TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy
Abstract
Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 02, 2020
- Source ID
- 10.1038/s41431-019-0563-6
Entities
People
- Alessandra Ferlini
- Amina Chaouch
- Andreas Roos
- Annemieke Aartsma-Rus
- Chiara Scotton
- Craig M. McDonald
- Eric Hoffman
- Erik H. Niks
- Francesco Muntoni
- H. Eka D. Suchiman
- Hanns Lochmüller
- Irina Zaharieva
- Luca Bello
- Mariacristina Scoto
- Mireille Claustres
- Mojgan Reza
- Monika Hiller
- Peter A.C. 't Hoen
- Pietro Spitali
- Sebahattin Cirak
- Stefan Böhringer
- Sylvie Tuffery-giraud
- The Cinrg Investigators
- Zaida Koeks
Organizations
- French Muscular Dystrophy Association
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- United States Department of Defense
- United States Department of Education