A new study looking into the sex-based differences in the genetic causes of dilated cardiomyopathy (DCM) identifies desmoplakin (DSP) gene variants as a key risk factor in women. Writing in the August 5 issue of the Journal of the American College of Cardiology, the study’s authors revealed that DSP protein-altering variants were nearly three times more prevalent in women than in men (7.3% vs. 2.5%). “This study shows that predicted Loss of Function (pLoF) variants in desmoplakin account for a larger proportion of female patients with DCM compared with male patients, and variants in DSP confer a greater risk of DCM in women,” the authors wrote. Biobank validation Led by Massimo Mangino, PhD, from Imperial College London, the team validated the results in the UK Biobank dataset of nearly half a million individuals. In addition, the study employed whole genome sequencing and rigorous variant curation across 902 clinically diagnosed DCM cases, enabling the authors to pinpoint gene-specific and sex-specific patterns with high precision. “These results have clinical significance,” the study authors said. “DSP variants are associated with adverse outcomes compared with non-DSP variants, and female sex is an adverse prognostic marker in DSP cardiomyopathy, potentially identifying a higher risk subgroup of female patients with DCM.” TTN variant Conversely, truncating variants in the titin (TTN) gene, another common genetic driver of DCM, were more penetrant in men, further highlighting the gene- and sex-specific nature of risk. “We show that variants in DSP show higher penetrance in women and truncating variants in TTN show higher penetrance in men,” said the authors. “Variants in other DCM genes did not appear to account for a different proportion of cases amongst men and women.” The research team suggested that genetic screening and clinical management strategies may need to be sex-specific to better identify and protect high-risk patients, particularly women with DSP mutations. Further research was needed to explore the biological and environmental mechanisms behind these sex-based differences, as well as their implications for personalized treatment and long-term outcomes, they concluded. Sources: Mangino M, Barton PJR, Buchan R, et al. Sex Differences in the Genetic Architecture of Dilated Cardiomyopathy. J Am Coll Cardiol. 2025;86:396–409. Image Credit: Syda Productions – stock.adobe.com