KDM5C – Syndromic X-linked Intellectual Disability Claes-Jensen Type

KDM5C encodes a histone H3 lysine 4 demethylase and is causally linked to syndromic X-linked intellectual disability Claes-Jensen type (MONDO:0010355). A broad spectrum of KDM5C variants disrupts neuronal gene regulation, leading to severe cognitive impairment often accompanied by short stature, speech delay and behavioral abnormalities.

Genetic evidence supports an X-linked recessive inheritance pattern with hemizygous males invariably affected and carrier females variably penetrant. Over 175 unrelated probands harboring KDM5C variants have been reported to date (PMID:39835750), establishing the gene as a common cause of X-linked intellectual disability.

Segregation analyses in multiple families demonstrate co-segregation of KDM5C variants with disease. For example, a Brazilian kindred with a nonsense mutation exhibited three affected male siblings with severe intellectual disability and dysmorphic features (PMID:21575681). In aggregate, at least 12 additional affected relatives have been documented across pedigrees.

The variant spectrum includes missense substitutions within catalytic and reader domains, frameshift and nonsense mutations causing loss of function, and splice-site alterations. Representative variants include c.3344G>A (p.Arg1115His) identified in a patient with Claes-Jensen–like symptoms (PMID:29670509). Both unique and recurrent alleles underscore the allelic heterogeneity.

Functional assays in vitro and in vivo consistently demonstrate that pathogenic KDM5C mutations impair demethylase activity or protein stability. Missense mutations in the ARID and JmjC domains reduce H3K4me2/3 demethylation and alter transcriptional repression in neuronal cells, while zebrafish and neuron-specific models show defective neuronal survival and dendritic outgrowth (PMID:17320160; PMID:25666439).

Collectively, genetic and experimental evidence converge on haploinsufficiency as the predominant mechanism. Loss of KDM5C activity disrupts chromatin remodeling at promoters of neurodevelopmental genes, resulting in aberrant transcriptional programs and the hallmark cognitive and growth phenotypes.

Key Take-home: Genetic testing for KDM5C variants should be prioritized in males with syndromic intellectual disability and characteristic dysmorphic features, as rapid molecular diagnosis informs family counseling and anticipatory management.

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
• Frontiers in molecular neuroscience • 2018 • Altered Gene-Regulatory Function of KDM5C by a Novel Mutation Associated With Autism and Intellectual Disability. PMID:29670509
• 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
• Human molecular genetics • 2015 • Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity. PMID:25666439
• Molecular genetics & genomic medicine • 2025 • Clinical Features and Genetic Characteristics of XLID Patients With KDM5C Gene Mutations: Insights on Phenotype-Genotype Correlations From 175 Previous Cases and Identification of a Novel Variant. PMID:39835750

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