New U of A study shows heart-brain connection in KBG syndrome

Promising research has already changed clinical guidelines for patients.

Jon Pullin - 2 July 2024

A groundbreaking study by Department of Medical Genetics associate professor Anastassia Voronova and her team has provided clarity on the heart-brain connection in KBG syndrome, a rare genetic neurodevelopmental disorder. 

Heart defects are often found in children with rare neurodevelopmental disorders, but scientists aren’t sure why.

KBG syndrome can cause unusual facial development, skeletal abnormalities, intellectual underdevelopment and heart defects. The syndrome is caused by mutations in the ANKRD11 gene, which plays a crucial role in brain development. 

Despite its known effects on the brain, the role of ANKRD11 in heart development was not known until now. This study, enabled by the cutting-edge Vizgen Merscope technology and the U of A’s Core Research Facilities team, will hopefully pave the way for improved diagnosis, clinical care and treatment. 

The experiment and findings

Voronova's team observed that mice with the ANKRD11 gene removed from their neural crest cells — which are crucial for heart development — had abnormal heart formation and function. Their research had several important findings.

The mice without the ANKRD11 gene developed multiple heart defects. In one defect, known as persistent truncus arteriosus, the heart's outflow tract did not properly divide into the aorta and pulmonary arteries, leading to inefficient blood circulation. In another, enlarged heart ventricles affected the heart's ability to pump blood. ANKRD11-deficient mice also developed abnormal heart valves. 

The mice also had their signalling pathways affected, which are essential for proper cell function and development.

In their previous work published earlier this year, the Voronova team showed that ANKRD11 is important for the development of brain cells, helping them grow and move to the right places. Mice with the ANKRD11 gene removed showed a disruption in the organization of brain cells which led to structural problems. Importantly, these deficiencies in mice were also found in KBG syndrome patients and led to the discovery of a novel clinical phenotype — the absence of smell. 

The next steps are to investigate how the heart and brain influence each other’s development in children with KBG syndrome. The team is also investigating the link with the peripheral (sensory) nervous system. 

Implications for KBG syndrome

The team's ongoing research shows how the ANKRD11 gene can affect both heart and brain development, suggesting an important link between these two organs. A better understanding of this connection is vital for developing improved care and treatment for children with KBG syndrome. Notably, about 40 per cent of KBG syndrome patients display heart defects, including problems with heart valves and the walls between heart chambers.

Changing clinical guidelines

The study's findings have already started to influence clinical practices.

“The problem with rare disorders is that not all patients are evaluated the same way around the world,” says Voronova. “By showing a clear role of ANKRD11 in heart development, our work paves the way for including heart evaluations in clinical guidelines everywhere. This will help to ensure every child diagnosed with KBG syndrome will have their heart evaluated and corrected in a timely manner if needed.”

The team’s work, together with other recent studies, has changed the clinical guidelines for KBG syndrome, which now recommend heart evaluations for children diagnosed with KBG syndrome.

Collaboration and philanthropy

Voronova points out that the study is an example of the interdisciplinary cooperation needed for tackling complex health issues like KBG syndrome, which affects multiple body systems.

“We relied on a lot of outside collaborations. From fetal echocardiogram to micro-CT (computed tomography) imaging, neural crest cell and MERFISH expertise. This was an incredible local, national and international team effort. I believe the interdisciplinary nature of these studies is the future of science,” she says.

Voronova, who is a member of the Women and Children’s Health Research Institute and the Neuroscience and Mental Health Institute, also emphasized the importance of the Vizgen Merscope (MERFISH) platform in achieving these results. “The success of this research and publication was in large part enabled by the single-cell spatial transcriptomics platform (MERFISH) that the U of A obtained through philanthropic efforts,” she says. “I would also like to highlight this project was completely driven by our extremely talented first author and PhD student Yana Kibalnyk.”

Advancing knowledge and treatment

The implications of this study extend beyond understanding KBG syndrome. By pinpointing the role of ANKRD11 in heart and brain development, this research opens new avenues for treating other congenital heart defects and neurodevelopmental disorders. The insights gained from studying the ANKRD11 gene could lead to new therapies that improve the lives of patients with these conditions.

The work shows the important role of genetic research in understanding the underlying mechanisms of complex diseases. As researchers learn more about how genes like ANKRD11 function, they can develop treatments that address the root causes of these disorders, rather than only manage their symptoms.

This research was supported by the Stollery Children's Hospital Foundation through a WCHRI Innovation Grant. First author Yana Kibalnyk, along with co-authors Kara Goodkey and Adrianne Watson, received funding from WCHRI graduate and summer studentships. Another graduate student, Nicole Dittmann, was funded by the NMHI.