KDM3B encodes a histone demethylase involved in H3K9 demethylation, a critical process in chromatin modification required for transcriptional regulation. KDM3B was first reported in relation to autosomal dominant syndromic intellectual disability in 2019 (Diets et al., PMID: 30929739). The disorder is characterized by developmental delay, mild to moderate intellectual disability, and facial dysmorphisms. Additional phenotypic features include feeding difficulties in infancy, hypotonia, joint hypermobility, short stature, and behavior problems, including autism spectrum disorder and ADHD. Eighteen variants (missense, nonsense, frameshift, and splice site) that have been reported in 19 probands in 5 publications (PMIDs: 28135719, 30885698, 30929739, 36274669, 36757469) are included in this curation. Most variants occur de novo, but can also be inherited from similarly affected parents. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including biochemical function, protein interaction, and a mouse model (PMIDs: 22615488, 29276005, 34217333). Several other genes encoding lysine demethylases have been implicated in intellectual disability and autism. In summary, there is definitive evidence supporting the relationship between KDM3B and autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 21, 2024 (SOP Version 10).
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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