ASH1L

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0030918

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0030918

Submitter: Illumina

The ASH1L gene is located on chromosome 1 at 1q22 and encodes the ASH1 like histone lysine methyltransferase protein, which is responsible for methylating Lys-36 of histone H3. ASH1L was first reported in relation to autosomal dominant ASH1L-related intellectual disability in 2012 (23033978: de Ligt et al. 2012). At least six unique de novo variants have been reported, including missense, frameshift, stop-gained variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least six probands in three publications (23033978: de Ligt et al. 2012; 28191889: Stessman et al. 2017; 29276005: Faundes et al. 2018). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease association is supported by somewhat limited experimental evidence, including expression of ASH1a in the zebrafish brain and during early epiphysial neurogenesis and a null zebrafish model that demonstrates importance of ASH1a in neurogenesis in zebrafish (12702659: Cau and Wilson 2003). In summary, there is strong evidence to support the relationship between ASH1L and autosomal dominant ASH1L-related intellectual disability.

Inheritance Pattern: AD

Disease ID:MONDO:0030918

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030918

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

*ASH1L* was first reported in relation to an autosomal dominant intellectual disability disorder in 2012 (de Ligt et al., PMID: 23033978). Phenotypes are variable with most probands having intellectual disability or developmental delay, autism spectrum disorder, variable dysmorphic features, and behavioral problems including attention deficit hyperactivity disorder and self-injurious behavior. Less prevalent features include cryptorchidism, penile torsion, abnormal brain MRI, hypotonia, seizures, pectus, scoliosis, cervical spine fusion, hyperopia, strabismus, nystagmus, and ptosis (PMIDs: 29753921, 28394464, 34373061, 23033978, 29276005, 28191889). This gene has been curated under the disease entity syndromic complex neurodevelopmental disorder. There are nine *de novo* heterozygous variants found in nine probands reported in six publications (PMIDs: 29753921, 28394464, 34373061, 23033978, 29276005, 28191889) included in this curation. Of these, seven variants are nonsense or frameshift, supporting a hypothesized disease mechanism of haploinsufficiency; two additional variants included here are missense, but no functional studies were performed. Of note, two additional probands are available from the Brain Gene Registry (braingeneregistry.wustl.edu); the variants identified in these individuals are not formally documented in this curation due to technical limitations, but they are available in ClinVar (ClinVar IDs: SCV003927994.1 and SCV003927995.1). These individuals, one presenting with a *de novo* frameshift variant and one with a *de novo* nonsense variant, added the phenotypes of ataxic gait, mixed-receptive language disorder, anxiety, and depression to the phenotypic spectrum. At present, there is no experimental evidence to support the gene-disease relationship. Two mouse models have been reported in the literature but have not been scored as they did not sufficiently recapitulate the human disease phenotype. In summary, there is definitive evidence to support the relationship between *ASH1L* and syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on February 23, 2023 (SOP 9).