Submission Details

TRPV4 was first reported in relation to autosomal dominant metatropic dysplasia as early as 2009 (Krakow et al., PMID: 19232556). Clinical phenotypes include short limbs, long and narrow trunk that develops into kyphoscoliosis, prominent forehead, square jaw, odontoid hypoplasia, cervical myelopathy, stenosis, sensorineural hearing loss, and respiratory compromise (PMID: 19232556). Twelve variants (11 missense, 1 in-frame indel) reported in 16 probands in 5 publications (PMIDs: 19232556, 21964829, 20425821, 20577006, 27530454) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is suggested to be gain of function (PMID: 31463371). This gene-disease association is also supported by experimental evidence including expression studies and in vitro functional assays (PMIDs: 31463371, 26249260, 19790068). Of note, variants in this gene have also been shown to cause spondyloepimetaphyseal dysplasia Maroteaux type, spondylometaphyseal dysplasia Kozlowski type, brachyolmia, and familial digital arthropathy with brachydactyly, which comprise a spectrum of phenotypes and will be curated separately. In some cases, there is overlap between skeletal and neuromuscular phenotypes caused by variants in TRPV4 (PMID: 31191204). Patients presenting with skeletal dysplasias may benefit from neurological, respiratory, and audiological evaluations. In summary, TRPV4 is definitively associated with autosomal dominant metatropic dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ClinGen Skeletal Disorders Gene Curation Expert Panel on 12/8/20 (SOP Version 8).