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TRPV4 – Familial Digital Arthropathy-Brachydactyly

Familial digital arthropathy-brachydactyly (FDAB) is an autosomal dominant, non-inflammatory osteoarthropathy affecting the fingers and toes, characterized by aggressive joint degeneration and shortening of the middle and distal phalanges. Heterozygous missense variants in the TRPV4 gene have been implicated in FDAB across multiple families, with phenotypic overlap noted with Thiemann disease ([PMID:21964574]).

Genetic Evidence

FDAB shows autosomal dominant inheritance with at least five affected individuals in four unrelated families. Three missense variants cluster in the ankyrin-repeat domain: c.809G>T (p.Gly270Val), c.812G>A (p.Arg271His), and c.819C>G (p.Phe273Leu), identified in three independent kindreds ([PMID:21964574]). A father–son pair with Thiemann-type presentations harbored the recurrent c.809G>T (p.Gly270Val) variant, confirming segregation in one additional affected relative ([PMID:31248428]).

Functional Evidence

In vitro expression of p.Gly270Val, p.Arg271Pro and p.Phe273Leu in HEK-293 cells demonstrated deficient cell-surface localization, significantly reduced calcium influx upon agonist stimulation, and loss of hypotonic response compared to wild-type TRPV4, supporting a loss-of-function mechanism ([PMID:21964574]).

Integration and Clinical Utility

Collectively, genetic segregation in multiple families and concordant functional assays establish a moderate level of clinical validity for TRPV4 in FDAB. Diagnostic testing for TRPV4 missense variants in the ankyrin domain can guide early recognition, familial risk assessment, and targeted counseling. Key Take-home: TRPV4 sequencing should be considered in dominant digital arthropathies with brachydactyly to confirm diagnosis and inform management.

References

  • Nature Genetics • 2011 • Mutations in TRPV4 cause an inherited arthropathy of hands and feet. PMID:21964574
  • Orphanet Journal of Rare Diseases • 2019 • Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin? PMID:31248428

Evidence Based Scoring (AI generated)

Gene–Disease Association

Moderate

5 probands in 4 unrelated families; reported father–son segregation; concordant in vitro functional studies

Genetic Evidence

Moderate

5 probands (3 unrelated families, including father–son pair); 3 ankyrin-domain missense variants; autosomal dominant inheritance

Functional Evidence

Moderate

In vitro assays show loss of TRPV4 channel function and impaired hypotonic response for p.Gly270Val, p.Arg271Pro, p.Phe273Leu ([PMID:21964574])