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De novo mutations responsible for some cases of congenital heart disease
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About 10% of congenital heart defects are caused by spontaneous de novo mutations, according to findings from a new study.
A research team organized through the NHLBI-supported Pediatrics Cardiac Genomics Consortium investigated parent–offspring trios with healthy parents and a child with congenital heart disease (n=362) and parent–offspring trios with healthy parents and children (n=264).
Using novel sequencing techniques, the researchers compared exomes. The exomes of children with congenital heart disease showed a significant excess of protein-altering de novo mutations. These mutations appeared in about 10% of the children with congenital heart disease. The OR for damaging mutations among those children was 7.5, which is consistent with ORs seen across the main classes of congenital heart disease.
The researchers found that several hundred different genes could contribute to the trait, but they were concentrated in a pathway that regulates important developmental genes and affect a system of chemical tags that modifies gene expression. In particular, many of the genes affected are involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or H2BK120 ubiquitination, which is required for H3K4 methylation.
Although the healthy children’s exomes also showed signs of de novo mutations, they were less likely to appear in genes that are highly expressed in the developing heart, researcher Christine E. Seidman, MD, of the department of genetics at Harvard Medical School, and also affiliated with Brigham and Women’s Hospital and the Howard Hughes Medical Institute in Chevy Chase, Md., said in a press release.
The researchers said future research should aim to better understand what causes these mutations in order to treat congenital heart disease and maybe even prevent it in early stages of heart formation.
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