Prakash research published in PLOS One
Recent research identifying potential novel candidates for genetic testing in patients with bicuspid aortic valve (BAV) defects, led by the lab of Siddharth Prakash, MD, PhD, professor in the Department of Internal Medicine, and primary contributors Hasan Albasha and Steven Carlisle, has been published in PLOS One.
The paper, titled “Rare Genomic Copy Number Variants Implicate New Candidate Genes for Bicuspid Aortic Valve,” can be found by clicking here.
“Our research focused on the genetic causes of bicuspid aortic valve, the most prevalent congenital heart defect,” Prakash said. “BAV can lead to severe complications such as valve disease or thoracic aortic aneurysms that may require surgery to correct or cause life-threatening complications.”
The lab focused on rare genomic alterations called Copy Number Variants (CNVs), which are large DNA segments that are either duplicated or deleted and are often linked with other congenital heart defects. For the data, the team recruited more than 250 families with a rare form of early-onset BAV disease, each experiencing their first clinical event related to BAV before the age of 30.
“Most people with BAV experience complications much later in life, around age 60,” Prakash said. “Individuals with early-onset BAV disease are so unusual that we had to recruit our cohort from more than 15 collaborating medical centers across the world.”
Using single nucleotide polymorphism (SNP) microarrays, the lab analyzed genomic DNA to identify CNVs across the genome. They then compared the data from the early-onset BAV group to a control group of over 22,000 individuals. By employing three different CNV detection methods, the lab pinpointed the rare CNVs in the BAV group and determined their significant prevalence compared to the control group.
The lab’s research revealed that about 10% of people with early-onset BAV have rare CNVs likely contributing to the condition, indicating that these genetic changes play a crucial role in the development of BAV, especially for those facing early-life complications. Additionally, the team found two genes, GATA4 and DSCAM, which are known to play crucial roles in heart development. These genes displayed CNVs more frequently in the BAV cohort, suggesting they may potentially be strong candidates for future genetic screening or risk assessment.
“These findings are important because they move us closer to personalized medicine for BAV patients,” Prakash said. “With further research, we may be able to use genetic information to predict which individuals are more likely to develop severe BAV complications and tailor their care accordingly.”
Next steps for the Prakash Lab include investigating how CNVs directly impact the progression of BAV and deciphering the underlying biological mechanisms. They’ll explore how these genetic changes lead to BAV development and why some individuals with the variants face severe complications while others do not. Additionally, the lab will explore how the research can be translated into clinical practice by developing genetic tests to identify patients at higher risk for BAV-related complications or using the insights to guide personalized treatment plans.
“One key takeaway from this research is the complexity of BAV,” Prakash said. “It is not caused by a single genetic mutation but likely results from a combination of genetic changes that affect how the heart develops. The fact that we identified rare CNVs in nearly 10% of patients highlights the importance of looking beyond single-gene mutations and considering broader genomic changes.
“This study also demonstrates the potential of CNV analysis as a tool for understanding congenital heart diseases like BAV. By continuing to investigate these genetic factors, we hope to offer better predictive tools and more personalized treatments for patients.”
The project required a large and long-term collaborative effort with contributions from many researchers across the world. The lab would like to acknowledge Dianna Milewicz, MD, PhD, professor and vice chair in the Department of Internal Medicine, for her leadership and expertise, as well as Simon Body, MBChB, MPH, FAHA, and his investigators at the International BAV Consortium and many other collaborators across North America and Europe.