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A Population-Based Study of Dystrophin Mutations in Canada

  • Jean K. Mah (a1), Kathryn Selby (a2), Craig Campbell (a3), Amelie Nadeau (a4), Mark Tarnopolsky (a5), Anna McCormick (a6), Joseph M. Dooley (a7), Hanna Kolski (a8), Andrew J. Skalsky (a9), R. Garth Smith (a10), David Buckley (a11), Peter N. Ray (a12) and Grace Yoon (a13)...

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: 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 chez 63% des patients (ET 23). Deux cent quarante-six (43%) des mutations étaient situées dans les exons 45 à 53. Les 10 délétions les plus fréquentes (n = 147), soit 26%, étaient situées dans les exons 45-47, 45-48, 45, 45-50, 45-55, 51, 45-49, 45-52, 49-50 et 46-47. Cent soixante-neuf mutations (29%) étaient situées dans les exons 2 à 20. Les duplications les plus fréquentes (n = 29), soit 5,1% étaient situées dans les exons 2, 2-7, 2-17, 3-7, 8-11, 10, 10-11 et 12.

Conclusion:

Il s’agit du compte rendu le plus complet sur les mutations du gène de la dystrophine au Canada. D’ici une dizaine d’années, des lignes directrices de consensus concernant l’approche diagnostique des dystrophinopathies réduiront sans doute les disparités géographiques dans le taux de détection des mutations du gène de la dystrophine.

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Copyright

Corresponding author

Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, T3B 6A8, Canada

References

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A Population-Based Study of Dystrophin Mutations in Canada

  • Jean K. Mah (a1), Kathryn Selby (a2), Craig Campbell (a3), Amelie Nadeau (a4), Mark Tarnopolsky (a5), Anna McCormick (a6), Joseph M. Dooley (a7), Hanna Kolski (a8), Andrew J. Skalsky (a9), R. Garth Smith (a10), David Buckley (a11), Peter N. Ray (a12) and Grace Yoon (a13)...

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