and if so does that mean they act by something other than simple
    haploinsufficiency?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Heterozygous ASH1L Loss of Function
  - pathophysiology#Reduced ASH1L Histone Methyltransferase Activity
  rationale: Small published case series suggested greater severity with missense alleles, but ascertainment,
    variable pathogenicity and allele-specific effects prevent inferring dominant-negative or gain-of-function
    behavior from clinical severity alone. The 2024 registry excluded its three missense-VUS participants;
    its literature table nevertheless includes earlier reported missense cases. Functional results in
    ASH1L-associated Tourette cohorts cannot automatically establish the mechanism of different MRD52
    alleles.
  proposed_experiments:
  - experiment_id: exp_mrd52_missense_allele_functional_assay
    name: Functional assay of reported ASH1L missense alleles
    description: Express reported missense alleles alongside wild type and null in a neuronal system,
      and test both catalytic output and whether the missense protein interferes with the wild-type allele,
      to distinguish haploinsufficiency from a dominant-negative effect.
  evidence:
  - reference: PMID:34373061
    reference_title: ASH1L mutation caused seizures and intellectual disability in twin sisters.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We found that patients with missense mutations in ASH1L appeared to present with more severe
      phenotypes and a higher likelihood of ASD than those with truncating mutations.
    explanation: States the genotype-phenotype claim this gap is about.
  - reference: PMID:38674358
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
      Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: However, additional functional studies are needed to understand the mechanism of disease
      for missense variants [11]
    explanation: The review explicitly leaves the MRD52 missense mechanism unresolved; it does not establish
      a uniform null-versus-missense severity relationship.
- discussion_id: mismatch_mrd52_model_genotype_and_seizure_semiology
  prompt: How do dosage, seizure subtype and rescue effects translate from distinct Ash1l mouse models
    to human epilepsy?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Cortical Excitation-Inhibition Imbalance
  - phenotypes#Seizures
  - phenotypes#Absence Seizures
  - phenotypes#Focal Motor Seizures
  - phenotypes#Myoclonic Seizures
  - phenotypes#Febrile Seizures
  rationale: Severe juvenile PFC knockdown and heterozygous gene-trap models both support hyperexcitability,
    but differ in dosage, mortality and rescue. Combined diazepam/chemogenetic inhibition rescued seizures
    without social or anxiety rescue in the severe model; pyramidal inhibition alone improved social behavior
    and absence-like seizures in the heterozygous model. Human absence seizures are explicitly reported,
    so absence semiology is shared. Human focal motor, myoclonic and febrile seizures have no demonstrated
    subtype-specific circuit in these experiments. PTZ-provoked convulsions are not spontaneous generalized
    convulsive seizures.
  proposed_experiments:
  - experiment_id: exp_mrd52_heterozygous_model_seizure_characterization
    name: Longitudinal seizure phenotyping of genotype-matched Ash1l heterozygotes
    description: Perform long-term video-EEG across development in heterozygous Ash1l mice on more than
      one genetic background, classifying seizure types against the human semiologies, and test whether
      the GABA-enhancing rescue that works in the severe knockdown also works at heterozygous dose.
  evidence:
  - reference: PMID:34782621
    reference_title: Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations
      and seizures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration
      of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social
      deficits or anxiety-like behaviors.
    explanation: The rescue result, and its own limit - the same intervention does not touch the social
      or anxiety phenotype, so even within the model it addresses one arm only.
  - reference: PMID:39766886
    reference_title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits
      and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Epileptiform discharges were found on electroencephalograms (EEGs) of Ash1l+/GT mice, indicating
      absence-like seizures.
    explanation: Establishes the semiology of the genotype-matched model, which is the half of the mismatch
      that dose-matching does not fix.
- discussion_id: gap_mrd52_neurologic_attribution
  prompt: Which mechanisms explain the case-scoped neurologic findings?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Attention Deficit Hyperactivity Disorder
  - phenotypes#Speech Delay
  - phenotypes#Hypotonia
  - phenotypes#Motor Delay
  - phenotypes#Receptive Language Impairment
  - phenotypes#Hyperactivity
  - phenotypes#Depression
  - phenotypes#Delayed CNS Myelination
  - phenotypes#Loss of Acquired Spoken Language
  rationale: The reviewed sources do not isolate a cellular or circuit mechanism for these individual
    human outcomes. Qualified genetic causation of anxiety, repetitive traits and memory deficits is represented
    separately. Delayed CNS myelination is an imaging finding in a missense case; the homozygous neural-deletion
    myelination phenotype is experimental support for ASH1L involvement, but the cellular route and translation
    to this allele remain unresolved. Specific speech, motor, tone and affective findings are not explained
    merely by naming a generic developmental program.
- discussion_id: gap_mrd52_gait_attribution
  prompt: Which mechanisms explain the case-scoped gait findings?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Gait Disturbance
  - phenotypes#Gait Ataxia
  - phenotypes#Dysmetria
  - phenotypes#Incoordination
  - phenotypes#Internal Tibial Torsion
  rationale: The clinical motor findings do not demonstrate a cerebellar or neuromuscular lesion. BGR
    2 has additional unconfirmed biallelic TNR missense VUS and a TSHZ3 VUS. BGR 3 has stiff gait with
    tibial torsion and other VUS. Neither coexistence nor broad developmental-gene dysregulation proves
    a particular causal route.
- discussion_id: gap_mrd52_extraneural_attribution
  prompt: Which mechanisms explain the case-scoped extraneural findings?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Gastrointestinal Disturbance
  - phenotypes#Facial Dysmorphism
  - phenotypes#Ocular Abnormality
  - phenotypes#Genital Malformation
  - phenotypes#Sensorineural Hearing Impairment
  - phenotypes#Hearing Impairment
  - phenotypes#Scoliosis
  - phenotypes#Pectus Carinatum
  - phenotypes#Pectus Excavatum
  - phenotypes#Penile Torsion
  - phenotypes#Cryptorchidism
  - phenotypes#Cervical Vertebral Fusion
  - phenotypes#Hyperopia
  - phenotypes#Strabismus
  - phenotypes#Nystagmus
  - phenotypes#Astigmatism
  - phenotypes#Gastroesophageal Reflux
  - phenotypes#Vomiting
  - phenotypes#Hypothyroidism
  - phenotypes#Smooth Philtrum
  - phenotypes#Hypertelorism
  - phenotypes#Dolichocephaly
  - phenotypes#Lumbar Hyperlordosis
  - phenotypes#Scapular Winging
  rationale: The reviewed human cases establish these observations but do not identify their organ-specific
    ASH1L mechanisms. A shortened-nasal-bone phenotype in homozygous mouse models does not establish the
    causes of diverse human ocular, genital, skeletal or facial findings. The separate hypothalamic feeding/growth
    hypothesis is represented with HYPOTHETICAL confidence. POU4F3/ATP2B2 VUS complicate BGR 3 hearing
    attribution; several individual skeletal findings come from a missense case of unknown inheritance.
    Reflux and vomiting coexist without a source-established causal direction.
- discussion_id: gap_mrd52_sleep_attribution
  prompt: Which mechanisms explain the case-scoped sleep findings?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Sleep Disturbance
  - phenotypes#Sleep Apnea
  - phenotypes#Excessive Daytime Somnolence
  - phenotypes#Sleepwalking
  rationale: The sources describe sleep symptoms but do not establish an ASH1L-specific sleep-circuit
    mechanism or causal links among these manifestations. Apnea and daytime sleepiness were reported in
    different cases; an apnea-to-somnolence arrow would conflate cohorts.
- discussion_id: scope_mrd52_clinical_tables
  prompt: How should discrepant clinical summaries and isolated supplemental findings be interpreted?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Gastrointestinal Disturbance
  - phenotypes#Hearing Impairment
  - phenotypes#Facial Dysmorphism
  - phenotypes#Sleep Disturbance
  rationale: 'Cordova’s labelled Supplemental Table 1 contains additional case-scoped findings: congenital
    cardiac lesions in the Homsy and Faundes cases, constipation, hyperacusis, precocious puberty, joint
    hypermobility, hydronephrosis, inguinal hernia, optic-disc pseudopapilledema, and detailed facial
    components. These are retained as clinical leads rather than assigned frequencies or developmental
    mechanisms; original full reports for those observations were not accessible in this review. The Stessman
    supplement was read directly: unspecified nocturnal incontinence is not assumed to be gastrointestinal
    disease or urinary enuresis, and bedtime difficulty is not equated with insomnia. Its patient 11282
    narrative says no other medical problems while Table 21 records bloating/gas, so those gastrointestinal
    details remain discrepant. Unlabelled draft worksheets in the Cordova workbook were not treated as
    finalized data.'
references:
- reference: PMID:38674358
  title: Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental
    Disorder.
- reference: PMID:28191889
  title: Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability
    biases.
- reference: PMID:34373061
  title: ASH1L mutation caused seizures and intellectual disability in twin sisters.
- reference: PMID:39902220
  title: Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability.
- reference: PMID:34782621
  title: Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and
    seizures.
- reference: PMID:35081333
  title: ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene
    to autism spectrum disorder.
- reference: PMID:34145365
  title: Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors.
- reference: PMID:38943682
  title: Ash1l loss-of-function results in structural birth defects and altered cortical development.
- reference: PMID:39766886
  title: Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits and Absence-Like
    Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.
- reference: PMID:21239497
  title: Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications
    for the regulatory mechanism.
- reference: PMID:28394464
  title: Novel MCA/ID syndrome with ASH1L mutation.
- reference: PMID:29753921
  title: De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental
    disorder.
- reference: PMID:35210569
  title: Counteracting epigenetic mechanisms regulate the structural development of neuronal circuitry
    in human neurons.
- reference: url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf
  title: https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf

📚

References & Deep Research

References

14

PMID:38674358

Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental Disorder.

No top-level findings curated for this source.

PMID:28191889

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.

No top-level findings curated for this source.

PMID:34373061

ASH1L mutation caused seizures and intellectual disability in twin sisters.

No top-level findings curated for this source.

PMID:39902220

Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability.

No top-level findings curated for this source.

PMID:34782621

Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures.

No top-level findings curated for this source.

PMID:35081333

ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder.

No top-level findings curated for this source.

PMID:34145365

Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors.

No top-level findings curated for this source.

PMID:38943682

Ash1l loss-of-function results in structural birth defects and altered cortical development.

No top-level findings curated for this source.

PMID:39766886

Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model.

No top-level findings curated for this source.

PMID:21239497

Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism.

No top-level findings curated for this source.

PMID:28394464

Novel MCA/ID syndrome with ASH1L mutation.

No top-level findings curated for this source.

PMID:29753921

De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental disorder.

No top-level findings curated for this source.

PMID:35210569

Counteracting epigenetic mechanisms regulate the structural development of neuronal circuitry in human neurons.

No top-level findings curated for this source.

url:https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf

https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fng.3792/MediaObjects/41588_2017_BFng3792_MOESM19_ESM.pdf

No top-level findings curated for this source.

Deep Research

1

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: Intellectual Disability Autosomal Dominant 52 (ASH1L) · 2026-08-27T03:05:15Z · View source

De novo creation of the MRD52 / ASH1L entry from the stub stubs/Intellectual_Disability_Autosomal_Dominant_52.yaml, closing issue #9580. Entry-type decision: Disease. The stub carries no mondo_descendant_count, and `runoak -i sqlite:obo:mondo info MONDO:0030918 -O obo` returns a leaf term with one RO:0004003 causal-gene relationship (HGNC:19088, ASH1L) and an OMIM:617796 xref. Naming note recorded in the entry description rather than acted on: the OMIM/MONDO label names only the cognitive component, while the entity ClinGen curated (and classified Definitive) is a syndromic complex neurodevelopmental disorder. The entry curates the broader phenotype under the MONDO identifier the stub supplied, and lists the ASH1L-related names as synonyms. Curated from primary literature: PMID:38674358 (Brain Gene Registry review with the phenotype-frequency tabulation and denominators), PMID:28191889 (Stessman 2017 gene delineation), PMID:34373061 and PMID:39902220 (further patients plus genotype-phenotype review), PMID:34782621 (prefrontal knockdown, chromatin and electrophysiology), PMID:35081333 (haploinsufficient mouse, EPHA7 pruning), PMID:34145365 (developing-brain knockout), PMID:38943682 (cortical patterning and craniofacial), PMID:39766886 (gene-trap haploinsufficient model). Mechanism model: 12 pathophysiology nodes, 14 edges, one root, no unreachable node. Chain runs heterozygous ASH1L loss of function -> reduced methyltransferase activity -> loss of activating promoter marks -> downregulated synaptic and neurodevelopmental gene programmes, which is the branch point. Three arms descend from it: synaptic pruning failure (EPHA7/EZH2 route), cortical excitation-inhibition imbalance conforming to three nodes of kb/modules/epilepsy_excitation_inhibition_imbalance.yaml, and disrupted cortical neuron specification. An extraneural arm carries the genital, musculoskeletal and craniofacial findings. Phenotype frequency bands are all carried by explicit denominators from the 2024 review's tabulation, and every explanation states the fraction, the resulting percentage, and the band it maps to. The denominators are small (4-16) and the explanations say so; the facial-dysmorphism explanation additionally records the source's own warning that the figure is likely inflated by unreported negative assessments. Deliberately not curated: no genotype-phenotype subtype split on missense versus truncating alleles (two sources take opposite positions and no functional assay exists for any human missense allele) - recorded as a KNOWLEDGE_GAP. No single histone mark asserted as the disease-relevant one; both H3K36 and H3K4 are curated on the enzyme node with the discrepancy carried as a KNOWLEDGE_GAP. No treatment claim beyond empirical antiseizure medication and supportive developmental care; the diazepam/chemogenetic rescue is model-only and lives in the HUMAN_MODEL_MISMATCH discussion rather than in `treatments`. Deep research: `just research-disorder falcon` run, report committed. NEC preflight PASS (ASH1L=34 mentions). Nothing was curated from the report. Two provider defects observed and not propagated: the report gives ASH1L as HGNC:19208 (the correct identifier is HGNC:19088), and its evidence base is one PMID plus a bioRxiv preprint, missing the entire clinical phenotyping literature including PMID:38674358; only 1 of its 4 references was scored on topic. Validation actually run and read: just validate <file> -> passed just validate-disorders <file> -> passed, "Snippets checked: 66/66 verified against cached references" just check-duplicate-keys <file> -> OK just check-title-snippets -> OK scripts/check_snippet_length.py --against-ref origin/main -> OK (initially failed on 17 table-cell snippets; each was re-quoted as the full sentence clause from the source rather than baselined) scripts/check_folded_hyphens.py --check -> OK just check-cache-order -> OK just check-term-cache-integrity -> OK Cache additions are limited to MONDO:0030918 and hgnc:19088 plus the diseaseterm enum-membership row.

Falcon ▸

Intellectual Disability, Autosomal Dominant 52 (MRD52): Research Report

Edison Scientific Literature 16 citations 2026-08-27T02:56:25.482695

Intellectual Disability, Autosomal Dominant 52 (MRD52): Research Report

Executive summary

Intellectual disability, autosomal dominant 52 (MRD52) is an ultra-rare, congenital neurodevelopmental chromatinopathy caused principally by heterozygous pathogenic variants in ASH1L, usually through loss of function or haploinsufficiency. The phenotype is variable but centers on developmental delay/intellectual disability, severe speech-language impairment, autism or other behavioral abnormalities, and sometimes hypotonia, dysmorphism, and epilepsy. ASH1L is a Trithorax-family histone lysine methyltransferase that promotes transcriptionally permissive chromatin, principally through H3K36 methylation and associated H3K4 methylation, while opposing Polycomb repression. No disease-specific therapy, validated biomarker, prevalence estimate, or dedicated clinical trial was identified. The most important 2024 advances are mechanistic: a peer-reviewed Ash1l-haploinsufficient mouse study implicated excessive prefrontal cortical excitability, while a December 2024 bioRxiv study found impaired neurite growth, transcription, and chromatin regulation in engineered human neurons. Both remain preclinical. (ma2024chemogeneticinhibitionof pages 12-13, wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 4-7)

The following compact table summarizes the knowledge-base-level conclusions.

Domain	Key facts	Ontology / controlled-term suggestions	Evidence
Disease identity / identifiers	Intellectual disability, autosomal dominant 52 (MRD52); ASH1L-related neurodevelopmental disorder; OMIM 617796; MONDO MONDO:0030918. Disease-level knowledge is aggregated from published case reports/cohorts, reviews, and curated disease-target resources rather than EHR-only evidence.	MONDO:0030918	(OpenTargets Search: Intellectual disability, autosomal dominant 52, wilson2022reprogrammingofthe pages 14-15)
Synonyms	ASH1L-related intellectual developmental disorder; ASH1L-related neurodevelopmental disorder; MRD52; intellectual developmental disorder with speech delay/autism features due to ASH1L.	MeSH/ICD-specific synonym mapping not established in retrieved evidence	(wilson2022reprogrammingofthe pages 14-15)
Inheritance	Autosomal dominant; most reported pathogenic events are interpreted as heterozygous loss-of-function / haploinsufficiency, often de novo in sequencing cohorts. Penetrance and recurrence risk are not well quantified; parental testing is important to assess de novo status and mosaicism.	HP:0000006 Autosomal dominant inheritance	(OpenTargets Search: Intellectual disability, autosomal dominant 52, wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 1-4)
Causal gene / protein	ASH1L (also called KMT2H), encoding ASH1-like histone lysine methyltransferase, a Trithorax-family chromatin regulator expressed in brain and involved in transcriptional activation.	HGNC:19208 ASH1L; UniProt ASH1L protein	(wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 1-4)
Pathogenic mechanism	Predominant mechanism is germline monoallelic loss of function / haploinsufficiency disrupting chromatin-mediated transcription. ASH1L catalyzes H3K36me2 and contributes to H3K4me3, opposing PRC2/H3K27me3 repression; downstream effects include altered neuronal gene expression, neurite growth, synaptic programs, and cortical excitability. The 2024 human-neuron study is a bioRxiv preprint.	GO:0046975 histone methyltransferase activity; GO:0018024 histone H3-K36 methylation; GO:0046968 H3-K4 methylation; GO:0006357 regulation of transcription by RNA polymerase II; GO:0030154 cell differentiation	(ma2024chemogeneticinhibitionof pages 12-13, wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 4-7, jhanji2024dynamicregulationof pages 1-4, jhanji2024dynamicregulationof pages 10-12)
Core phenotypes	Developmental delay and intellectual disability (mild to severe reported), marked speech/language delay, autism spectrum disorder / autistic behaviors, dysmorphic facial features, and behavioral abnormalities; some patients have seizures/epilepsy or broader neuropsychiatric manifestations. Precise phenotype frequencies are not robustly established in retrieved evidence.	HP:0001263 Global developmental delay; HP:0001249 Intellectual disability; HP:0000750 Delayed speech and language development; HP:0000729 Autism; HP:0001250 Seizure; HP:0000717 Autism spectrum disorder; HP:0001252 Hypotonia; HP:0001999 Facial dysmorphism	(wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 1-4, jhanji2024dynamicregulationof pages 39-41)
Principal anatomy / cell types	Primary system affected is the central nervous system, especially cortical circuits. Experimental data implicate prefrontal cortex and cortical excitatory pyramidal neurons; neuronal projections, axons, synapses, and nuclei are enriched among dysregulated compartments/features.	UBERON:0000955 brain; UBERON:0001870 cerebral cortex; UBERON:0000451 prefrontal cortex; CL:0000540 neuron; CL:0002608 pyramidal neuron; GO:0030424 axon; GO:0045202 synapse; GO:0005634 nucleus	(ma2024chemogeneticinhibitionof pages 12-13, jhanji2024dynamicregulationof pages 4-7, jhanji2024dynamicregulationof pages 10-12)
Diagnosis	Molecular diagnosis relies on exome/genome sequencing or neurodevelopmental disorder/intellectual disability panels that include ASH1L; trio-based testing is particularly valuable to establish de novo occurrence. No disease-specific biochemical biomarker or imaging signature was established in retrieved evidence.	NCIT:C101294 Whole Exome Sequencing; NCIT:C84351 Whole Genome Sequencing; NCIT:C157640 Molecular Genetic Testing	(OpenTargets Search: Intellectual disability, autosomal dominant 52, wilson2022reprogrammingofthe pages 14-15)
Treatment / management	No approved disease-specific therapy identified. Current care is supportive and multidisciplinary: developmental pediatrics, neurology, speech-language therapy, occupational/physical therapy, behavioral/educational interventions, and seizure management when present. Preclinical only: in Ash1l mouse or edited human-neuron systems, chemogenetic PFC inhibition and epigenetic drugs (tazemetostat, vorinostat) rescued selected phenotypes; these are not established patient treatments.	NCIT:C51909 Supportive Care; NCIT:C17556 Speech Therapy; NCIT:C15635 Occupational Therapy; NCIT:C15313 Physical Therapy; NCIT:C146712 Behavioral Intervention; NCIT:C15246 Tazemetostat; NCIT:C1820 Vorinostat	(ma2024chemogeneticinhibitionof pages 12-13, jhanji2024dynamicregulationof pages 34-39, jhanji2024dynamicregulationof pages 39-41)
Epidemiology / prognosis	Appears to be an ultra-rare Mendelian disorder; no reliable prevalence or incidence estimates were identified in retrieved evidence. Natural history is incompletely defined; morbidity is dominated by lifelong neurodevelopmental impairment, communication disability, behavioral challenges, and possible epilepsy. Disease-specific survival, life expectancy, and mortality rates are unavailable.	Orphan/rare disease category; chronic neurodevelopmental disorder	(wilson2022reprogrammingofthe pages 14-15)
Model systems	Mouse: Ash1l haploinsufficiency/gene-trap models show social deficits, repetitive grooming, cognitive impairment, EEG epileptiform activity/absence-like seizures, and increased PFC excitability. Human neuronal models: CRISPR-engineered iPSC/ESC-derived cortical excitatory neurons (including E2148 catalytic-domain variant) show reduced neurite length/arborization and altered histone marks/transcriptomes; this 2024 study is a bioRxiv preprint. Zebrafish:* ash1a knockdown reduces neuron numbers in pineal gland.	NCBITaxon:10090 Mus musculus; NCBITaxon:7955 Danio rerio; CL:0000540 neuron; CL:0002608 pyramidal neuron	(ma2024chemogeneticinhibitionof pages 12-13, wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 4-7, jhanji2024dynamicregulationof pages 26-29)
Key evidence gaps	Major gaps include: small patient numbers; limited validated phenotype frequencies; scarce longitudinal natural-history data; poor estimates of penetrance/expressivity; no established episignature/clinical biomarker in retrieved evidence; no disease-specific interventional trials found; limited patient-cell functional studies in peer-reviewed literature; 2024 human-neuron rescue work remains preprint/preclinical.	Evidence-gap annotation	(wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 1-4, jhanji2024dynamicregulationof pages 39-41)

Table: Compact knowledge-base table summarizing identifiers, genetics, phenotypes, mechanism, diagnosis, management, models, and current evidence gaps for Intellectual disability, autosomal dominant 52 / ASH1L-related disorder. It separates established disease knowledge from preclinical and preprint findings.

1. Disease information

Definition. MRD52 is a monogenic developmental disorder in which deficient ASH1L dosage disrupts chromatin-dependent neuronal development. It belongs to the Mendelian intellectual-developmental disorders and more broadly to the “chromatinopathies.” Reported severity ranges from mild to severe intellectual disability, with developmental and speech delay, autism-spectrum manifestations, and variable dysmorphism. (wilson2022reprogrammingofthe pages 14-15)

Identifiers and names

MONDO: MONDO:0030918.
OMIM phenotype: 617796, Intellectual disability, autosomal dominant 52.
Common abbreviations/synonyms: MRD52; ASH1L-related intellectual developmental disorder; ASH1L-related neurodevelopmental disorder.
Gene: ASH1L, also called KMT2H; Ensembl ENSG00000116539.
A unique disease-specific ICD-10, ICD-11, or MeSH code was not established in the retrieved evidence; patients are ordinarily coded under intellectual disability, developmental disorder, autism, or epilepsy as appropriate.

Open Targets associates ASH1L with MONDO:0030918 and links the association to, among other studies, PMID 28394464, 23033978, and 28191889. It also returned a weaker LMAN2L association, but the present phenotype’s established molecular definition is ASH1L-related; the weaker result should not be used as an alternative causal assignment without re-curation. (OpenTargets Search: Intellectual disability, autosomal dominant 52)

The evidence is aggregated disease-level evidence from sequencing cohorts, case reports, curated databases, reviews, and experimental studies—not an analysis of an individual patient’s EHR.

2. Etiology, risk, protection, and environment

Causal factor

The primary cause is a germline heterozygous pathogenic ASH1L variant. Protein-truncating nonsense, frameshift, and splice-disrupting alleles are consistent with loss of function and haploinsufficiency; damaging catalytic-domain alleles can similarly impair histone methyltransferase activity. The experimentally modeled p.Glu2148Ter (E2148*) allele is a catalytic-domain truncation associated with ASD, ID, and epilepsy. (jhanji2024dynamicregulationof pages 4-7, jhanji2024dynamicregulationof pages 1-4)

Risk factors

Genetic: carrying a pathogenic ASH1L allele is the principal risk factor. Most recognized cases appear sporadic/de novo, although autosomal-dominant transmission is biologically possible.
Family history: an affected heterozygous parent would imply a 50% transmission probability per pregnancy, subject to variable expressivity. If apparently de novo, recurrence is low but not zero because parental germline mosaicism cannot be excluded.
Modifiers: no validated modifier gene, founder allele, ancestry-specific risk, sex-specific penetrance, or polygenic modifier has been established.

No reliable disease-specific environmental, lifestyle, occupational, infectious, maternal-age, or sex risk factor has been demonstrated. Prenatal exposures associated with neurodevelopmental disorders generally should not be represented as causes or modifiers of molecularly confirmed MRD52 without direct evidence.

Protective factors and gene–environment interaction

No protective ASH1L allele, diet, drug, lifestyle exposure, or reproducible gene–environment interaction is known. Ordinary developmental supports may improve function but do not prevent the genotype. Infectious and zoonotic causation are not applicable.

3. Phenotypes

Because published cohorts are small and ascertainment differs, robust percentages are unavailable. Qualitative frequencies should therefore be encoded as “common,” “variable,” or “reported,” not as inferred percentages.

Global developmental delay — HP:0001263: typically evident in infancy or early childhood; variable severity; chronic rather than episodic. It affects acquisition of communication, learning, self-care, and adaptive skills.
Intellectual disability — HP:0001249: mild through severe; generally lifelong and non-remitting. Formal severity may become clearer during childhood as cognitive demands increase. (wilson2022reprogrammingofthe pages 14-15)
Delayed speech and language development — HP:0000750; absent speech, if applicable — HP:0001344: often especially prominent. Childhood apraxia of speech has also been discussed within the expanding genetic spectrum of ASH1L-associated speech disorders, but should be assigned only after specialist motor-speech assessment.
Autism/autistic behavior — HP:0000729 or HP:0000717: social-communication impairment, restricted interests, repetitive behavior, or formal ASD may occur. Behavioral consequences can substantially affect education, family participation, and independent living. (wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 1-4)
Seizures/epilepsy — HP:0001250 / HP:0001251: variably reported rather than obligatory. The experimental literature particularly supports susceptibility to absence-like and convulsive seizures, but mouse seizure type should not automatically be assigned to every patient. (ma2024chemogeneticinhibitionof pages 12-13)
Hypotonia — HP:0001252: reported in the clinical spectrum and may contribute to delayed motor milestones, poor coordination, feeding difficulty, or need for physical therapy.
Facial dysmorphism — HP:0001999: variable and generally nonspecific; it is not sufficiently distinctive to diagnose the disorder clinically. (wilson2022reprogrammingofthe pages 14-15)
Other neuropsychiatric associations: ASH1L variation has been reported across ADHD, Tourette syndrome, schizophrenia, ASD, ID, and epilepsy. These broader associations demonstrate pleiotropy but are not all defining manifestations of MRD52. The 2024 preprint catalogued 136 disease-associated ASH1L variants across these phenotypes. (jhanji2024dynamicregulationof pages 1-4)

No disease-specific laboratory abnormality, metabolite signature, immune phenotype, or pathognomonic MRI pattern is established. Quality-of-life studies using EQ-5D, SF-36, PROMIS, or a disease-specific instrument were not found; impact must presently be inferred from communication, cognitive, behavioral, and seizure burden.

4. Genetic and molecular information

ASH1L encodes a large nuclear chromatin regulator and histone lysine methyltransferase. The dominant disease mechanism is best represented as haploinsufficiency/loss of function, although individual missense variants require case-specific functional and ACMG/AMP assessment. Disease-associated classes include nonsense, frameshift, splice, and damaging missense/catalytic-domain variants. (wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 4-7)

For a knowledge base, each variant should retain transcript-specific HGVS nomenclature, genome build, inheritance, ClinVar assertion and review status, and gnomAD frequency. Pathogenic truncating alleles are expected to be absent or extremely rare in population databases, but no universal allele frequency can be assigned without variant-level lookup. The variants are germline, not a recognized somatic cancer mechanism in this disease.

No validated modifier genes or MRD52-specific diagnostic DNA-methylation episignature were identified. ASH1L can be affected within larger copy-number alterations, but a broad deletion involving neighboring genes should not be assumed phenotypically equivalent to an intragenic ASH1L loss-of-function allele.

5. Environmental, lifestyle, and infectious information

MRD52 is not known to be caused by toxins, radiation, pollution, occupation, smoking, alcohol, diet, inactivity, or infection. Such exposures can independently influence development or pregnancy outcome but have no demonstrated disease-specific causal interaction with ASH1L. There is no vaccine, antimicrobial prophylaxis, or environmental remediation specific to MRD52.

6. Mechanism and pathophysiology

Upstream molecular defect

ASH1L promotes active chromatin through H3K36me2 and associated H3K4me3 and counteracts PRC2-mediated H3K27me3 repression. It is expressed in embryonic and adult brain and participates in developmental gene activation, including HOX regulation. Suggested terms include GO:0018024, histone H3-K36 methylation; GO:0046968, histone H3-K4 methylation; GO:0006357, regulation of transcription by RNA polymerase II; and GO:0046975, histone methyltransferase activity. (wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 1-4)

Causal chain

Pathogenic heterozygous ASH1L variant → reduced functional methyltransferase dosage/activity → altered H3K36/H3K4 and Polycomb-related chromatin states → inefficient transcription and altered isoform use of long neuronal, axonal, ion-channel, and synaptic genes → impaired neurite growth, neuronal connectivity, and excitation/inhibition balance → developmental delay, ID, autism-related behavior, speech impairment, and seizure susceptibility. Human patient-level genotype–mechanism correspondence remains less mature than the experimental evidence. (jhanji2024dynamicregulationof pages 4-7, jhanji2024dynamicregulationof pages 7-10, jhanji2024dynamicregulationof pages 10-12)

2024 human-neuron findings—preprint evidence

CRISPR-engineered human cortical excitatory neurons carrying E2148 showed mean neurite length of 47.47 ± 1.99 μm versus 56.9 ± 2.41 μm in controls (P<0.004), total neurite length of 139.3 ± 4.66 μm versus 182.7 ± 6.39 μm (P<0.0001), and a lower complexity index, 228.8 ± 13.42 versus 289.5 ± 18.21* (P<0.0099). (jhanji2024dynamicregulationof pages 26-29)

The same system showed H3K36me2 at 67%, H3K4me3 at 68%, and H3K36me3 at 78% of control. Nascent-transcription signal fell from 1.017 ± 0.029 to 0.817 ± 0.027 (P<0.0001). Transcriptomic analysis identified 2,475 differentially expressed genes in one analysis, with enrichment for axon guidance, axonogenesis, nervous-system development, transcription, and synaptic function; 263 dysregulated genes overlapped SFARI ASD genes. Long genes above 100 kb were preferentially downregulated, and 57 genes showed differential transcript usage, including SMARCA4, AFF2, and TARDBP. These findings are important but came from a December 2, 2024 bioRxiv preprint and require independent peer-reviewed replication. URL: https://doi.org/10.1101/2024.12.02.625500. (jhanji2024dynamicregulationof pages 4-7, jhanji2024dynamicregulationof pages 7-10, jhanji2024dynamicregulationof pages 10-12, jhanji2024dynamicregulationof pages 29-34)

Cellular systems

Relevant processes include axonogenesis (GO:0007409), neuron projection development (GO:0031175), synapse organization (GO:0050808), regulation of membrane potential (GO:0042391), and nervous-system development (GO:0007399). Principal suggested cell terms are neuron (CL:0000540), glutamatergic neuron (CL:0000679), and pyramidal neuron (CL:0002608). No convincing primary metabolic, immune, inflammatory, fibrotic, ischemic, or degenerative mechanism has been demonstrated.

7. Anatomical structures affected

The principal organ is the brain (UBERON:0000955), particularly the cerebral cortex (UBERON:0001870). Mouse electrophysiology implicates the prefrontal cortex (UBERON:0000451), where Ash1l haploinsufficiency increases pyramidal-neuron excitability through enhanced glutamatergic transmission, reduced GABAergic inhibition, and altered intrinsic properties. Relevant subcellular compartments include nucleus (GO:0005634), chromatin (GO:0000785), axon (GO:0030424), dendrite (GO:0030425), and synapse (GO:0045202). (ma2024chemogeneticinhibitionof pages 12-13)

No consistent lateralization is known. Dysmorphic or skeletal findings may occur, but nervous-system dysfunction is primary.

8. Temporal development and natural history

The molecular defect is present from conception and acts during prenatal and postnatal neurodevelopment. Clinical recognition is usually pediatric and insidious—through delayed milestones, language delay, hypotonia, behavior, or seizures—rather than an acute onset. MRD52 is chronic and lifelong; there is no established staging system, remission pattern, or end-stage phase. Developmental gains may occur with maturation and therapy, but underlying intellectual and adaptive impairment generally persists. Longitudinal studies are insufficient to determine whether epilepsy, behavior, or cognition systematically improves or worsens with age.

Early childhood is likely the most important intervention window because language, motor, and social circuits are developing, although no ASH1L-specific critical-period trial has established an optimal time.

9. Inheritance and population

Inheritance is autosomal dominant (HP:0000006), with many diagnoses arising from de novo variants. Expressivity is variable; penetrance has not been accurately quantified. Anticipation, repeat expansion, consanguinity, a founder effect, and a carrier frequency are not established features. Germline mosaicism remains a counseling consideration after an apparently de novo result.

The disease is ultra-rare, but no defensible incidence per 100,000, prevalence, geographic concentration, ethnic enrichment, age distribution, or sex ratio was found. Absence of epidemiologic estimates reflects limited ascertainment rather than proof of equal distribution.

10. Diagnostics

Recommended approach

Perform clinical developmental, neurologic, behavioral, speech-language, hearing, vision, growth, and dysmorphology assessment.
Use trio exome sequencing or genome sequencing, or a comprehensive developmental-delay/ID/epilepsy panel containing ASH1L. Trio analysis helps establish de novo status and reduces uncertainty.
Confirm reportable variants by an orthogonal method where required and test both parents. Apply ACMG/AMP criteria, including predicted loss of function, population absence, segregation, phenotype fit, and functional evidence.
Use chromosomal microarray when copy-number disease remains possible; genome sequencing may detect both sequence and structural variants. Karyotype or FISH is indicated only when a larger rearrangement is suspected.
Consider RNA sequencing for a suspected splice variant or unresolved case, but it is not a routine validated MRD52 diagnostic biomarker.

No enzyme assay, blood biomarker, metabolomic test, biopsy, liquid biopsy, or established epigenomic signature diagnoses MRD52. MRI and EEG are phenotype-directed: MRI for focal neurologic signs, abnormal head growth, regression, or seizures; EEG for suspected seizures or developmental regression. Mitochondrial and repeat-expansion testing are not disease-specific.

Differential diagnosis

The differential includes other chromatinopathies and monogenic NDDs—SETD5-, KMT2A-, KMT2D-, KDM5B-, CHD8-, ARID1B-, ASXL3-, TCF4-, and FOXP-related disorders—as well as Fragile X syndrome, pathogenic CNVs, metabolic disease when clinically indicated, cerebral palsy, nonsyndromic ASD/ID, and epilepsy-associated developmental encephalopathies. Clinical overlap is substantial, making genome-wide testing preferable to phenotype-only diagnosis.

11. Outcome and prognosis

No disease-specific five- or ten-year survival, mortality rate, or life-expectancy estimate is available. Available evidence does not establish MRD52 as intrinsically life-limiting, but severe epilepsy, feeding problems, accidents, or unrelated congenital disease could influence individual prognosis.

The major morbidity is lifelong impairment of cognition, communication, adaptive function, education, employment, and independent living. Prognosis is likely influenced by intellectual-disability severity, functional speech, epilepsy control, hypotonia/motor impairment, ASD/behavioral burden, and access to early services. No validated molecular prognostic biomarker exists.

12. Treatment and current applications

There is no approved ASH1L-directed therapy and no disease-specific treatment-response rate. Current real-world implementation is genotype-informed supportive care:

individualized education and early developmental intervention;
speech-language therapy, including augmentative and alternative communication when needed;
occupational and physical therapy;
behavioral and ASD-focused interventions;
standard antiseizure treatment selected by seizure type and tolerability;
feeding, sleep, psychiatric, hearing, vision, and orthopedic management as indicated;
social-work, respite, and transition-to-adult-care planning.

Suggested NCIT annotations include Supportive Care (NCIT:C51909), Speech Therapy (NCIT:C17556), Occupational Therapy (NCIT:C15635), Physical Therapy (NCIT:C15313), and Behavioral Intervention (NCIT:C146712).

Experimental therapy

In Ash1l+/GT mice, chemogenetic inhibition of prefrontal pyramidal neurons improved social deficits and abolished absence-like seizures, indicating that cortical hyperexcitability is modifiable. This DREADD experiment is mechanistic and is not a clinically available treatment. URL and publication date: Genes, December 2024, https://doi.org/10.3390/genes15121619. (ma2024chemogeneticinhibitionof pages 12-13)

In engineered human neurons, tazemetostat (EZH2 inhibitor, 0.5 μM) and vorinostat (HDAC inhibitor, 0.1 μM) improved selected neurite/chromatin readouts. Vorinostat increased total neurite length from 163.3 ± 4.83 μm under vehicle to 225.2 ± 8.38 μm and markedly increased H4K16ac; tazemetostat reduced H3K27me3. These agents have substantial systemic effects and are not recommended for MRD52 outside ethically approved research. (jhanji2024dynamicregulationof pages 34-39, jhanji2024dynamicregulationof pages 39-41)

No ASH1L-specific gene replacement, CRISPR, ASO, siRNA, mRNA, cell therapy, immunotherapy, surgery, pharmacogenomic rule, or registered interventional trial was identified.

13. Prevention

The genotype cannot be prevented by lifestyle change, vaccination, or prophylactic medication. Appropriate measures are:

Primary reproductive prevention: genetic counseling, parental testing, discussion of recurrence risk, prenatal diagnosis, and preimplantation genetic testing for a known familial pathogenic variant.
Secondary prevention: prompt etiologic sequencing in unexplained DD/ID and early developmental, speech, hearing, and seizure assessment.
Tertiary prevention: therapies and surveillance intended to limit communication disability, contractures/deconditioning, behavioral crisis, untreated epilepsy, sleep disruption, and caregiver burden.
Cascade testing: appropriate if a pathogenic variant is inherited; routine population or newborn screening is not currently justified.

14. Other species and natural disease

No well-characterized naturally occurring veterinary counterpart, breed predisposition, animal-to-human transmission, or zoonotic risk was identified. Relevant orthologs are Ash1l in mouse (Mus musculus, NCBI Taxon 10090) and ash1-family orthologs in zebrafish (Danio rerio, NCBI Taxon 7955). Conservation of chromatin regulation and neuronal-development functions makes these experimentally informative, but engineered phenotypes are not natural animal disease.

15. Model organisms and experimental systems

Mouse, gene-trap haploinsufficiency. Ash1l+/GT mice exhibited social deficits, increased self-grooming, cognitive impairment, EEG epileptiform discharges/absence-like seizures, and increased pentylenetetrazole susceptibility. Whole-cell recordings showed hyperexcitable prefrontal pyramidal neurons, enhanced glutamatergic transmission, and diminished GABAergic inhibition. This is the strongest recent peer-reviewed mechanistic model, but mouse social behavior and chemogenetic rescue do not directly predict human treatment efficacy. (ma2024chemogeneticinhibitionof pages 12-13)

Human cellular model. Isogenic pluripotent-stem-cell-derived cortical excitatory neurons carrying E2148* reproduced impaired neurite outgrowth, simpler arbors, altered H3K36/H3K4 regulation, reduced transcription, long-gene vulnerability, and isoform changes. Its human genetic background and cell-type specificity are strengths; lack of organismal development, glial circuitry, pharmacokinetics, and peer review are limitations. (jhanji2024dynamicregulationof pages 4-7, jhanji2024dynamicregulationof pages 7-10, jhanji2024dynamicregulationof pages 26-29)

Zebrafish and other mouse alleles. Zebrafish ash1a knockdown reportedly reduces pineal neuron number, while catalytically inactive Ash1l mice have skeletal anomalies and impaired fertility. These models support developmental conservation but only partially reproduce the human neurobehavioral syndrome. (wilson2022reprogrammingofthe pages 14-15)

Authoritative interpretation and evidence gaps

The current expert interpretation is that MRD52 is best understood as a developmental chromatin-regulation disorder, not simply isolated intellectual disability. The convergence of human genetics, neuronal chromatin/transcriptomic data, and mouse electrophysiology supports a model in which altered epigenetic regulation produces abnormal neuronal connectivity and cortical excitation/inhibition. However, the field remains constrained by small clinical cohorts, heterogeneous variant ascertainment, limited longitudinal phenotyping, and a lack of patient-derived functional studies in peer-reviewed literature. The 2024 human-neuron work is promising but is a preprint; its epigenetic-drug rescues should be treated as hypothesis-generating rather than therapeutic evidence. (wilson2022reprogrammingofthe pages 14-15, jhanji2024dynamicregulationof pages 1-4, jhanji2024dynamicregulationof pages 39-41)

Two concise source statements capture the current evidence:

“Clinical phenotypes in MRD52 individuals include mild-severe intellectual disability, autism spectrum disorder, speech delay, facial dysmorphisms, and developmental delay.” — synthesis of the peer-reviewed chromatin/NDD review, published October 2022, https://doi.org/10.1080/10409238.2021.1979457. (wilson2022reprogrammingofthe pages 14-15)

“Chemogenetic inhibition of pyramidal neurons in the PFC of Ash1l+/GT mice ameliorated autism-like social deficits and abolished absence-like seizures.” — Ma et al., published December 2024, https://doi.org/10.3390/genes15121619. (ma2024chemogeneticinhibitionof pages 12-13)

Accordingly, immediate clinical value lies in molecular diagnosis, recurrence counseling, anticipatory neurologic/developmental care, and access to individualized services. Disease-modifying treatment, validated natural-history endpoints, and prospective genotype–phenotype statistics remain priority research needs.

References

(ma2024chemogeneticinhibitionof pages 12-13): Kaijie Ma, Kylee McDaniel, Daoqi Zhang, Maria Webb, and Luye Qin. Chemogenetic inhibition of prefrontal cortex ameliorates autism-like social deficits and absence-like seizures in a gene-trap ash1l haploinsufficiency mouse model. Genes, 15(12):1619, Dec 2024. URL: https://doi.org/10.3390/genes15121619, doi:10.3390/genes15121619. This article has 2 citations.
(wilson2022reprogrammingofthe pages 14-15): Khadija D. Wilson, Elizabeth G. Porter, and Benjamin A. Garcia. Reprogramming of the epigenome in neurodevelopmental disorders. Critical Reviews in Biochemistry and Molecular Biology, 57:73-112, Oct 2022. URL: https://doi.org/10.1080/10409238.2021.1979457, doi:10.1080/10409238.2021.1979457. This article has 33 citations and is from a peer-reviewed journal.
(jhanji2024dynamicregulationof pages 4-7): Megha Jhanji, Joseph A. Ward, Calvin S. Leung, Colleen L. Krall, Foster D. Ritchie, Alexis Guevara, Kai Vestergaard, Brian Yoon, Krishna Amin, Stefano Berto, Judy S. Liu, and Sofia B. Lizarraga. Dynamic regulation of the chromatin environment by ash1l modulates human neuronal structure and function. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.02.625500, doi:10.1101/2024.12.02.625500. This article has 0 citations.
(OpenTargets Search: Intellectual disability, autosomal dominant 52): Open Targets Query (Intellectual disability, autosomal dominant 52, 3 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(jhanji2024dynamicregulationof pages 1-4): Megha Jhanji, Joseph A. Ward, Calvin S. Leung, Colleen L. Krall, Foster D. Ritchie, Alexis Guevara, Kai Vestergaard, Brian Yoon, Krishna Amin, Stefano Berto, Judy S. Liu, and Sofia B. Lizarraga. Dynamic regulation of the chromatin environment by ash1l modulates human neuronal structure and function. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.02.625500, doi:10.1101/2024.12.02.625500. This article has 0 citations.
(jhanji2024dynamicregulationof pages 10-12): Megha Jhanji, Joseph A. Ward, Calvin S. Leung, Colleen L. Krall, Foster D. Ritchie, Alexis Guevara, Kai Vestergaard, Brian Yoon, Krishna Amin, Stefano Berto, Judy S. Liu, and Sofia B. Lizarraga. Dynamic regulation of the chromatin environment by ash1l modulates human neuronal structure and function. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.02.625500, doi:10.1101/2024.12.02.625500. This article has 0 citations.
(jhanji2024dynamicregulationof pages 39-41): Megha Jhanji, Joseph A. Ward, Calvin S. Leung, Colleen L. Krall, Foster D. Ritchie, Alexis Guevara, Kai Vestergaard, Brian Yoon, Krishna Amin, Stefano Berto, Judy S. Liu, and Sofia B. Lizarraga. Dynamic regulation of the chromatin environment by ash1l modulates human neuronal structure and function. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.02.625500, doi:10.1101/2024.12.02.625500. This article has 0 citations.
(jhanji2024dynamicregulationof pages 34-39): Megha Jhanji, Joseph A. Ward, Calvin S. Leung, Colleen L. Krall, Foster D. Ritchie, Alexis Guevara, Kai Vestergaard, Brian Yoon, Krishna Amin, Stefano Berto, Judy S. Liu, and Sofia B. Lizarraga. Dynamic regulation of the chromatin environment by ash1l modulates human neuronal structure and function. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.02.625500, doi:10.1101/2024.12.02.625500. This article has 0 citations.
(jhanji2024dynamicregulationof pages 26-29): Megha Jhanji, Joseph A. Ward, Calvin S. Leung, Colleen L. Krall, Foster D. Ritchie, Alexis Guevara, Kai Vestergaard, Brian Yoon, Krishna Amin, Stefano Berto, Judy S. Liu, and Sofia B. Lizarraga. Dynamic regulation of the chromatin environment by ash1l modulates human neuronal structure and function. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.02.625500, doi:10.1101/2024.12.02.625500. This article has 0 citations.
(jhanji2024dynamicregulationof pages 7-10): Megha Jhanji, Joseph A. Ward, Calvin S. Leung, Colleen L. Krall, Foster D. Ritchie, Alexis Guevara, Kai Vestergaard, Brian Yoon, Krishna Amin, Stefano Berto, Judy S. Liu, and Sofia B. Lizarraga. Dynamic regulation of the chromatin environment by ash1l modulates human neuronal structure and function. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.02.625500, doi:10.1101/2024.12.02.625500. This article has 0 citations.
(jhanji2024dynamicregulationof pages 29-34): Megha Jhanji, Joseph A. Ward, Calvin S. Leung, Colleen L. Krall, Foster D. Ritchie, Alexis Guevara, Kai Vestergaard, Brian Yoon, Krishna Amin, Stefano Berto, Judy S. Liu, and Sofia B. Lizarraga. Dynamic regulation of the chromatin environment by ash1l modulates human neuronal structure and function. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.02.625500, doi:10.1101/2024.12.02.625500. This article has 0 citations.

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Phenotypes

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Medical Actions

Diagnosis

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Animal Models

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References & Deep Research

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Intellectual Disability, Autosomal Dominant 52 (MRD52): Research Report

Executive summary

1. Disease information

2. Etiology, risk, protection, and environment

Causal factor

Risk factors

Protective factors and gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

5. Environmental, lifestyle, and infectious information

6. Mechanism and pathophysiology

Upstream molecular defect

Causal chain

2024 human-neuron findings—preprint evidence

Cellular systems

7. Anatomical structures affected

8. Temporal development and natural history

9. Inheritance and population

10. Diagnostics

Recommended approach

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current applications

Experimental therapy

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Authoritative interpretation and evidence gaps

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