ARHGAP4 – Intellectual Disability

ARHGAP4 encodes a Rho GTPase activating protein located on the X chromosome ARHGAP4. Hemizygous loss‐of‐function of ARHGAP4 has been observed in male patients with intellectual disability (PMID:22965914). In dizygotic twin brothers, a 17 905 bp contiguous deletion spanning the entire AVPR2 gene and extending into intron 7 of ARHGAP4 resulted in nephrogenic diabetes insipidus and variable cognitive impairment; their mother was an unaffected carrier (PMID:22965914). A separate Chinese pedigree revealed an X-linked missense variant p.Thr491Met in the proband with intellectual disability; the mother was a carrier and no other affected relatives were identified (PMID:26707211). No additional segregation beyond the carrier mothers has been reported, and extended family studies are lacking.

Inheritance is X-linked recessive with hemizygous males affected and carrier females typically unaffected. To date, only three affected males have been described across two unrelated families, with no reports of cognitive assessments in ARHGAP4-specific knockout models or rescue experiments in neural cells. There is a paucity of functional data directly linking ARHGAP4 deficiency to neurodevelopmental defects.

Overall, the clinical validity of the ARHGAP4–intellectual disability association is Limited given the small number of probands, absence of segregation in extended pedigrees, and lack of mechanistic studies. Genetic evidence remains Limited, and experimental support is also Limited. Additional familial studies and in vitro or in vivo models investigating ARHGAP4 in neuronal development are needed.

Key Take-home: X-linked ARHGAP4 variants have been tentatively linked to intellectual disability, but the association requires further genetic and functional validation for definitive clinical utility.

References

• American journal of medical genetics. Part A • 2012 • A novel contiguous gene deletion of AVPR2 and ARHGAP4 genes in male dizygotic twins with nephrogenic diabetes insipidus and intellectual disability. PMID:22965914
• Gene • 2016 • ARHGAP4 mutated in a Chinese intellectually challenged family. PMID:26707211

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