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Some risk for non-syndromic congenital heart disease inherited from healthy parents
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Researchers have discovered genetic evidence that some of the risk for non-syndromic congenital heart disease is inherited from healthy parents.
“We are aiming to understand the genetics of the development of the human heart. This is the first study to quantify the role that rare inherited variants play in non-syndromic [congenital heart disease], and is extremely valuable as these patients make up 90% of [congenital heart disease] patients worldwide,” Matthew Hurles, PhD, from the Wellcome Trust Sanger Institute, Cambridge, England, said in a press release.
Hurles and colleagues sequenced and analyzed the exome of 1,891 probands of patients with congenital heart disease. Of those, 610 were associated with syndromic congenital heart disease and 1,281 were associated with non-syndromic congenital heart disease.
The data revealed that the syndromic congenital heart disease probands had the largest excess of de novo protein-truncating variants (27 variants; OR = 81; P = 1.21 x 10-43) and de novo missense variants (22 variants; OR = 8.6; P = 7.35 x 10-15) for autosomal dominant congenital heart disease genes.
There were also a large number of de novo protein-truncating variants in autosomal dominant developmental-disorder-associated genes not currently associated with congenital heart disease (12 variants; OR = 18.4; P = 3.49 x 10-13). Non-syndromic congenital heart disease probands, however, had a lower number of de novo protein-truncating variants in genes associated with congenital heart disease (four variants; OR = 7.3; P = 2.61 x 10-4).
The researchers discovered that although syndromic congenital heart disease is often caused by spontaneous mutation not seen in the parents, non-syndromic congenital heart disease is not caused this way and oftentimes is the result of inheriting damaging gene variants from unaffected parents. In addition, they also found three new genes, CHD4, CDK13 and PRKDA, in which the spontaneous mutation that causes syndromic congenital heart disease can occur.
“Previous smaller-scale studies have hinted at the possibility that non-syndromic [congenital heart disease] could be caused by inherited gene variants, but this is the first time that we have been able to show it with statistical evidence,” Marc-Phillip Hitz, MD, PhD, from the Sanger Institute and the University Medical Center of Schleswig-Holstein, Kiel, Germany, said in the release. – by Tracey Romero
Disclosure: Hurles reports being a founder of and holding shares in Congenica Ltd. The other researchers report no relevant financial disclosures.
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