The KDM4B gene is located on chromosome 19 at 19p13.3 and is a histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a role in histone code. The KDM4B gene was first reported in relation to intellectual developmental disorder, autosomal dominant 65 in 2020 (Duncan et al. 2020, PMID: 33232677). This disorder is characterized by global developmental delay, intellectual disability, language delays, structural brain anomalies, characteristic facial features, and clinodactyly.. Ten unique variants (4 missense, 4 insertion/deletion, 1 splice-site, 1 synonymous) that have been reported in 10 individuals from 2 publications are included in this curation (PMIDs: 33232677, 38270710). In seven of the ten individuals, variants were reported as de novo occurrences. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence including biochemical function and two mouse models recapitulating the human phenotype (PMIDs: 35186950, 27023172, 33232677). In summary, there is strong evidence to support the relationship between KDM4B and Intellectual developmental disorder, autosomal dominant 65. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date November 6th, 2024 (SOP Version 11).
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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