Submission Details

ARHGEF10 was first described in 2003 in a Belgian family with slowed nerve conduction velocities and onion bulb formations with an autosomal dominant inheritance pattern (Verhoeven et al., PMID: 14508709). Clinically, the affected individuals did not develop a clinical Charcot-Marie-Tooth (CMT) phenotype, but an electrophysiological phenotype of NCV slowing (Nelis et al., PMID: 9678704; de Jonghe et al., PMID: 10520946). With a LOD score of 9.93, the variant p.Thr332Ile co-segregated in 12 affected family members (Verhoeven et al., PMID: 14508709) and is supported by functional evidence (Chaya et al., PMID: 21719701). Due to incomplete phenotype and lacking co-segregation and functional evidence, other reported variants (e.g. PMID: 24627108) did not further support the gene-disease relationship. ARHGEF10 encodes a Rho guanine nucleotide exchange factor involved in actin cytoskeleton organization and vesicle trafficking. Rho GTPase pathways and membrane recycling are both common mechanisms in hereditary neuropathies. In an immunofluorescence assay of HeLa cells, ARHGEF10 colocalized with exocytotic vesicle proteins (Shibata et al., PMID: 27550519). Genome-wide association studies performed in 4074 dogs with a profound CMT phenotype revealed biallelic loss-of-function mutations in ARHGEF10 in 1.3% of the cases (Ekenstedt et al., PMID: 25275565). In contrast to this, knock-out mice did not develop a clear neuropathy (Lu et al., PMID: 29456827). In patients, a constitutive activation of the Rho GTPase is hypothesized as the underlying gain-of-function mechanism (Chaya et al., PMID: 21719701). However with one affected family only, the overall evidence to establish a clear gene-disease relationship has not been upheld over time. The panel therefore classifies ARHGEF10 in the category “Limited evidence”.