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February 26, 2025 – New York, NY – Scientists at the Icahn School of Medicine at Mount Sinai, in collaboration with other research institutions, have uncovered new genetic interactions that could play a significant role in congenital heart disease (CHD), one of the most common birth defects worldwide. Their groundbreaking findings were recently published in The American Journal of Human Genetics.
“Our research reveals the potential for digenic inheritance—where two genes work together to cause disease—expanding our understanding of the genetic underpinnings of congenital heart disease,” said Dr. Yuval Itan, PhD, Associate Professor of Genetics and Genomic Sciences and a core member of The Charles Bronfman Institute for Personalized Medicine at Mount Sinai. He co-supervised the study alongside Dr. Bruce Gelb, MD, Director of The Mindich Child Health and Development Institute at the Icahn School of Medicine.
A New Perspective on CHD Genetics
Congenital heart disease is the most common congenital anomaly, impacting millions of newborns each year. Despite extensive research, over 50% of CHD cases remain without a clear molecular diagnosis. In this study, researchers analyzed trio exome sequencing data—comparing genetic information from affected and unaffected children—collected by the Pediatric Genomic Consortium (PCGC). Through this approach, they identified 10 novel gene pairs that could contribute to the development of CHD.
“Our work demonstrates that genetic interactions, rather than single-gene mutations alone, may play a crucial role in congenital heart disease. By identifying these gene pairs and their combined effects, we are broadening the scope of genetic research, which could lead to improved diagnosis, enhanced risk assessment, and more informed genetic counseling,” said lead author Dr. Meltem Ece Kars, MD, PhD, a postdoctoral fellow at The Bronfman Institute.
Cutting-Edge Computational Approaches
The researchers employed an advanced computational method to pinpoint gene pairs that may work together to trigger CHD. This technique represents a significant leap in genetic research, as it allows scientists to explore the complex interactions between genes that could contribute to disease formation.
“Our study provides a framework for future research on genetic interactions, not just for congenital heart disease but also for other complex disorders. With the tools we’ve developed, we hope to uncover hidden genetic risks across a wide range of diseases,” said Dr. Itan.
Looking ahead, the research team aims to apply their digenic model to other diseases traditionally studied using a single-gene approach. This could help explain some of the missing heritability in these disorders. Their ultimate goal is to develop a comprehensive polygenic framework capable of identifying multiple disease-causing variants in patients, leading to more personalized treatment strategies.
“Our findings hold promise for improving genetic diagnoses, offering better risk assessments, and ultimately guiding more personalized treatments for individuals with congenital heart disease,” added Dr. Kars.
Reference: “Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data” by Meltem Ece Kars, David Stein, Peter D. Stenson, David N. Cooper, Wendy K. Chung, Peter J. Gruber, Christine E. Seidman, Yufeng Shen, Martin Tristani-Firouzi, Bruce D. Gelb, and Yuval Itan, published on February 20, 2025, in The American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2025.01.024
Funding and Support: This research was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) and the U.S. Department of Health and Human Services through multiple grants, including UM1HL128711, UM1HL098162, UM1HL098147, UM1HL098123, UM1HL128761, and U01HL131003. Additional funding was provided through the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences.
Disclaimer: This article summarizes recent scientific research and is intended for informational purposes only. It does not constitute medical advice or diagnosis. Individuals with concerns about congenital heart disease should consult a qualified healthcare professional for personalized guidance.
