RT Journal Article SR Electronic T1 Delineation of a new fibrillin-2-opathy with evidence for a role of FBN2 in the pathogenesis of carpal tunnel syndrome JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 778 OP 782 DO 10.1136/jmedgenet-2020-107085 VO 58 IS 11 A1 Silke Peeters A1 Arne Decramer A1 Stuart Alan Cain A1 Peter Houpt A1 Frederik Verstreken A1 Jan Noyez A1 Christophe Hermans A1 Werner Jacobs A1 Martin Lammens A1 Erik Fransen A1 Ajay Anand Kumar A1 Geert Vandeweyer A1 Bart Loeys A1 Wim Van Hul A1 Clair Baldock A1 Eveline Boudin A1 Geert Mortier YR 2021 UL http://jmg.bmj.com/content/58/11/778.abstract AB 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.