Link between the genetics of heart defects and neurodevelopmental disorders

Congenital heart disease (CHD) is the most common of all birth defects; severe forms were once fatal, but can now be corrected surgically in most newborns. However, while many children continue to lead healthy lives, a significant number develop disabling cognitive and social problems.

A massive, multi-institutional project that analyzed all the genes of more than 1,200 coronary artery disease patients and their relatives has identified new mutations that contribute to the disease. The researchers were surprised, however, when the results showed that some of the genetic mutations linked to severe coronary heart disease were also associated with later neurodevelopmental problems such as autism.

“These results indicate that certain genes, in particular a class called chromatin modifiers that influence gene expression, are required for both normal heart and brain function, and that a single mutated gene in this class can cause problems in both organs,” Richard said. Lifton, Sterling Professor and chair of Yale’s Department of Genetics and co-lead author of the paper published online Dec. 3 in the journal Science.

The study was led by Lifton, a Howard Hughes Medical Institute researcher, and Martina Brueckner, a Yale professor of pediatrics and genetics, along with colleagues from Harvard, Columbia, University of Pennsylvania and Icahn School of Medicine at Mt. Sinai.

About 40% of children born with severe congenital heart defects go on to develop cognitive or social abnormalities such as autism. It was unclear whether these neurodevelopmental disorders were caused by a lack of oxygen supply to the brain, a complication of corrective surgery, or underlying biological mechanisms.

“The similarities in the genetics of coronary heart disease and neurodevelopmental disorders are a real surprise,” said Matthew State, chair of psychiatry at the University of California San Francisco, an expert in autism genetics, who n was not one of the authors of this study. “Genetic testing of patients with coronary artery disease at birth offers the possibility of identifying infants at very high risk for neurodevelopmental disorders, enabling the development of approaches to mitigate adverse effects.”

Yale’s Samir Zaidi was co-first author of the study, which was funded by the National Institutes of Health.