Background: TRPV4 mutations have been identified in Charcot-Marie-Tooth type 2 (CMT2), scapuloperoneal spinal muscular atrophy and distal hereditary motor neuropathy (dHMN).
Objective: We aimed to screen the TRPV4 gene in 422 British patients with inherited neuropathy for potentially pathogenic mutations.
Methods: We sequenced TRPV4 coding regions and splice junctions in 271 patients with CMT2 and 151 patients with dHMN. Mutations were clinically and genetically characterised and screened in ≥345 matched controls.
Results: 13 missense and nonsense variants were identified, of which five were novel and absent from controls (G20R, E218K, N302Y, Y567X and T701I). N302Y and T701I mutations were present in typical CMT2 cases and are potentially pathogenic based on in silico analyses. G20R was detected in a patient with dHMN and her asymptomatic father and is possibly pathogenic with variable expressivity. The Y567X variant segregated with disease in a family with severe CMT2 but also with a MFN2 mutation reported to cause a mild CMT2 phenotype. Although Y567X caused nonsense mediated mRNA decay, the amount of TRPV4 protein on western blotting of patient lymphoblasts was no different to control. Y567X is therefore unlikely to be pathogenic. E218K is unlikely to be pathogenic based on segregation.
Conclusions: In this comprehensive analysis of the TRPV4 gene, we identified mutations in <1% of patients with CMT2/dHMN. We found that TRPV4 likely harbours many missense and nonsense non-pathogenic variants that should be analysed in detail to prove pathogenicity before results are given to patients.