SHANK1 was first reported in relation to autosomal dominant autism spectrum disorder (ASD) in 2012 (Sato et al., PMID: 22503632). The authors reported a male proband with a de novo deletion spanning SHANK1 and SYT3, and a multigenerational family with six individuals carrying a deletion of SHANK1 and CLEC11A, in which the males, but not the carrier mothers, had ASD. None of these cases were awarded points in this curation because the deletions encompass other genes. Subsequently, May et al. (2021, PMID: 34113010) reported de novo truncating variants in SHANK1 in six probands with a spectrum of neurodevelopmental disorders, including motor and speech delays, intellectual disability or learning disabilities, ASD, hypotonia, and seizures. At least 9 additional probands with SHANK1 truncating variants and complex neurodevelopmental disorder, including intellectual disability, developmental delay, ASD, and epilepsy, have been reported in large cohort studies (PMIDs: 27824329, 29100083, 33057194, 34113010, 34374989, 35982160, 36980980). Seven de novo truncating variants (nonsense, frameshift, and splice) that have been reported in seven probands in two publications (PMIDs: 27824329, 34113010) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. In addition to the two unaffected deletion carrier mothers mentioned above (PMID: 22503632), a SHANK1 de novo truncating variant was observed in an unaffected male sibling of an ASD proband (PMID: 35982160), suggesting incomplete penetrance. The mechanism of pathogenicity is loss of function (PMID: 34113010).
This gene-disease relationship is also supported by experimental evidence, including functional alteration, biochemical function, and animal models. SHANK1 is a member of the SHANK gene family, which includes SHANK1, SHANK2, and SHANK3, and encodes scaffolding proteins that are enriched in the postsynaptic density of glutamatergic synapses. SHANK2 and SHANK3 are also involved in neurodevelopmental disorders associated with ASD and intellectual disability.
In summary, there is definitive evidence supporting the relationship between SHANK1 and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 20, 2024 (SOP Version 10).
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