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Novel disease loci
Short report
Delineation of a new fibrillin-2-opathy with evidence for a role of FBN2 in the pathogenesis of carpal tunnel syndrome
  1. Silke Peeters1,
  2. Arne Decramer2,
  3. Stuart Alan Cain3,
  4. Peter Houpt4,
  5. Frederik Verstreken5,
  6. Jan Noyez2,
  7. Christophe Hermans6,
  8. Werner Jacobs7,
  9. Martin Lammens8,
  10. Erik Fransen1,
  11. Ajay Anand Kumar1,9,
  12. Geert Vandeweyer1,10,
  13. Bart Loeys1,
  14. Wim Van Hul1,
  15. Clair Baldock3,
  16. Eveline Boudin1,
  17. Geert Mortier1
  1. 1 Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium
  2. 2 Department of Orthopaedics and Traumatology, AZ Delta, Roeselare, Belgium
  3. 3 Division of Cell-Matrix Biology and Regenerative Medicine, Wellcome Centre for Cell-Matrix Research, The University of Manchester, Manchester, UK
  4. 4 Department of Plastic Surgery, Isala Clinic Zwolle, Zwolle, The Netherlands
  5. 5 Department of Orthopaedic Surgery, AZ Monica, Deurne, Belgium
  6. 6 Center for Oncological Research Antwerp (CORE), University of Antwerp, Edegem, Belgium
  7. 7 Department of Forensic Medicine and Pathology, Antwerp University Hospital and University of Antwerp, Edegem, Belgium
  8. 8 Department of Pathological Anatomy, Antwerp University Hospital, Edegem, Belgium
  9. 9 Department of Paediatrics, Wellcome-MRC Cambridge Stem Cell Institute Cambridge, Cambridge University, Cambridge, UK
  10. 10 Biomedical Informatics Research Network Antwerp (Biomina), University of Antwerp, Edegem, Belgium
  1. Correspondence to Dr Geert Mortier, Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium; geert.mortier{at}uantwerpen.be

Abstract

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
  • orthopedics

https://doi.org/10.1136/jmedgenet-2020-107085

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    Footnotes

    • Twitter @geertvandeweyer

    • Correction notice This article has been corrected since it was published Online First. The title has been amended.

    • 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.

    • Provenance and peer review Not commissioned; externally peer reviewed.