Although carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. We report here on a unique family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons. We identified a novel heterozygous variant (p.Phe1670Cys) in FBN2 as the cause of disease in this family. A variant burden test in a large cohort of sporadic CTS patients revealed a significantly increased frequency of rare and high-impact FBN2 variants in patient alleles compared to controls. These findings strongly suggest a role of FBN2 in the pathogenesis of CTS. (By Dr. Silke Peeters, https://jmg.bmj.com/content/early/2020/09/07/jmedgenet-2020-107085 )