KDM5C – X-linked Intellectual Disability

KDM5C encodes a histone H3 lysine-4 demethylase localized to Xp11.22 and is a well-established cause of X-linked intellectual disability (PMID:15586325). Loss-of-function variants in affected males lead to moderate to severe cognitive impairment often accompanied by short stature, speech delay, facial dysmorphism and behavioral disturbances.

Genetic studies have identified >60 distinct KDM5C variants in over 50 unrelated probands, including frameshift, nonsense and missense changes clustering in functional domains. In a systematic screen of 210 XLID families, seven families harbored truncating and missense mutations co-segregating with nonsyndromic intellectual disability, with absence or marked reduction of mutant transcript (PMID:15586325). A Brazilian pedigree demonstrated co-segregation of a novel nonsense variant c.2172C>A (p.Cys724Ter) in exon 15 with three affected males and a mildly impaired carrier mother (PMID:21575681).

Inheritance is X-linked recessive, with skewed X-inactivation protecting most heterozygous females. Segregation data include at least 19 additional affected male relatives across multiple pedigrees. The variant spectrum comprises >40 truncating alleles and >20 missense changes, with recurrent loss-of-function events as the predominant pathogenic mechanism.

Functional assays demonstrate that patient‐derived KDM5C mutations abolish demethylase activity or reduce protein stability. SMCX/JARID1C missense mutations impair removal of H3K4me3 and disrupt neurite outgrowth in zebrafish and neuronal cell models, confirming epigenetic dysregulation as the pathogenic mechanism (PMID:17320160).

No significant conflicting evidence has been reported; all pathogenic variants yield consistent loss-of-function effects. Together, genetic and experimental data meet ClinGen criteria for a Definitive gene‐disease relationship.

Key Take-home: KDM5C loss-of-function variants cause a well-defined X-linked intellectual disability syndrome via haploinsufficiency of its histone demethylase activity, supporting its use in diagnostic and genetic counseling workflows.

References

• American Journal of Human Genetics • 2005 • Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. PMID:15586325
• Neuroscience Letters • 2011 • A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay. PMID:21575681
• Cell • 2007 • The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. PMID:17320160

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