Complex Mix Of Gene Effects Causes Congenital Heart Defect

The overall risk of congenital heart defects - the leading cause of birth defect-related deaths - is determined by a complex combination of gene effects both inside and outside of the heart, a new study has found.

Understanding how genetic alterations cause such defects is complicated by the fact that many of the critical genes are unknown, and those that are known often contribute only small increases in congenital heart defects (CHD) risk.

Researchers at University of California, Irvine (UCI) found that the role of genes in CHD is more complex than previously realised.

Normal heart formation depends on interactions of multiple cell types that collaborate in precise times and places throughout development.

To figure out how these interactions can go awry, researchers studied atrial septal defects (ASDs) - a common type of heart defect - in a mouse model of the developmental disorder Cornelia de Lange Syndrome (CdLS).

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Most cases of Cornelia de Lange Syndrome are caused by mutations that inactivate a single copy of Nipbl, a gene that directs the expression of many hundreds of other genes in tissues throughout the body.

Just as people with Cornelia de Lange Syndrome have a high incidence of heart defects, 30 per cent of mice that harbour similar Nipbl mutations exhibit atrial septal defects. Employing genetically modified mouse models, the researchers used a novel technology to selectively introduce or remove Nipbl mutations in different tissues during embryonic development.

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They found that no Nipbl deficiency in any single tissue -including the tissue that forms the heart itself - could account for the development of atrial septal defects.

Rather, the heart defects were determined by interactions between heart-forming tissues and the rest of the body.

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Nipbl deficiency in some tissues even seemed to protect against the development of atrial septal defects, in certain situations.

"Our results lead us to hypothesise that heart defects such as ASDs occur when the heart does not grow quickly enough to meet the demands of the developing body - in other words, that heart size and body size must be coordinated for the heart to develop without defects," said Anne Calof, professor at UCI.

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"To our knowledge, this is the first genetic demonstration that major risk factors for heart defects are likely to lie outside of the heart itself," Calof said.

"When a single gene change causes a birth defect, we often assume that it's because one thing goes wrong in one cell type. The big difference in our studies may have to do with the fact that Nipbl controls a large number of other genes," said Arthur Lander, professor at UCI.

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"Given that most human CHDs are now thought to be caused by gene variants acting in combination, what we learned from Nipbl-deficient mice may actually be more typical of the way most CHDs arise," Lander said.

The study was published in the journal PLOS Biology.