Nine genes, including ESRRA and GEMIN4, were identified as potential modifiers of cardiomyopathy severity in 54 DMD patients, of which 33% had severe cardiomyopathy.
Variant burden analysis identified nine potential genetic modifiers of cardiomyopathy severity in Duchenne Muscular Dystrophy, highlighting pathways such as insulin resistance and inflammation for future therapeutic targeting.
Absolute Event Rate: 0% vs 0%
Abstract Background This study was designed to identify genes for further study as modifiers of the severity of cardiomyopathy in DMD- related Duchenne Muscular Dystrophy (DMD). Methods We evaluated genome sequencing results in a well-phenotyped DMD cohort with severe cardiomyopathy against those with less severe cardiomyopathy. Using combined annotation-dependent depletion variant annotation to look at variant burden, we created a difference between group mean (DBGM) summative C-Scores by gene. We completed analyses on three groups. For each analysis, we normalized DBGM summative C-Score and determined which genes had a value > three standard deviations from the mean in all three analyses. Results There were 54 DMD males in this analysis. 18 individuals (33%) had severe cardiomyopathy and 36 individuals (67%) had less severe cardiomyopathy. Nine genes were identified as possible cardiomyopathy severity modifiers: ANKLE1 , ESRRA , FRAS1 , GEMIN4 , GXYLT1 , MTCH2 , PKD1L2 , PRSS2 and QRFPR . Conclusion DBGM summative C-Scores in well-phenotyped groups are a feasible exploratory method to identify genetic targets for additional study. There is preliminary evidence from this and other studies suggesting further evaluation of ESRRA , GEMIN4 , and MTCH2 as modifiers of cardiomyopathy severity could advance understanding of DMD cardiomyopathy progression. Impact This article identifies possible genetic modifiers of DMD cardiomyopathy severity via a novel method of looking at variant burden between groups. This adds to the existing literature by providing new evidence for modifier pathway targets for possible therapeutic targets or drug repurposing in a rare genetic disorder.
Geddes et al. (Wed,) reported a other. Nine genes, including ESRRA and GEMIN4, were identified as potential modifiers of cardiomyopathy severity in 54 DMD patients, of which 33% had severe cardiomyopathy.