36 Scopus citations

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.

Original languageEnglish
Pages (from-to)815-825
Number of pages11
JournalEuropean Journal of Human Genetics
Volume28
Issue number6
DOIs
StatePublished - 1 Jun 2020

Funding

FundersFunder number
National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Seventh Framework Programme
National Institute for Health Research
National Institutes of Health
Great Ormond Street Hospital for Children
Omics Research of Rare Neuromuscular and Neurodegenerative Diseases
U.S. Department of Education
University College London
NEUROMICS
Deutsche ForschungsgemeinschaftCI 218/1–1
U.S. Department of Defense81XWH-12-1-0417, W81XWH-12-1-0417
National Institute of Arthritis and Musculoskeletal and Skin DiseasesR01AR061875
European CommissionHEALTH-2009-2.4.4-1
Department of Industry, Innovation, Climate Change, Science, Research and Tertiary Education#H133B031118, #H133B090001
Fondazione TelethonNot Available
FP7 Health241665, 305444, 305121
Association Française contre les Myopathies17013, 17724
National Institute on Disability and Rehabilitation Research133B090001, 133B031118

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