Researchers find genetic link between heart disease and brain development

Congenital heart disease (CHD) affects approximately 1% of live births. Thanks to surgical advancements, infants born with CHD are now surviving into adulthood. However, these individuals face a high risk of neurodevelopmental impairments that can affect learning, communication, and cognitive function.

Many experience autism spectrum disorders, intellectual disabilities, and behavioral challenges. These deficits significantly impact their quality of life, making everyday tasks and education more difficult.

Initially, researchers believed that these neurological impairments stemmed from oxygen deprivation and the complications of multiple cardiac surgeries. However, new evidence suggests that intrinsic factors, including genetics, may play a more significant role.

A growing body of research points to genetic mutations as a key contributor to both heart defects and neurodevelopmental abnormalities, shifting the focus toward early detection and potential therapeutic interventions.

Researchers at the University of Pittsburgh School of Medicine have identified genetic mutations that contribute to both CHD and neurological impairment.

A study published in Nature Communications highlights the role of two genes—Sap130 and Pcdha9—in causing congenital heart defects and neurobehavioral disorders. These genes play crucial roles in brain development, suggesting a shared genetic basis for heart and neurological conditions.

Among CHD patients, the most severe cases are associated with hypoplastic left heart syndrome (HLHS). This condition, characterized by an underdeveloped left side of the heart, requires a complex three-stage surgical intervention to sustain life.

Despite surgical success, HLHS is frequently accompanied by significant neurodevelopmental delays. Children with HLHS are at risk for lower IQ scores, behavioral challenges, and adaptive skill deficits. Approximately 25% of HLHS fetuses show signs of microcephaly, brain malformations, or missing brain structures, underscoring the neurological impact of the disorder.

Microcephaly, a condition where the head and brain are abnormally small, is a strong predictor of early neurological complications. Studies have shown that even when fetal intervention is performed to restore blood flow to the brain, developmental outcomes do not necessarily improve. This suggests that the brain abnormalities observed in CHD patients may not be solely due to reduced oxygen supply but could be rooted in fundamental genetic mechanisms.

Not everyone with Sap130 and Pcdha9 mutations develops CHD or neurodevelopmental disorders. This phenomenon, known as incomplete penetrance, means that even individuals with the same genetic mutations can exhibit different disease severities or, in some cases, no symptoms at all. The variability is believed to be influenced by epigenetics—changes in gene expression that occur without altering the underlying DNA sequence.

Epigenetic modifications, such as DNA methylation, can determine whether specific genes are turned on or off. When these regulatory mechanisms go awry, they can contribute to the onset of disease. In CHD patients with neurodevelopmental disorders, researchers found significant alterations in DNA methylation patterns, particularly in genes linked to autism, cognitive development, and synaptic connectivity.

"We know that some genes can cause heart disease, but even in families, siblings could have the same mutation, and only one might develop congenital heart disease while the other remains unaffected," said Cecilia Lo, Distinguished Professor of Developmental Biology in Pediatrics at the University of Pittsburgh.

By analyzing the genome-wide methylation profiles of CHD patients, researchers discovered that many of the affected genes were involved in pathways associated with autism and neurodevelopmental disorders. This finding suggests that the same molecular mechanisms driving CHD may also be responsible for brain abnormalities.

"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 involved in 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."

Both Sap130 and Pcdha9 play crucial roles in neural development. Sap130 is a component of the Sin3A complex, which regulates chromatin remodeling and histone deacetylation—processes essential for gene expression and brain development.

Deficiencies in Sin3A-related proteins are linked to neurodevelopmental disorders, including Witteveen-Kolk syndrome, which is characterized by intellectual disability, autism, and microcephaly. Additionally, the Sin3A complex interacts with MECP2, a gene associated with Rett syndrome, one of the most common causes of cognitive impairment in females.

The Pcdha9 gene belongs to the Protocadherin-alpha cluster, which encodes proteins that help neurons form proper connections. These proteins are essential for establishing the brain’s wiring, allowing for proper cognitive and behavioral function. Disruptions in this gene cluster have been associated with autism and congenital heart defects, further linking CHD to neurodevelopmental disorders.

In studies using an Ohia mouse model—engineered to carry mutations in Sap130 and Pcdha9—scientists observed significant changes in brain structure and function. Mice with these mutations exhibited impaired neuronal differentiation, abnormal brain morphology, and behavioral deficits. Forebrain-specific deletions of Sap130 in mice led to microcephaly, mirroring findings in CHD patients.

To better understand the molecular mechanisms at play, researchers used RNA sequencing and DNA methylation analysis to examine gene expression patterns in mutant mice. They found that Sap130 plays a key role in regulating the epigenome by recruiting proteins involved in DNA methylation. When this process is disrupted, genes critical for neurodevelopment are misregulated, potentially leading to cognitive and behavioral impairments.

"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.

The discovery that DNA methylation changes contribute to neurodevelopmental deficits in CHD patients opens new possibilities for therapeutic intervention. Unlike genetic mutations, which are permanent, epigenetic modifications are potentially reversible. This raises the possibility of using pharmacological agents to modify DNA methylation patterns and restore normal gene expression.

"If DNA methylation changes play a role in determining behavior and brain abnormalities in CHD patients, there is the possibility for therapy through pharmacological intervention, which is not so easy to accomplish for a genetic alteration," Lo added.

Epigenetic therapies, including drugs that target DNA methylation and histone modification, are already being explored for neurodevelopmental and psychiatric disorders. If similar approaches prove effective in CHD patients, they could offer a novel way to mitigate the neurobehavioral challenges associated with congenital heart defects.

The findings from this study highlight the complex interplay between genetics and brain development in CHD patients. While surgical advancements have improved survival rates, understanding the genetic and epigenetic factors underlying neurodevelopmental impairments is crucial for improving long-term outcomes.

Future research may pave the way for targeted therapies that could enhance cognitive function and quality of life for those living with CHD.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

Like these kind of feel good stories? Get The Brighter Side of News' newsletter.