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Heterozygous pathogenic variants in KDM6B have been linked to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities. A recent case report described an 11-year-old male with a de novo frameshift variant c.2705del (p.Leu902HisfsTer13) presenting with facial dysmorphisms, dysgraphia, behavioral traits, a single seizure, and a novel cerebellar heterotopia (PMID:38326731).
An international cohort study of 85 unrelated individuals with mostly de novo likely pathogenic KDM6B variants confirmed the association and expanded the phenotype beyond coarse facies and distal skeletal features to include cognitive deficits, hypotonia, and psychiatric manifestations (PMID:37196654). These variants comprised truncating, missense, and in-frame indels distributed across the JmjC and Zn-containing domains.
The variant spectrum includes loss-of-function changes (e.g., c.1085_1088del (p.Glu362fs)) and recurrent missense alleles, all arising de novo, consistent with an autosomal dominant mechanism and absence of multi-generational segregation (PMID:37196654).
Functional studies using a dual Drosophila gain-of-function assay demonstrated that missense and in-frame indels in enzymatic domains disrupt KDM6B activity, impair memory and behavior, and recapitulate human phenotypes, supporting a loss-of-function mechanism (PMID:37196654).
No conflicting reports have been documented. The convergence of extensive de novo genetic evidence and robust in vivo functional concordance establishes a definitive gene–disease relationship. Key take-home: KDM6B testing should be considered in patients with unexplained neurodevelopmental delay, facial dysmorphism, and skeletal anomalies to inform diagnosis and counseling.
Gene–Disease AssociationDefinitive85 de novo probands with consistent phenotype and extensive functional validation Genetic EvidenceStrong85 unrelated probands with de novo heterozygous variants across multiple variant classes ([PMID:37196654]) Functional EvidenceModerateDrosophila gain-of-function assays demonstrate disruptive effect of KDM6B variants on neurodevelopment ([PMID:37196654]) |