Photo caption: Researchers from Pitt’s School of Medicine found mutations in genes Sap130 and Pcdha9 not only cause complex CHD but also cause abnormalities and neurobehavioral deficits.
By Kat Procyk
Congenital heart disease (CHD) affects up to 1% of live births. Though modern surgical advances have allowed babies with CHD to survive to adulthood, they are still at high risk of experiencing neurodevelopmental disabilities like impaired social and communication skills, autism, intellectual disability, and other cognitive and behavioral deficits.
Such adverse outcomes were previously thought to result from hypoxia or surgical trauma associated with cardiac surgeries. However, it’s now believed these outcomes may be intrinsic to the patient and are likely genetic.
In a recent study published in Nature Communications in December 2024, researchers at the University of Pittsburgh School of Medicine found mutations in two genes, Sap130 and Pcdha9, not only cause complex CHD but also cause abnormalities and neurobehavioral deficits.
They also found that the defects resulting from these mutations exhibit incomplete penetrance, meaning not all individuals with both mutations will develop congenital heart disease (CHD) or neurodevelopmental disorders. Even among those with the same genetic mutations, the severity and manifestation of symptoms can vary. This variability is influenced by epigenetic regulation, which affects gene expression without altering the underlying DNA sequence.
“We know that there are some genes that can cause heart disease, but, even in families, siblings could have the same mutation, but only one might have congenital heart disease and one have no disease,” said coauthor Cecilia Lo, Distinguished Professor of Developmental Biology in Pediatrics at Pitt.
Their study shows that epigenetic factors, particularly DNA methylation, are important in modulating gene expression to affect disease state. When genes are methylated, their ability to be expressed can be modified or silenced, such that differences in methylation can contribute to incomplete penetrance.
“When we looked at what genes were associated with these methylation sites and did a gene-enrichment analysis, we found they landed in many of the pathways that are involved in these brain anomalies like autism,” Lo explained. “It corroborates the notion that these epigenetic changes in the form of methylation are involved in modulating these pathways that are reflected in the phenotypes we observed.”
These gene expression alterations are actually being driven by the gene Sap130, which likely play a role in recruiting proteins involved in regulating DNA methylation and the epigenome.
“We show that Sap130 DNA binding is associated with many genes that show DNA methylation and gene expression changes, genes that are also associated with neurodevelopmental and neurobehavioral pathways,” Lo said.
If DNA methylation changes play a role in determining behavior and brain abnormalities in CHD patients, Lo added, there is the possibility for therapy through pharmacological intervention, which is not so easy to accomplish for a genetic alteration.