Submission Details

TRPV4 was first reported in relation to autosomal dominant brachyolmia (BO) in 2008 (Rock et al., PMID: 18587396). This disorder is characterized by “short trunk, scoliosis and mild short stature” (Rock et al., PMID: 18587396). At least 4 missense variants in TRPV4 have been reported in at least 4 probands diagnosed with BO in 3 publications (PMIDs: 18587396, 24677493, 22791502). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. The mechanism of pathogenicity is suggested to be gain of function (PMID: 31463371). This gene-disease relationship is also supported by expression studies and in vitro functional assays (PMIDs: 18762026, 19790068, 21964574, 20605796). Variants in this gene have also been shown to cause metatropic dysplasia, spondylometaphyseal dysplasia Kozlowski type (SMD-K), spondyloepimetaphyseal dysplasia Maroteaux type (SMD-M), 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: 22419508). Patients presenting with skeletal dysplasias may benefit from neurological, respiratory, and audiological evaluations. There were also probands that present with intermediate phenotypes between BO and spondylometaphyseal dysplasia Kozlowski type (SMD-K) particularly. Intermediate probands were not counted in this curation. In summary, there is moderate but suggestive evidence to support this gene-disease relationship. While more published evidence is needed to establish this relationship definitively, no convincing contradictory evidence has been published. This curation was approved by the ClinGen Skeletal Disorders Gene Curation Expert Panel on 9/1/21 (SOP Version 8).