Relevance to Autism

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (De Rubeis et al., 2014). A fourth de novo LoF variant in this gene was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017. Additional de novo likely gene-disruptive/protein-truncating variants in KDM5B 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 KDM5B 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 KDM5B as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a histone demethylase that demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code.

External Links

References

Model Summary

The Kdm5b knockout mouse shows incomplete penetrance in perinatal lethality. This model has deficits in social behavior, in memory paradigms and an increase in anxiety. Aside from the behavioral phenotypes, the Kdm5b knockout shows abnormal skeletal development, specifically it shows craniofacial and vertebral abnormalities.

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