KDM6B encodes a histone demethylase that plays key roles in the regulation of gene expression during development. Although KDM6B variants were initially observed in large-scale sequencing studies in autism spectrum disorder and intellectual disability (ID) between 2014 and 2017 (PMIDs: 25363760, 25363768, 27479843, 28263302), the first report focusing on variants in KDM6B as a cause of autosomal dominant syndromic ID was published in 2019 (PMID: 31124279). Heterozygous KDM6B de novo truncating variants have been reported in at least 12 individuals (PMIDs: 25363768, 31124279). Affected individuals present with motor and speech delays, ID, and dysmorphic facial features; variable features include autism spectrum disorder and mild hand and feet anomalies (PMID: 31124279). Heterozygous de novo KDM6B missense and in-frame variants have also been reported, but no functional studies were performed to assess their pathogenicity (PMIDs: 25363760, 25363768, 27479843, 31124279). According to gnomAD (v2.1.1), KDM6B is intolerant to truncating variants (pLI = 1) but not to missense variants (Z = 1.32). Homozygous KDM6B variants have been reported in three consanguineous families with syndromic ID (PMIDs: 21937992, 26077850, 28097321); the disease association in these cases is not clear and will be curated separately.
In summary, KDM6B is definitively associated with autosomal dominant syndromic ID. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 19 2022 (SOP Version 8).
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