NEW YORK – New research has revealed dozens of genes containing inherited or de novo alterations that increase the risk of congenital heart disease, congenital heart malformations that can lead to infant mortality, or long-term complications affecting the heart and other systems.
As they reported in the Proceedings of the National Academy of Sciences on Monday, researchers from Yale School of Medicine, Rockefeller University, Washington University, and other centers used targeted molecular inversion probe (MIP) panel sequencing to search for damaging inherited or de novo mutations across 248 genes in 5,929 clinically phenotyped individuals with CHD from the Pediatric Cardiac Genomics Consortium effort. They also brought in exome sequencing profiles for another 3,887 parent-child trios and 1,739 singleton CHD cases from the Pediatric Heart Network.
Together, the sequence data highlighted 60 genes with higher-than-usual rates of de novo mutations in 60 genes, including 13 genes not linked to CHD in the past. These de novo and inherited variants, which were predicted to be damaging, turned up in just over 10 percent of the CHD cases considered.
"The clinical implications for prevention and mitigation provided by early molecular diagnosis are increasingly apparent and support the routine use of genomic analysis in evaluation of CHD," co-senior and co-corresponding authors Richard Lifton, a human genetics and genomics researcher with Rockefeller University, and Martina Brueckner, a genetics and pediatrics researcher with Yale School of Medicine, and their colleagues wrote.
When the team focused on phenotypes associated with the variants, it found single cardiac phenotype manifestations for alterations in 33 of the genes. Variants in the cardiac alpha-myosin heavy chain-coding gene and 11 other genes had more variable phenotypes, on the other hand, showing apparent ties to as many as four CHD subtypes. Another 15 genes contained damaging CHD-associated variants that did not coincide with any of the CHD subtypes or symptom clusters.
Isolated CHD was linked to variants in seven genes, particularly genes with enhanced or selective expression in the cardiomyocyte lineage, the investigators reported. Meanwhile, they noted that at least 37 genes — including brain-expressed genes linked to neurodevelopmental delay — appeared to influence phenotypes or symptoms found beyond the heart.
"Mutations often produced variable congenital heart disease (CHD) and extracardiac (EC) phenotypes," the authors reported, noting that "[p]robands with mutations associated with syndromic CHD were frequently not clinically diagnosed, often due to the absence of characteristic phenotypes."
Together, the authors suggested the new findings "demonstrate the significantly greater precision of molecular diagnosis of CHD to establish an early diagnosis for the syndromic genes frequently mutated in CHD."