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Background <p>This study was designed to identify genes for further study as modifiers of the severity of cardiomyopathy in <i>DMD-</i>related Duchenne Muscular Dystrophy (DMD).</p> Methods <p>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 &gt; three standard deviations from the mean in all three analyses.</p> Results <p>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: <i>ANKLE1</i>, <i>ESRRA</i>, <i>FRAS1</i>, <i>GEMIN4</i>, <i>GXYLT1</i>, <i>MTCH2</i>, <i>PKD1L2</i>, <i>PRSS2</i> and <i>QRFPR</i>.</p> Conclusion <p>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 <i>ESRRA</i>, <i>GEMIN4</i>, and <i>MTCH2</i> as modifiers of cardiomyopathy severity could advance understanding of DMD cardiomyopathy progression.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>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.</p> </ItemContent> </UnorderedList></p>

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Variant burden and severity of cardiomyopathy in patients with DMD-related Duchenne muscular dystrophy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月7日

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  • Gabrielle C. Geddes,
  • Stephanie M. Ware,
  • Tae-Hwi Schwantes-An,
  • Marco A. Abreu,
  • John J. Parent,
  • Conner C. Earl,
  • Jonathan H. Soslow,
  • Larry W. Markham

摘要

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.