TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy

CINRG Investigators

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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 (US)
JournalEuropean Journal of Human Genetics
StateAccepted/In press - 2020

Bibliographical note

Funding Information:
Acknowledgements We acknowledge Raimo Tanzi and Vincent Pignol for the technical support for sequencing and data analysis. We acknowledge Dr Teresinha Evangelista, Dr Michela Guglieri, Dr Chiara Marini-Bettolo, Dr Antonio Atalaia, Dr Volker Straub and Dr Kate Bushby for following up the patients and collecting samples. We acknowledge Dr Stanley F. Nelson and Dr Richard T. Wang (UCLA), and Dr Akanchha Kesari and Dr Jaya Punetha for generating genotype data for the CINRG cohort. We acknowledge all CINRG investigators for collecting the clinical data and samples used for the validation. This work was supported by the European Commission FP7 funded grant “Bio-NMD: Identifying and validating pre-clinical biomarkers for diagnostics and therapeutics of Neuromuscular Disorders” (HEALTH-2009-2.4.4-1: Rare neurological diseases), grant agreement 241665. The work was also funded by the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 305121 “Integrated European Project on Omics Research of Rare Neuromuscular and Neurodegenerative Diseases (NEUROMICS)” and grant agreement n° 305444 “RD-Connect”. PS would like to acknowledge the Association Française contre les Myopathies (grants n. 17013 and 17724) for supporting this work. FM is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The support of the Muscular Dystrophy UK to the Dubowitz Neuromuscular Centre and of the MRC Neuromuscular Centre Biobank is also gratefully acknowledged. This study was also partially supported by the NIHR grant “Rare Diseases Translational Research Collaboration” on Duchenne muscular dystrophy to FM. CINRG was supported by grants from the US Department of Defense (grant #W81XWH-12-1-0417), US Department of Education/NIDRR (grants #H133B031118, #H133B090001), and US National Institutes of Health/NIAMS (grant #R01AR061875). SC is supported by the German Research Foundation (DFG CI 218/1–1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2020, The Author(s).

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