Delineation of a new fibrillino-2-pathy with evidence for a role of FBN2 in the pathogenesis of carpal tunnel syndrome

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Silke Peeters
  • Arne Decramer
  • Peter Houpt
  • Frederik Verstreken
  • Jan Noyez
  • Christophe Hermans
  • Werner Jacobs
  • Martin Lammens
  • Erik Fransen
  • Ajay Anand Kumar
  • Geert Vandeweyer
  • Bart Loeys
  • Wim Van Hul
  • Eveline Boudin
  • Geert Mortier


BACKGROUND: Although carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. An estimated heritability index of 0.46 and an increased familial occurrence indicate that genetic factors must play a role in the pathogenesis.

METHODS AND RESULTS: We report on a family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons resulting in toe walking in childhood. Using exome sequencing, we identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 (FBN2) gene that co-segregated with the phenotype in the family. Functional assays showed that the missense variant impaired integrin-mediated cell adhesion and migration. Moreover, we observed an increased transforming growth factor-β signalling and fibrosis in the carpal tissues of affected individuals. A variant burden test in a large cohort of patients with CTS revealed a significantly increased frequency of rare (6.7% vs 2.5%-3.4%, p<0.001) and high-impact (6.9% vs 2.7%, p<0.001) FBN2 variants in patient alleles compared with controls.

CONCLUSION: The identification of a novel FBN2 variant (p.Phe1670Cys) in a unique family with early onset CTS, together with the observed increased frequency of rare and high-impact FBN2 variants in patients with sporadic CTS, strongly suggest a role of FBN2 in the pathogenesis of CTS.

Bibliographical metadata

Original languageEnglish
JournalJournal of Medical Genetics
Early online date8 Sep 2020
Publication statusE-pub ahead of print - 8 Sep 2020