UCLA

Background Duchenne muscular dystrophy (DMD) is caused by mutations in one gene, DMD, that disrupts production of functional dystrophin and consistently results in skeletal myopathy and wheelchair requirement for ambulation typically by early teenage years. DMD results in nearly universal left ventricular (LV)-predominant cardiomyopathy; however, cardiomyopathy phenotype varies significantly, suggesting influences beyond the dystrophin gene. Objectives We sought to identify variation in genes that could explain this variability. Methods Whole genome sequencing (WGS) was conducted and compared to cardiac magnetic resonance (CMR) phenotypic measurements in boys with DMD enrolled in a previously completed clinical trial (NCT01521546). A list of myocardial-specific genes was generated from prior transcriptomic studies and a large population-based genome-wide association study of all dilated cardiomyopathies; this was further reduced to those with rare, exonic, and nonsynonymous variants, indicating potential for protein alteration. Results LV ejection fraction (LVEF) averaged 55 ± 8% in this cohort of 38 boys age 14 [12–18] years. Myocardial disease ranged from mild to moderate by LV systolic circumferential strain (−15.5 [−12.1 to −17.4]%) and by LV extent of scar by late gadolinium enhancement (LGE) (2 [1 to 5] segments). Among 173 genes, the rare variant burden in ATP10A was strongly associated with LVEF. Association between XIRP2 variants and LGE burden narrowly missed the Bonferroni threshold, and none were associated with LV strain. Conclusion ATP10A and XIRP2 haplotypes are variably associated with myocardial disease severity in DMD. Prospective studies to examine their impact on cardiomyopathy progression and treatment response warrant consideration.