Dystrophin Genotype–Cardiac Phenotype Correlations in Duchenne and Becker Muscular Dystrophies Using Cardiac Magnetic Resonance Imaging

Animesh Tandon, John L. Jefferies, Chet R. Villa, Kan N. Hor, Brenda L. Wong, Stephanie M. Ware, Zhiqian Gao, Jeffrey A. Towbin, Wojciech Mazur, Robert J. Fleck, Joshua J. Sticka, D. Woodrow Benson, Michael D. Taylor

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Duchenne and Becker muscular dystrophies are caused by mutations in dystrophin. Cardiac manifestations vary broadly, making prognosis difficult. Current dystrophin genotype–cardiac phenotype correlations are limited. For skeletal muscle, the reading-frame rule suggests in-frame mutations tend to yield milder phenotypes. We performed dystrophin genotype–cardiac phenotype correlations using a protein-effect model and cardiac magnetic resonance imaging. A translational model was applied to patient-specific deletion, indel, and nonsense mutations to predict exons and protein domains present within truncated dystrophin protein. Patients were dichotomized into predicted present and predicted absent groups for exons and protein domains of interest. Development of myocardial fibrosis (represented by late gadolinium enhancement [LGE]) and depressed left ventricular ejection fraction (LVEF) were compared. Patients (n = 274) with predicted present cysteine-rich domain (CRD), C-terminal domain (CTD), and both the N-terminal actin-binding and cysteine-rich domains (ABD1 + CRD) had a decreased risk of LGE and trended toward greater freedom from LGE. Patients with predicted present CTD (exactly the same as those with in-frame mutations) and ABD1 + CRD trended toward decreased risk of and greater freedom from depressed LVEF. In conclusion, genotypes previously implicated in altering the dystrophinopathic cardiac phenotype were not significantly related to LGE and depressed LVEF. Patients with predicted present CRD, CTD/in-frame mutations, and ABD1 + CRD trended toward milder cardiac phenotypes, suggesting that the reading-frame rule may be applicable to the cardiac phenotype. Genotype–phenotype correlations may help predict the cardiac phenotype for dystrophinopathic patients and guide future therapies.

Original languageEnglish (US)
Pages (from-to)967-971
Number of pages5
JournalAmerican Journal of Cardiology
Volume115
Issue number7
DOIs
StatePublished - Apr 1 2015

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Dystrophin
Duchenne Muscular Dystrophy
Cysteine
Magnetic Resonance Imaging
Phenotype
Gadolinium
Stroke Volume
Reading Frames
Mutation
Exons
Nonsense Codon
Sequence Deletion
Actins
Skeletal Muscle
Proteins
Fibrosis
Genotype

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Dystrophin Genotype–Cardiac Phenotype Correlations in Duchenne and Becker Muscular Dystrophies Using Cardiac Magnetic Resonance Imaging. / Tandon, Animesh; Jefferies, John L.; Villa, Chet R.; Hor, Kan N.; Wong, Brenda L.; Ware, Stephanie M.; Gao, Zhiqian; Towbin, Jeffrey A.; Mazur, Wojciech; Fleck, Robert J.; Sticka, Joshua J.; Benson, D. Woodrow; Taylor, Michael D.

In: American Journal of Cardiology, Vol. 115, No. 7, 01.04.2015, p. 967-971.

Research output: Contribution to journalArticle

Tandon, A, Jefferies, JL, Villa, CR, Hor, KN, Wong, BL, Ware, SM, Gao, Z, Towbin, JA, Mazur, W, Fleck, RJ, Sticka, JJ, Benson, DW & Taylor, MD 2015, 'Dystrophin Genotype–Cardiac Phenotype Correlations in Duchenne and Becker Muscular Dystrophies Using Cardiac Magnetic Resonance Imaging', American Journal of Cardiology, vol. 115, no. 7, pp. 967-971. https://doi.org/10.1016/j.amjcard.2015.01.030
Tandon, Animesh ; Jefferies, John L. ; Villa, Chet R. ; Hor, Kan N. ; Wong, Brenda L. ; Ware, Stephanie M. ; Gao, Zhiqian ; Towbin, Jeffrey A. ; Mazur, Wojciech ; Fleck, Robert J. ; Sticka, Joshua J. ; Benson, D. Woodrow ; Taylor, Michael D. / Dystrophin Genotype–Cardiac Phenotype Correlations in Duchenne and Becker Muscular Dystrophies Using Cardiac Magnetic Resonance Imaging. In: American Journal of Cardiology. 2015 ; Vol. 115, No. 7. pp. 967-971.
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