Truncating ASXL2 variants were first reported in relation to syndromic intellectual disability in 2016 (Shashi et al., 2016; PMID 27693232). ASXL2 encodes a chromatin protein involved in transcriptional regulation. Clinical features in affected individuals include variable developmental or intellectual impairments, macrocephaly, distinct facial dysmorphisms, facial nevus flammeus, neonatal feeding difficulties, and hypotonia. The mechanism of pathogenicity is proposed to be dominant negative since variants cluster in the last and penultimate exons and cDNA studies on three probands showed that the mutant transcripts escape nonsense-mediated mRNA decay (PMID: 27693232). At least 10 unique nonsense and frameshift variants have been reported in 10 probands included in this curation (PMIDs: 27693232, 33751773, 29907797, 33057194, 27479843, 28135719). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants are de novo in all probands. This gene-disease association is also supported by experimental evidence. The ASXL gene family (ASXL1, ASXL2, and ASXL3) participates in body patterning during embryogenesis and encodes proteins involved in epigenetic and transcriptional regulation (PMID: 23736028). Germline de novo truncating variants in ASXL1 and ASXL3 have been implicated in Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of intellectual disability and dysmorphic features (PMIDs: 21706002, 23383720). In summary, ASXL2 is definitively associated with autosomal dominant syndromic intellectual disability. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 09/28/2021 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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