KDM5B – Intellectual Disability

KDM5B encodes a histone H3K4 demethylase critical for chromatin regulation during neurodevelopment. Autosomal recessive bi‐allelic loss‐of‐function variants in KDM5B have been implicated in intellectual disability (ID), characterized by developmental delay, cognitive impairment, and dysmorphic features. Testing for KDM5B should be considered in individuals with unexplained AR ID.

Genetic evidence supports an autosomal recessive inheritance mode with AR bi‐allelic truncating and splice variants leading to ID. A recent retrospective series described 21 unrelated individuals with likely pathogenic KDM5B variants, including bi‐allelic disruptive alleles, all presenting with developmental delay and ID ([PMID:39202393]). One patient harbored a de novo frameshift, c.1791_1794del (p.Glu598LeufsTer12), alongside a 2q deletion; the KDM5B allele correlated with dysmorphic facial and finger features ([PMID:35278764]). Variant spectrum across studies includes c.1791_1794del (p.Glu598LeufsTer12) and multiple loss‐of‐function and splice defects.

Segregation data are limited, with no additional affected relatives reported beyond the probands, consistent with a recessive pattern.

Functional assays demonstrate that Jarid1B homologs demethylate H3K4me3 in vivo, with overexpression reducing H3K4me3 levels in human cells ([PMID:17310255]). A Jarid1b knockout mouse model exhibits neonatal lethality due to respiratory failure, neural defects including disorganized cranial nerves and increased H3K4me3 at developmental gene loci, paralleling human neurodevelopmental phenotypes ([PMID:23637629]).

Conflicting evidence arises from studies reporting heterozygous loss‐of‐function and missense variants in unaffected individuals, suggesting that haploinsufficiency alone may not underlie ID and that biallelic disruption is required for pathogenicity ([PMID:30217758]).

In summary, bi‐allelic KDM5B inactivation causes a recessive intellectual disability syndrome supported by multiple unrelated probands with loss‐of‐function alleles and concordant functional models. Further identification of additional families and detailed segregation studies will refine penetrance estimates. Key take‐home: KDM5B should be included in AR intellectual disability gene panels when biallelic truncating or splice variants are identified.

References

• Gene • 2018 • Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences PMID:30217758
• Seizure • 2022 • A complex epileptic and dysmorphic phenotype associated with a novel frameshift KDM5B variant and deletion of SCN gene cluster PMID:35278764
• PLoS Genetics • 2013 • The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3 PMID:23637629
• Nature Structural & Molecular Biology • 2007 • Demethylation of trimethylated histone H3 Lys4 in vivo by JARID1 JmjC proteins PMID:17310255
• Genes • 2024 • A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants PMID:39202393

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