A Population-Based Study of Dystrophin Mutations in Canada

Abstract

Introduction:We carried out a population-based study of dystrophin mutations in patients followed by members of the Canadian Paediatric Neuromuscular Group (CPNG) over a ten-year period. Objectives: We aimed to describe the changes in diagnostic testing for dystrophinopathy and to determine the frequency of dystrophin mutations from 2000 to 2009. Methods: De-identified data containing the clinical phenotypes, diagnostic methods, and mutational reports from dystrophinopathy patients followed by CPNG centres from January 2000 to December 2009 were analyzed using descriptive statistics. Results: 773 patients had a confirmed diagnosis of dystrophinopathy based on genetic testing (97%), muscle biopsy (2%), or family history (1%). 573 (74%) had complete deletion/duplication analysis of all 79 exons or whole gene sequencing, resulting in 366 (64%) deletions, 64 (11%) duplications, and 143 (25%) point mutations. The percentage of patients who were diagnosed using currently accepted genetic testing methods varied across Canada, with a mean of 63% (SD 23). 246 (43%) mutations involved exons 45 to 53. The top ten deletions (n=147, 26%) were exons 45-47, 45-48, 45, 45-50, 45-55, 51, 45-49, 45-52, 49-50, and 46-47. 169 (29%) mutations involved exons 2 to 20. The most common duplications (n=29, 5.1%) were exons 2, 2-7, 2-17, 3-7, 8-11, 10, 10-11, and 12. Conclusion: This is the most comprehensive report of dystrophin mutations in Canada. Consensus guidelines regarding the diagnostic approach to dystrophinopathy will hopefully reduce the geographical variation in mutation detection rates in the coming decade.RÉSUMÉ: Étude de population sur les mutations de la dystrophine au Canada. Contexte : Nous avons effectué une étude de population sur les mutations du gène de la dystrophine chez des patients suivis par des membres du Canadian Paediatric Neuromuscular Group (CPNG) au cours d'une période de 10 ans. Objectifs : Notre but était de décrire l'évolution des tests diagnostiques des dystrophinopathies et de déterminer la fréquence des mutations du gène de la dystrophine de 2000 à 2009. Méthode : Nous avons analysé par des méthodes statistiques descriptives des données anomymisées, soit le phénotype clinique, les méthodes diagnostiques et l'identification de la mutation, chez des patients atteints de dystrophinopathies suivis dans des centres du CPNG de janvier 2000 à décembre 2009. Résultats : Un diagnostic de dystrophinopathie, confirmé par un test génétique (97%), une biopsie musculaire (2%) ou une histoire familiale (1%), a été posé chez 773 patients. Chez 573 patients (74%) une analyse complète des délétions/duplications des 79 exons ou un séquençage complet du gène a été effectué. Nous avons identifié des délétions chez 366 (64%) patients, des duplications chez 64 (11%) et des mutations ponctuelles chez 143 (25%). Le pourcentage de patients chez qui le diagnostic de la maladie a été posé au moyen d'un test génétique dont la méthode de laboratoire est actuellement reconnue, était variable à travers le Canada, soit c...

CUGC for Duchenne muscular dystrophy (DMD)

“…Studies using single platform mutational analysis have reported sensitivities between 92 and 99% [32,34,42]. Deep intronic variants can be characterised through directed sequencing based on results from sequencing cDNA derived from skeletal muscle mRNA [43].…”

Clinical Utility Gene Card for: Becker muscular dystrophy

“…Array CGH can identify complex rearrangements that go undetected by MLPA [36]. Directed sequencing based on results from sequencing cDNA derived from skeletal muscle mRNA can reveal variants affecting splicing, including those located within deep intronic regions [37].…”

Genetic diagnosis of Duchenne/Becker muscular dystrophy using next-generation sequencing: Validation analysis of DMD mutations

“…We used exons 70-79 as we rarely observed mutations in the patients. [4][5][6] We used the average value of Figure S3).…”

“…3 The mutational spectrum was reported to be as follows: deletions iñ 60% of patients, duplications in~10% of patients and small mutations in~30% of patients, including small insertions or deletions within an exon (~7%) and nonsense mutations (~15%). [4][5][6] Multiplex ligation-dependent probe amplification (MLPA) is a widely used method, and it is the initial diagnostic test of choice in many hospitals. Although MLPA can only diagnose patients with deletions/duplications, another 30% of patients with point mutations need direct sequencing of all coding regions.…”