Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual...

TRPV4 encodes a polymodal calcium-permeable plasma membrane channel. Dominant pathogenic mutations in TRPV4 lead to a wide spectrum of abnormal phenotypes. This is the first report of biallelic TRPV4 mutations and we describe two compound heterozygous siblings presenting with a complex phenotype including severe neuromuscular involvement. In light of previously well described dominant inheritance for TRPV4-related neuromuscular disease, our study suggests a role for compound heterozygosity and loss-of-function as a potential novel disease mechanism for this group of disorders. Profound intellectual disability was also noted in both affected children, suggesting that TRPV4 may be necessary for normal brain development.