TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy.,European Journal of Human Genetics

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TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy.
European Journal of Human Genetics ( IF 3.7 ) Pub Date : 2020-01-02 , DOI: 10.1038/s41431-019-0563-6
Pietro Spitali ₁ , Irina Zaharieva ₂ , Stefan Bohringer ₃ , Monika Hiller ₁ , Amina Chaouch _{4,

5} , Andreas Roos ₄ , Chiara Scotton ₆ , Mireille Claustres ₇ , Luca Bello _{8,

9} , Craig M McDonald ₁₀ , Eric P Hoffman ₈ , , Zaida Koeks ₁₁ , H Eka Suchiman ₁₂ , Sebahattin Cirak _{2,

13,

14} , Mariacristina Scoto ₂ , Mojgan Reza ₄ , Peter A C 't Hoen ₁ , Erik H Niks ₁₁ , Sylvie Tuffery-Giraud ₇ , Hanns Lochmüller _{4,

15,

16} , Alessandra Ferlini ₆ , Francesco Muntoni _{2,

17} , Annemieke Aartsma-Rus _{1,

4}

Affiliation

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Dubowitz Neuromuscular Centre, University College London Great Ormond Street Institute of Child Health, London, UK.
Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne, UK.
Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Salford, UK.
Department of Medical Sciences, Section of Microbiology and Medical Genetics, University of Ferrara, Ferrara, Italy.
Laboratory of Genetics of Rare Diseases (LGMR - EA7402), University of Montpellier, Montpellier, France.
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA.
Department of Neuroscience, University of Padova, Padova, Italy.
University of California Davis Medical Center, Sacramento, CA, USA.
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Pediatrics, University Hospital Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.
Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada.
National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, UK.

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.

中文翻译：

TCTEX1D1是杜兴氏肌营养不良症疾病进展的遗传修饰因子。

Duchenne肌营养不良症（DMD）是由DMD基因中的致病变异引起的，导致缺乏肌营养不良蛋白。疾病过程的可变性表明其他因素影响疾病的进展。通过这项研究，我们旨在确定可能导致临床表现变异的遗传因素。我们比较了27位具有极端表型的DMD患者的全外显子测序（WES）数据，以确定可能影响疾病进展的候选变体。在两个独立的队列中分别对候选SNP进行了验证，包括301（BIO-NMD队列）和109（欧洲血统的CINRG队列）DMD患者。Tctex1域中包含1号（TCTEX1D1）基因的Tctex1域中的变异与走动丧失的年龄有关。两个独立变体的次要等位基因，已知会影响TCTEX1D1编码序列并诱导其第4外显子跳过的人，与较早的下床活动有关。我们的数据表明DMD的疾病进展受到1号染色体上新位点的影响，并证明了通过研究具有极端表型的患者的WES数据并进行多层验证，可以鉴定罕见疾病中的遗传修饰因子。

更新日期：2020-01-02

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