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Congenital Heart Disease Exomes Lead to Risky Rare Inherited Variants, De Novo Mutations

NEW YORK (GenomeWeb) – An international research team led by investigators at Yale University, Harvard University, Brigham and Women's Hospital, Rockefeller University, and Mount Sinai has identified a dozen new genes with apparent ties to congenital heart disease (CHD) — a heart development problem that can lead to cardiac arrhythmia, heart failure, and other serious complications.

As they reported in Nature Genetics, the researchers examined exome sequence profiles for almost 2,900 individuals with congenital heart disease. More than 2,600 of these affected individuals were part of parent-child trios that were exome-sequenced for the study. With this large exome collection, they got a glimpse at rare, recessive, inherited variants and newly detected de novo mutations associated with CHD, including de novo mutations falling in genes affected by such alterations in autism spectrum disorder.

"The discoveries revealed through this work not only teach us about the fundamental biology through which the heart gets built, but also have important clinical implications: Detecting these mutations could help us alert patients and parents to risk of ongoing problems that can be addressed and managed, and define risk for a second child," co-corresponding author Christine Seidman, director of the Brigham and Women's Hospital cardiovascular genetics center, said in a statement.

"Doubling the size of our sequenced cohort more than doubled the number of identified CHD risk genes," Seidman and her colleagues wrote in their paper. "The current data set includes 66 genes with two or more damaging [de novo mutations], compared to 21 previously, and 19 with two or more [loss-of-function de novo mutations], compared to five previously."

Using cases assembled through the Pediatric Cardiac Genomics Consortium and Pediatric Heart Network, the investigators analyzed exome sequences for 2,871 individuals with congenital heart disease: 2,645 individuals from parent-child trios and 226 singleton cases.

More than 1,200 parent-child trios were sequenced for prior studies, the authors noted. They sequenced the remaining exomes, captured with Roche SeqCap EZ MedExome target enrichment kits, using Illumina sequencing. The team also tallied cardiac phenotypes in the cases, classifying them into five main groups depending on the congenital structural heart problem involved.

From these data, the researchers estimated that rare mutations contribute to nearly 2 percent of CHD cases. The risk variants were over-represented in genes already implicated in CHD, along with 12 genes without prior ties to the condition. Sifting through these alterations also revealed inherited variants that were over-represented in certain forms of CHD.

In the CHD cases with a phenotype known as Tetralogy of Fallot, for example, they frequently found dominant mutations in the FLT4 gene. On the other hand, a significant proportion of cases with a form of CHD marked by alterations affecting the left side of the heart involved recessive mutations in the alpha-myosin heaving chain-coding gene MYH6.

In the subset of CHD-affected individuals of Ashkenazi Jewish ancestry, meanwhile, the team noted than roughly 5 percent of severe childhood cases could be traced back to homozygous mutations affecting the GDF1 gene.

While de novo mutations occurred in 8.3 percent of CHD cases considered, the researchers detected de novo mutations in almost 30 percent of individuals with CHD in conjunction with neurodevelopmental problems. Hundreds of genes harbored these potentially risky de novo mutations, they noted, including several genes from chromatin modification pathways. Another 19 genes were altered by de novo mutations in both CHD and ASD cases.

"This study indicates that continued sequencing of large, well-phenotyped cohorts will provide an increasingly complete picture of the genetic underpinnings of CHD, allowing new insight into mechanisms governing human development, improved prediction of clinical outcome, and the opportunity to mitigate these risks," the authors wrote.