Scientists at the Icahn School of Medicine at Mount Sinai have uncovered new genetic interactions that may contribute to congenital heart disease (CHD), one of the most common birth defects worldwide.
Their findings, published in The American Journal of Human Genetics, reveal that CHD may often result from the combined effects of two interacting genes, rather than a single gene mutation.
This discovery could improve diagnosis, risk assessment, and future treatments for children born with CHD.
Congenital heart disease affects millions of newborns every year, yet in more than half of cases, the exact genetic cause remains unknown.
Traditional genetic research has mainly focused on single-gene mutations (monogenic causes), but this new study suggests that digenic inheritance—where two specific genes work together to trigger the disease—may be a significant factor in CHD development.
According to Dr. Yuval Itan, one of the study’s senior authors, this research uncovers “hidden genetic risks” by identifying gene pairs that interact to cause CHD. This knowledge could lead to more precise diagnoses and personalized treatments for affected individuals.
To explore genetic interactions in CHD, researchers analyzed trio exome sequencing data—which examines the DNA of both parents and their child—from the Pediatric Genomic Consortium (PCGC).
By comparing the genetic makeup of children with and without CHD, they identified 10 new gene pairs that may be linked to the disease.
The study’s lead author, Dr. Meltem Ece Kars, explains that these findings challenge the traditional view that only single-gene mutations cause CHD. Instead, certain gene combinations may work together to disrupt heart development.
This discovery could broaden the scope of genetic testing, helping doctors identify at-risk families earlier and provide more accurate genetic counseling.
Current genetic tests often fail to detect the cause of CHD in many patients. If digenic inheritance plays a key role, integrating this new model into clinical genetic testing could significantly increase diagnostic success rates. For families affected by CHD, this means:
- Better risk assessments for future pregnancies
- More clarity on the genetic cause of their child’s condition
- Potential for personalized treatments based on genetic profiles
Additionally, these findings could apply to other complex diseases beyond CHD. Many disorders with unclear genetic origins—such as neurological conditions, metabolic disorders, and immune system diseases—might also involve hidden gene interactions.
What’s Next?
The research team plans to expand this digenic approach to other diseases traditionally studied using single-gene models. Their ultimate goal is to develop a polygenic framework, which could identify multiple interacting genetic factors in diseases where the exact cause is still unknown.
Dr. Kars believes this work has the potential to transform how genetic diseases are diagnosed and treated, leading to more targeted therapies for individuals with congenital heart disease and other inherited conditions.
By shifting the focus from single genes to gene interactions, this study opens new doors for understanding the hidden complexity of genetic diseases—offering hope for better diagnostics, early interventions, and improved patient carein the future.
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The research findings can be found in The American Journal of Human Genetics.
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