NYC Gazette

Scientists at the Icahn School of Medicine at Mount Sinai, in collaboration with other researchers, have discovered new genetic interactions that may play a role in congenital heart disease (CHD). This finding was published on February 20 in The American Journal of Human Genetics.

Co-corresponding senior author Yuval Itan, PhD, stated, "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." He emphasized that identifying these gene pairs and their effects could improve diagnostic accuracy and lead to personalized treatment strategies. Dr. Itan supervised the study alongside Bruce Gelb, MD.

Congenital heart disease is a prevalent birth defect affecting millions globally. Despite extensive research efforts, over half of CHD cases still lack a molecular diagnosis. The research team analyzed trio exome sequencing data from both affected and unaffected children within the Pediatric Genomic Consortium (PCGC), leading to the identification of 10 novel gene pairs potentially linked to CHD development.

First author Meltem Ece Kars, MD, PhD, noted, "Our work demonstrates that genetic interactions, rather than single-gene causes alone, could play a significant role in congenital heart disease." She added that integrating digenic models into clinical genetic testing could enhance diagnostic outcomes and guide targeted therapies.

The researchers employed a computational method to identify gene pairs acting together to cause CHD. This approach might change how genetic studies are conducted for complex diseases by providing deeper insights into genetics' role in disease development.

Dr. Itan remarked that their tools offer a framework for future studies on genetic interactions affecting various human diseases. Researchers plan to apply this digenic approach to other diseases traditionally studied with monogenic models. Ultimately, they aim to extend it into a polygenic framework capable of identifying multiple disease-causing variants and genes.

"Our findings hold promise for improving genetic diagnoses, offering better risk assessments, and ultimately guiding more personalized treatments for individuals with congenital heart disease," said Dr. Kars.

The paper is titled “Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data.” Other contributors include David Stein from Icahn School of Medicine at Mount Sinai; Peter D. Stenson and David N. Cooper from Cardiff University; Wendy K. Chung from Boston Children’s Hospital and Harvard Medical School; Peter J. Gruber from Yale School of Medicine; Christine E. Seidman from Harvard Medical School; Yufeng Shen from Columbia University Irving Medical Center; and Martin Tristani-Firouzi from University of Utah School of Medicine.

This research received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health and other U.S. Department of Health and Human Services grants.

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