Diversity of Dystrophin Gene Mutations and Disease Progression in a Contemporary Cohort of Duchenne Muscular Dystrophy

Katheryn E. Gambetta*, Michael A. McCulloch, Ashwin K. Lal, Kenneth Knecht, Ryan J. Butts, Chet R. Villa, Jonathan N. Johnson, Jennifer Conway, Matthew J. Bock, Kurt R. Schumacher, Sabrina P. Law, Joshua M. Friedland-Little, Shriprasad R. Deshpande, Shawn C. West, Irene D. Lytrivi, Carol A. Wittlieb-Weber

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Abnormal dystrophin production due to mutations in the dystrophin gene causes Duchenne Muscular Dystrophy (DMD). Cases demonstrate considerable genetic and disease progression variability. It is unclear if specific gene mutations are prognostic of outcomes in this population. We conducted a retrospective cohort study of DMD patients followed at 17 centers across the USA and Canada from 2005 to 2015 with goal of understanding the genetic variability of DMD and its impact on clinical outcomes. Cumulative incidence of clinically relevant outcomes was stratified by genetic mutation type, exon mutation location, and extent of exon deletion. Of 436 males with DMD, 324 (74.3%) underwent genetic testing. Deletions were the most common mutation type (256, 79%), followed by point mutations (45, 13.9%) and duplications (23, 7.1%). There were 131 combinations of mutations with most mutations located along exons 45 to 52. The number of exons deleted varied between 1 and 52 with a median of 3 exons deleted (IQR 1–6). Subjects with mutations starting at exon positions 40–54 had a later onset of arrhythmias occurring at median age 25 years (95% CI 18–∞), p = 0.01. Loss of ambulation occurred later at median age of 13 years (95% CI 12–15) in subjects with mutations that started between exons 55–79, p = 0.01. There was no association between mutation type or location and onset of cardiac dysfunction. We report the genetic variability in DMD and its association with timing of clinical outcomes. Genetic modifiers may explain some phenotypic variability.

Original languageEnglish (US)
Pages (from-to)855-867
Number of pages13
JournalPediatric cardiology
Issue number4
StatePublished - Apr 2022


  • Cardiomyopathy
  • Duchenne Muscular Dystrophy
  • Dystrophin
  • Genetics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pediatrics, Perinatology, and Child Health


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