By Esther Samson
Scientists at the Icahn School of Medicine at Mount Sinai, in collaboration with other research teams, have made groundbreaking discoveries regarding the genetic interactions behind congenital heart disease (CHD), one of the most common birth defects.
The study, published in The American Journal of Human Genetics, suggests that genetic interactions, rather than single-gene causes, may play a critical role in the development of CHD.
Associate Professor of Genetics and Genomic Sciences, Dr. Yuval Itan, at Mount Sinai and co-corresponding senior author, explained, “Our research reveals the potential for digenic inheritance—where two genes work together to cause disease—expanding our understanding of the genetic factors behind congenital heart disease.”
CHD is the most common congenital anomaly worldwide, yet over half of the cases remain without a clear molecular diagnosis.
According to the study, researchers analyzed trio exome sequencing data from both affected and unaffected children in the Pediatric Genomic Consortium (PCGC), identifying 10 novel gene pairs that may be linked to the disease.
Dr. Bruce Gelb, Gogel Family Professor and Director of The Mindich Institute, who co-supervised the study, added, “By identifying these gene pairs and understanding their combined effects, we uncover previously hidden genetic risks, which could improve diagnostic precision and open new avenues for personalized treatment strategies.”
First author Dr. Meltem Ece Kars, a postdoctoral fellow at Mount Sinai, highlighted the significance of their findings: “Our work demonstrates that genetic interactions, rather than single-gene causes alone, could play a significant role in congenital heart disease.
By developing a method to uncover these interactions, we are broadening the scope of genetic research, which could lead to improved diagnosis, enhanced risk assessment, and more informed genetic counseling.”
She also emphasized the potential impact of their research on clinical genetic testing: “As clinical genetic testing advances, integrating digenic models could significantly improve diagnostic yield, offering patients and their families greater clarity about their condition and guiding the development of targeted therapies and interventions.”
The study’s use of innovative computational methods to identify gene pairs that may act together to cause CHD could transform how genetic studies are conducted for complex diseases.
Dr. Itan stated, “With the tools we’ve developed, our research provides a framework for future studies into genetic interactions that could affect a wide range of human diseases.”
Moving forward, the team plans to apply the digenic approach to other complex diseases traditionally studied using the monogenic model.
Dr. Itan added, “We aim to extend the digenic approach into a robust polygenic framework capable of identifying multiple disease-causing variants and genes in patients.”
Dr. Kars concluded, “Our findings hold promise for improving genetic diagnoses, offering better risk assessments, and ultimately guiding more personalized treatments for individuals with congenital heart disease.”
