Genes beyond the main Duchenne mutation may help explain why some people with Duchenne muscular dystrophy (DMD) develop much more severe heart disease than others, according to a study published recently in Pediatric Research.
Researchers found preliminary evidence that several genes may either protect the heart or increase risk, offering new paths for understanding how cardiomyopathy progresses in DMD and how care might be improved in the future.
The analysis included 54 males with DMD. Eighteen individuals, or 33%, had severe cardiomyopathy and 36 individuals, or 67%, had less severe disease. The researchers compared genome sequencing results between these groups using a method that measures how often potentially harmful genetic variants appear in one group versus another. This approach allowed them to look for genes that consistently differed between people with severe and less severe heart involvement.
Heart imaging data were available for most participants. Among those with severe cardiomyopathy, the average age at the most recent cardiac MRI was 15.7 years and average left ventricular ejection fraction was 39.3%, reflecting reduced heart pumping ability.
Late gadolinium enhancement, a sign of heart muscle scarring, was seen in 89% of this group at an average age of 14.8 years. Twelve individuals with severe cardiomyopathy died during the study period at an average age of 19.6 years. In contrast, those with less severe cardiomyopathy had an average ejection fraction of 58.4%, with one death reported at age 23 years.
Read more about the prognosis of DMD
The researchers identified nine genes that stood out across all analyses: ANKLE1, ESRRA, FRAS1, GEMIN4, GXYLT1, MTCH2, PKD1L2, PRSS2 and QRFPR. Variants in five of these genes appeared more often in people with less severe cardiomyopathy, suggesting a possible protective effect. Variants in four genes appeared more often in those with severe disease, suggesting increased risk.
“[T]his method provides no functional evidence of the implications of the genes of interest or the specific variants’ effect on gene function,” explained this study’s authors.
Three genes drew particular interest. ESRRA and MTCH2 are linked to how cells manage energy and mitochondria, the structures that produce energy in heart muscle. GEMIN4 has connections to inflammation and cell stress. These pathways matter in DMD because muscle damage, inflammation, fibrosis and changes in energy use all contribute to heart failure over time.
“Being able to easily connect the final list of genes to pathways clearly relevant to DMD also allowed for us to have support that further evaluation of the genes of interest identified by this method are reasonable targets of future studies,” explained the authors.
For patients and families, this research does not change care today, but it points toward a future where genetic information could help predict heart risk earlier and guide personalized treatment. While more studies are needed, these findings move researchers closer to understanding why heart disease progresses differently in DMD and how to better protect the heart.
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