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.
- human genetics
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Contributors GM devised the project, the main conceptual ideas and proof outline. SP contributed to the design of the study, worked out almost all of the technical details and performed all experiments. EB, WVH, BL, CB and SAC supervised the work, helped with working out technical details and contributed to the interpretation of the results. EF, AAK, GV and SAC performed and supervised (bioinformatics) data analysis and statistical analyses. CH, ML and WJ were involved in the sample preparation, optimisation of histopathological staining procedures, technical support and interpretation of the data. AD, PH, FV and JN collected clinical data and provided blood and tissue samples of the patients. All authors discussed the results and implications and commented on the manuscript.
Funding Supported by grants from the European Community's Seventh Framework Programme (SYBIL; 602300), Methusalem (FFB190208), BBSRC (BB/R008221/1); a predoctoral grant from the University of Antwerp (to SP); a postdoctoral grant from the Research Foundation-Flanders (12A3814N) (to EB); a senior clinical investigator grant from the Research Foundation-Flanders and a ERC consolidator grant (ERC-COG-2017–7 71 945) (to BL).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was reviewed and approved by the Committee for Medical Ethics of the Antwerp University Hospital. The study was also approved by the institutional review boards of each collaborating hospital. The patients provided signed informed consents to participate in the study.
Provenance and peer review Not commissioned; externally peer reviewed.