Submission Details

EPB41L1 was first reported in relation to autosomal dominant nonsyndromic intellectual disability in 2011 (Hamdan et al., PMID: 21376300). EPB41L1 encodes a neuronal cytoskeletal protein that mediates interactions between the cytoskeleton and membrane proteins including synaptic receptors. Hamdan et al. reported a de novo missense variant, c.2560C>T (p.Pro854Ser), in an individual with severe intellectual disability (ID) and hypotonia with a normal brain MRI. Functional studies of EPB41L1 interaction with glutamate receptors supported a damaging protein change resulting in deficient EPB41L1 binding and trafficking (PMID: 21376300). To date, at least five additional missense variants have been reported in exome sequencing studies in individuals with autism spectrum disorder or developmental disorders, four of which were de novo (Matsunami et al., PMID: 24467814; Krumm et al., PMID: 25961944; Chen et al., PMID: 28344757; Kaplanis et al., PMID: 33057194). These variants are absent from gnomAD, affect highly conserved positions and are consistently predicted deleterious with various pathogenicity tools, but in the absence of functional studies were not scored. Large 20q11.22 deletions (>1.6 Mb) encompassing EPB41L1 have been reported in several individuals with ID, craniofacial dysmorphism, and anomalies of the extremities (PMID: 25572454). However, this is insufficient evidence to support pathogenicity due to EPB41L1 haploinsufficiency. EPB41L1 is intolerant to truncating variants (pLI = 0.88, LOEUF = 0.343; gnomAD v2.1.1), but is not significantly constrained for missense variants (Z = 1.94). Since only one missense variant in EPB41L1 has been reported in nonsyndromic intellectual disability, we decided to curate for the more general term complex neurodevelopmental disorder. This gene-disease relationship is supported by interactions with proteins previously implicated in ID and other neurodevelopmental disorders (KCC2, GRIA1, GRIA4). However, given the paucity of genetic evidence, this experimental evidence was not scored. In summary, there is limited evidence at this time to support the relationship between EPB41L1 and autosomal dominant complex neurodevelopmental disorder. Additional studies are required to verify this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 6 2022 (SOP Version 9).