New Genetic Discovery Sheds Light on Rare Heart and Organ Positioning Disorders
Researchers identify a new link between rare genetic pairs and increased risk of laterality defects, according to a new study published in The American Journal of Human Genetics.
Results revealed that rare combinations of genetic variants inherited from both parents may explain a significant number of previously unsolved cases of laterality defects, conditions where internal organs like the heart or stomach are abnormally positioned.
Instead of focusing on single gene mutations, the team explored a “digenic inheritance” model, where two mildly harmful variants in different genes, one from each parent, create an interaction together resulting in congenital heart disease (CHD). To assess this model, authors used a computation tool, DiGePred, to evaluate the likelihood that dysfunction of gene pairs leads to CHD phenotypes such as laterality defects.
Corresponding author Zeynep Coban Akdemir, PhD, and researchers analyzed DNA from nearly 600 children with laterality defects and found that up to 7.3% percent carried rare gene pairs likely responsible for their condition, compared to just 0.3% in healthy individuals.
Most of these gene pairs were involved in the formation and function of cilia, tiny hair-like structures that help determine the body’s left-right orientation during early development.
The DiGePred model confirmed that 29 of 39 gene pairs were biologically likely to contribute to CHD.
“This study highlights the importance of looking beyond single-gene causes and considering how gene interactions can lead to disease,” said Coban-Akdemir, assistant professor in Epidemiology. “It opens new doors for understanding and diagnosing complex congenital conditions.”
Results from the study add to growing evidence of the impact of combinations of genetic variants resulting in congenital heart disease. This discovery could lead to more accurate genetic testing and better support for families affected by these rare but serious disorders.
The research was led by faculty and students from the UTHealth Houston School of Public Health Human Genetics Center, including first author Archana Rai, PhD, post-doctoral associate, and Epidemiology doctoral students Iman Egab, MPH, and Jiaoyang Xu, MPH. Faculty from the Department of Epidemiology include Dean Eric Boerwinkle, PhD; Associate Professor A.J. Agopian, PhD; and Assistant Professor Zeynep Coban-Akdemir, PhD.
The study was a collaborative effort of researchers that include Baylor College of Medicine faculty James R. Lupski, MD, and Shaine A. Morris, MD, and researchers from the University of Pittsburgh, the Icahn School of Medicine at Mount Sinai, Harvard University, Brigham and Women’s Hospital, Texas Children’s Hospital, and the Baylor Research Institute and School of Medicine in Temple, Texas.