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Congenital Heart Disease Exomes Reveal De Novo Mutations Affecting Other Developmental Processes

NEW YORK (GenomeWeb) – A team from the US, UK, and Canada has tracked down excess de novo mutations in a subset of individuals with congenital heart disease, particularly within cases involving neurodevelopmental delay or other congenital features.

As they reported online today in Science, the researchers did exome sequencing on more than 1,200 children with congenital heart disease and their unaffected parents. Within these parent-child trios, they detected an over-representation of de novo mutations, often involving heart- and/or brain-expressed genes.

But while such mutations turned up in around 20 percent of the children who had a combination of congenital heart disease, neurodevelopmental disability, and other extra-cardiac abnormalities, excess de novo mutations were far less common in individuals with congenital heart disease alone, occurring in just 2 percent of cases.

"These findings reveal shared genetic contributions to [congenital heart disease], [neurodevelopmental disabilities], and [congenital abnormalities] and provide opportunities for improved prognostic assessment and early therapeutic intervention in [congenital heart disease] patients," the study's authors wrote.

Although congenital heart disease can occur in isolation, some 13 percent of cases involve congenital abnormalities that affect organs other than the heart, the team explained, and about 10 percent show neurodevelopmental problems affecting speech, cognition, movement, and/or social skills. In children with severe congenital heart disease, that proportion is even higher, coming in at around 50 percent.

To explore potential genetic overlap between such conditions, the researchers did exome sequencing on 1,213 parent-child trios enrolled through the Pediatric Cardiac Genetics Consortium or the Pediatric Heart Network.

The group included affected children with or without additional neurodevelopmental or congenital symptoms, though individuals who had been diagnosed with known genetic syndromes were excluded from the analysis.

When they compared coding sequences from the congenital heart disease trios to one another and to hundreds of autism-affected trios sequenced for a prior study, the researchers saw higher-than-usual rates of loss-of-function and missense variants across the congenital heart disease cases.

And de novo damaging mutations in congenital heart disease-affected individuals appeared to be especially enriched across a set of more than 4,400 genes known for enhanced expression in heart tissue during development — a pattern not found in unaffected control individuals.

Across the congenital heart disease cases, the team saw 21 genes with damaging de novo mutations in more than one individual, including seven genes linked to congenital heart disease in past studies.

The researchers determined that the rate of these de novo mutations was particularly elevated across three of these genes: PTPN11, KMT2D, and RBFOX2.

More broadly, their results pointed to de novo mutations affecting genes from pathways involved in anatomy, heart, neurodevelopment, and chromatin modification.

The researchers did not detect this jump in de novo mutations in individuals who suffered solely from heart symptoms. But when they looked at data from past studies of neurodevelopmental disability alone, they saw de novo mutations in dozens of the same genes detected in cases with congenital heart disease and neurodevelopmental features.

Based on these findings, the study's authors speculated that it may be possible to use genotyping to find congenital heart disease patients who are at risk of neurodevelopmental disease and could benefit from educational and other early interventions. 

They noted that the results may also prove useful for unraveling genes and regulatory features involved in the development of multiple organs, including the heart and brain.