Relevance to Autism

Four de novo loss-of-function (LoF) variants in the ASXL3 gene have been identified in ASD probands (PMIDs 24044690, 25363760, 28263302). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ASXL3 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo truncating variants in this gene have also been identified in individuals presenting with a syndrome that shares characteristics with Bohring-Opitz syndrome, including developmental delay, post-natal growth retardation and feeding problems (PMID 23383720, 27901041). Balasubramanian et al., 2017 reported 12 new patients with de novo heterozygous loss-of-function variants in ASXL3 and a diagnosis of Bainbridge-Ropers syndrome; nine of these patients were either formally diagnosed with autism or ASD, or were described as having autistic features (PMID 28100473). A de novo likely gene-disruptive variant in ASXL3 was identified in an ASD proband from the SPARK cohort in Feliciano et al., 2019; a meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA in the same report identified ASXL3 as an ASD candidate gene with a false discovery rate (FDR) 0.01. A detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome in Schirwani et al., 2021 found that a diagnosis of autism spectrum disorder was made in 30% of individuals, and autistic traits including stereotypies, poor eye contact, hand flapping, rocking, and head shaking were present in the majority of individuals. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified ASXL3 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility. Heterozygous de novo truncating variants in this gene were recently identified in patients with a novel clinical phenotype similar to Bohring-Opitz syndrome (Bainbridge et al., 2013).

External Links

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