NEW YORK – Researchers in the US and UK have identified forms of congenital heart disease (CHD) that stem from gene pair interactions, pointing to the possibility of uncovering previously unappreciated processes leading to heart structure changes during embryonic development.
"Our study demonstrates that alterations in more than one gene might contribute together to the increased risk for complex diseases such as CHD," first author Meltem Ece Kars, with the Icahn School of Medicine at Mount Sinai's Charles Bronfman Institute for Personalized Medicine, said in an email. "This indicates the need [for] greater exploration of non-monogenic mechanisms to fully understand disease pathogenesis."
In a paper published in the American Journal of Human Genetics on Thursday, Kars and colleagues from the Icahn School of Medicine at Mount Sinai and other centers in the US and the UK used gene burden, gene pair burden, network, and biological distance analyses to assess exome sequence data for 3,910 parent-child trios from the Pediatric Cardiac Genomics Consortium's Congenital Heart Disease Genetic Network Study.
As part of their systematic search for two-gene, or "digenic," interactions that were overrepresented in children with CHD compared to their unaffected parents, they also considered exome sequences from 3,644 CHD-free control trios involving parent-unaffected siblings enrolled in the Simons Foundation Powering Autism Research study.
"[W]e developed a novel method to investigate digenic inheritance using trio exome sequencing data and applied it to a congenital heart disease (CHD) cohort to identify digenic interactions contributing to CHD pathogenesis," Kars said.
Although past studies have identified single-gene contributors to CHD, only around 55 percent of CHD cases can be explained by known genetic factors, the authors explained, prompting them to take a closer look at non-monogenic contributors to the genetically heterogeneous condition.
"Our findings suggest that genetic variants in two different genes may contribute together to development of CHD in some of the patients," Kars said, "and could explain a portion of the missing heritability."
With their trio exome approach, the investigators narrowed in on 10 gene pairs with apparent ties to CHD, including genes with enhanced expression in developing embryonic heart tissue in their follow-up RNA sequencing analyses.
The team's findings so far suggested that there may be opportunities to improve CHD diagnoses and related genetic counseling efforts by considering gene-gene or multiple-gene interactions, along with single-gene causes for the heart condition.
"As clinical genetic testing advances, integrating digenic and oligogenic models could increase diagnostic yield, provide patients and their families with greater clarity about their condition, and may facilitate the development of targeted therapies and interventions," Kars said.
He and his coauthors emphasized that there may be yet-undetected gene pairs that contribute to CHD and called for additional work to continue teasing out the functional effects of digenic genes found in the current study as well as new candidate gene pairs.
"Our research establishes a framework for future studies on digenic interactions that may underlie a broad range of human diseases," Kars said, noting that members of the team "plan to extend our digenic approach to other disease groups traditionally studied through monogenic models to potentially uncover some of the missing heritability in such disorders."