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KDM6B encodes the histone H3 lysine 27 demethylase JMJD3, which regulates chromatin accessibility during neurodevelopment. Heterozygous de novo variants in KDM6B have emerged as a cause of global developmental delay and neurobehavioral manifestations, while rare bi-allelic variants further expand the inheritance spectrum.
In a cohort of 85 individuals with largely de novo (likely) pathogenic KDM6B variants, truncating (n = 47), missense/in-frame indels (n = 38) and splice site changes have been reported across 78 unrelated families, establishing a consistent neurodevelopmental phenotype (PMID:37196654). Concurrently, a consanguineous Pakistani pedigree with a homozygous non-frameshift duplication c.786_791dupACCACC (p.Pro263_Pro264dup) in KDM6B confirms that recessive alleles can also underlie syndromic neurodevelopmental disorder (PMID:39767643).
Parental testing in the AJHG cohort confirmed de novo origin for the majority of heterozygous variants, with no further segregation observed. These data achieve robust genetic evidence consistent with an autosomal dominant mechanism, supplemented by the single autosomal recessive case.
Functional assays demonstrate that 11 missense and in-frame indel variants disrupt JMJD3 enzymatic activity in a dual Drosophila gain-of-function model, correlating with impaired memory and behavior (PMID:37196654). Complementarily, Kdm6b haploinsufficient mice exhibit autistic-like social deficits, hyperactivity, and working memory impairment that are ameliorated by methylphenidate treatment, supporting a dosage-sensitive haploinsufficiency mechanism (PMID:35711692).
Collectively, abundant de novo and recessive variants, concordant functional models, and segregation data fulfill ClinGen criteria for a strong gene–disease association. The mechanistic convergence on altered H3K27 methylation underscores KDM6B’s critical role in neurodevelopment.
Key Take-home: KDM6B pathogenic variants—predominantly de novo heterozygous truncating or missense changes, with rare bi-allelic cases—cause a clinically distinctive neurodevelopmental disorder, supporting inclusion of KDM6B in diagnostic gene panels and informing genetic counseling.
Gene–Disease AssociationStrong85 probands with de novo heterozygous variants and one recessive family (PMID:37196654; PMID:39767643) Genetic EvidenceStrongLarge cohort of 85 unrelated individuals with varied de novo KDM6B variants plus a bi-allelic case; robust variant spectrum Functional EvidenceModerateConcordant Drosophila gain-of-function disruption and murine haploinsufficiency models demonstrating cognitive and behavioral deficits |