Truncating ASXL3 variants were first reported in relation to syndromic intellectual disability (also known as Bainbridge-Ropers syndrome) in 2013 (Bainbridge et al., PMID: 23383720). Clinical features in affected individuals include feeding difficulties, hypotonia, developmental delay, limited speech, intellectual disability of variable severity, and characteristic facial features. Behavioral issues, including autism spectrum disorder or autistic traits, are common. Seizures are reported in about a third of individuals.
Over 100 affected individuals with nonsense, frameshift, and splicing variants have been reported (PMID: 34436830). Most variants are de novo and cluster in the last and penultimate exons (PMID: 23383720). Both dominant negative (PMID: 23383720) and loss of function mechanisms (PMID: 26647312) have been proposed. Further studies are needed to understand the mechanism of disease.
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 ASXL2 have been implicated in Bohring-Opitz and Shashi-Pena syndromes, which result in overlapping features of intellectual disability and dysmorphic features (PMIDs: 21706002, 27693232). Further support is provided by animal models in mice (doi: 10.1101/2021.07.20.452995) and frogs (PMID: 32132929). The mouse model was not formally scored in this curation, as it has yet to be published.
In summary, there is definitive evidence supporting the relationship between ASXL3 and autosomal dominant syndromic intellectual disability. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on October 6, 2021 (SOP Version 8).
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