Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasia

BACKGROUND: Transient receptor potential cation channel subfamily V member 4 (TRPV4) is an ion channel permeable to Ca(2+) that is sensitive to physical, hormonal, and chemical stimuli. This protein is expressed in many cell types, including osteoclasts, chondrocytes, and sensory neurons. As such, pathogenic variants of this gene are associated with skeletal dysplasias and neuromuscular disorders. Pathogenesis of these phenotypes is not yet completely understood, but it is known that genotype–phenotype correlations for TRPV4 pathogenic variants often are not present. METHODS: Newly characterized, suspected pathogenic variant in TRPV4 was analyzed using protein informatics and personalized protein‐level molecular studies, genomic exome analysis, and clinical study. RESULTS: This statement is demonstrated in the family of our proband, a 47‐year‐old female having the novel c.2401A>G (p.K801E) variant of TRPV4. We discuss the common symptoms between the proband, her father, and her daughter, and compare her phenotype to known TRPV4‐associated skeletal dysplasias. CONCLUSIONS: Protein informatics and molecular modeling are used to confirm the pathogenicity of the unique TRPV4 variant found in this family. Multiple data were combined in a comprehensive manner to give complete overall perspective on the patient disease and prognosis.