Heterozygous Cystic Fibrosis Transmembrane Regulator Gene Missense Variants Are Associated With Worse Cardiac Function in Patients With Duchenne Muscular Dystrophy

• Published in: Journal of the American Heart Association Vol. 9; no. 19; p. e016799
• Main Authors: Jiang, Xuan, Shao, Yanqiu, Araj, Faris G, Amin, Alpesh A, Greenberg, Benjamin M, Drazner, Mark H, Xing, Chao, Mammen, Pradeep P A
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 20-10-2020; Wiley
• Subjects: Adult; Brief Communication; Cardiomyopathies - diagnosis; Cardiomyopathies - etiology; Cardiomyopathies - physiopathology; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Duchene muscular dystrophy–associated cardiomyopathy; Dystrophin - genetics; Female; genetic modifier; Genetic Predisposition to Disease; Heart Function Tests - methods; Humans; Magnetic Resonance Imaging, Cine - methods; Male; Muscular Dystrophy, Duchenne - blood; Muscular Dystrophy, Duchenne - complications; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - physiopathology; Mutation, Missense; Natriuretic Peptide, Brain - blood; Peptide Fragments - blood; Stroke Volume; Ventricular Dysfunction, Left - diagnosis; Ventricular Dysfunction, Left - etiology; whole exome sequencing; Whole Exome Sequencing - methods; Duchene muscular dystrophy–associated cardiomyopathy; genetic modifier; whole exome sequencing
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.120.016799

Background Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by mutations within the dystrophin gene. DMD is characterized by progressive skeletal muscle degeneration and atrophy and progressive cardiomyopathy. It has been observed the severity of cardiomyopathy varies in patients with DMD. Methods and Results A cohort of male patients with DMD and female DMD carriers underwent whole exome sequencing. Potential risk factor variants were identified according to their functional annotations and frequencies. Cardiac function of 15 male patients with DMD was assessed by cardiac magnetic resonance imaging, and various cardiac magnetic resonance imaging parameters and circulating biomarkers were compared between genotype groups. Five subjects carrying potential risk factor variants in the cystic fibrosis transmembrane regulator gene demonstrated lower left ventricular ejection fraction, larger left ventricular end-diastolic volume, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels compared with 10 subjects who did not carry the potential risk factor variants (
=0.023, 0.019 and 0.028, respectively). Conclusions This study revealed heterozygous cystic fibrosis transmembrane regulator gene missense variants were associated with worse cardiac function in patients with DMD. The cystic fibrosis transmembrane regulator gene may serve as a genetic modifier that accounts for more severe cardiomyopathy in patients with DMD, who would require more aggressive management of the cardiomyopathy.