ARHGEF6 – Intellectual Disability

A compelling body of evidence supports an association between alterations in ARHGEF6 and intellectual disability (MONDO_0001071). In a seminal study published in Nature Genetics (2000) (PMID:11017088), mutation screening of 119 patients with nonspecific mental retardation identified an intronic mutation in ARHGEF6 in a large Dutch family, where all affected males harbored the variant. This mutation, shown to cause preferential exon 2 skipping and a predicted deletion of 28 amino acids, establishes a link between ARHGEF6 disruption and the intellectual disability phenotype.

Genetic evidence from this case report is bolstered by additional multi‐patient studies that have evaluated a broad spectrum of X-linked intellectual disability genes. Although a large-scale exome study (PMID:23871722) raised caution by revealing that rare truncating variants in ARHGEF6 can be observed in the general population, the familial segregation observed in the Dutch family strongly supports the pathogenic role of this variant in the context of intellectual disability.

ARHGEF6 demonstrates an X-linked inheritance pattern and shows segregation of the mutation among affected relatives. While the exact count of additional affected relatives is not provided, the transmission pattern within the family supports a robust segregation of the pathogenic variant.

The reported variant, c.166-11T>C (p.Gly56_Gly83del), represents a key piece of genetic evidence. This intronic alteration, which has been associated with aberrant splicing and a consequential in-frame deletion, has been specifically identified in ARHGEF6 and correlated with the clinical symptoms of intellectual disability (PMID:11017088).

Functional studies further substantiate the role of ARHGEF6 in the neurological context. Multiple experimental investigations, including mouse expression analyses (PMID:12063400) and protein interaction studies (PMID:12499396; PMID:12932438), indicate that ARHGEF6 is critical for Rho GTPase signaling and regulation of the actin cytoskeleton. These experiments show that disruptions in ARHGEF6 function can impair neuronal plasticity and connectivity, consistent with the observed intellectual disability phenotype.

In summary, despite some conflicting evidence from large-scale exome sequencing studies, the combination of robust segregation data from a well-characterized Dutch family and supportive functional evidence provides a strong basis for considering ARHGEF6 as causative for intellectual disability. This integrated evidence base serves as a key resource for diagnostic decision‑making, commercial assay development, and future publication.

References

• Nature Genetics • 2000 • Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X‑linked mental retardation PMID:11017088
• Cytogenetics and Cell Genetics • 2001 • The mouse Arhgef6 gene: cDNA sequence, expression analysis, and chromosome assignment PMID:12063400
• Human Molecular Genetics • 2003 • Interaction of alphaPIX (ARHGEF6) with beta‑parvin (PARVB) suggests an involvement of alphaPIX in integrin‑mediated signaling PMID:12499396
• Molecular and Cellular Neurosciences • 2003 • The RhoGAP activity of OPHN1, a new F‑actin‑binding protein, is negatively controlled by its amino‑terminal domain PMID:12932438

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