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

Abstract

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 ( P =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.

PRRX1 Loss‐of‐Function Mutations Underlying Familial Atrial Fibrillation

“…Whole‐exome sequencing (WES) and informatics analyses in 4 affected family members (II‐1, III‐2, III‐3, and IV‐2; Figure 1 ) and 2 unaffected family members (III‐5 and IV‐1; Figure 1 ) were fulfilled as described elsewhere. 58 , 64 , 65 , 66 , 67 In short, for each family member to undergo WES, 3 μg of genomic DNA was fragmented randomly by an ultrasonicator (Covaris, Woburn, MA) to construct a whole‐exome library, and captured with the SureSelect Human All Exon V6 Kit (Agilent Technologies, Santa Clara, CA) as per the manufacturer’s protocol. The captured exome libraries were sequenced under the Illumina HiSeq 2000 Genome Analyzer (Illumina, San Diego, CA), by using the HiSeq Sequencing Kit (Illumina) following the manufacturer’s manual.…”

Therapeutic CFTR Correction Normalizes Systemic and Lung-Specific S1P Level Alterations Associated with Heart Failure

“…CFTR is widely expressed throughout the body (e.g., brain, lung, intestine, etc.) [25,75] and has been reported to be affected during various disease states [11,29,55,61,76], which may make CFTR a yet underexplored target for treatment in diseases other than cystic fibrosis. Similar to trials that verified Ivacaftor efficacy in COPD [77], our studies validate benefits of the CFTR modulator C18 in lung inflammation and cerebrovascular dysfunction [11] that associate with HF in our model.…”