Relevance to Autism

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). Additional de novo likely gene-disruptive/protein-truncating variants and/or damaging missense variants in KDM6B were identified in ASD probands from the SPARK cohort and the Autism Sequencing Consortium in Feliciano et al., 2019 and Satterstrom et al., 2020, respectively; furthermore, transmission and de novo association (TADA) analysis in both reports identified KDM6B as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified KDM6B as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code. Plays a central role in regulation of posterior development, by regulating HOX gene expression.

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Model Summary

Homozygous Kdm6b knockout mice exhibit neonatal mortality and die within 24 hours after birth. Heterozygous Kdm6b mice display autistic-like impaired sociability and object recognition memory, and increased locomotor activity and impulsivity. Methylphenidate treatment restores both locomotor hyperactivity and impulsivity in heterozygous Kdm6b mice.

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