TY - JOUR T1 - Delineation of a new fibrillin-2-opathy with evidence for a role of <em>FBN2</em> in the pathogenesis of carpal tunnel syndrome JF - Journal of Medical Genetics JO - J Med Genet SP - 778 LP - 782 DO - 10.1136/jmedgenet-2020-107085 VL - 58 IS - 11 AU - Silke Peeters AU - Arne Decramer AU - Stuart Alan Cain AU - Peter Houpt AU - Frederik Verstreken AU - Jan Noyez AU - Christophe Hermans AU - Werner Jacobs AU - Martin Lammens AU - Erik Fransen AU - Ajay Anand Kumar AU - Geert Vandeweyer AU - Bart Loeys AU - Wim Van Hul AU - Clair Baldock AU - Eveline Boudin AU - Geert Mortier Y1 - 2021/11/01 UR - http://jmg.bmj.com/content/58/11/778.abstract N2 - 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&gt;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&lt;0.001) and high-impact (6.9% vs 2.7%, p&lt;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. ER -