AP2M1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2019 (Helbig et al., PMID:31104773). The phenotype includes global developmental delay and intellectual disability, often associated with seizures, hypotonia, ataxia, and/or autism. Nine missense variants and one splice site variant have been reported in 14 probands from 9 publications (PMIDs: 36553572, 31104773, 37838930, 33057194, 31785789, 35982159, 28714951, 35982160, 37393044), all of which are included in this curation. The recurrent c.508C>T (p.Arg170Trp) variant has been identified as a de novo variant in five probands including four individuals with developmental and epileptic encephalopathy (DEE) (PMID:31104773, 37393044). The mechanism of pathogenicity is currently unknown.
In summary, there is definitive evidence supporting the relationship between AP2M1 and autosomal dominant 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 ClinGen Epilepsy GCEP on the meeting date October 1, 2024 (SOP Version 11).
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