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Study Links Chromosomal Variants to Bicuspid Aortic Valve Disease
A recent study led by researchers at UTHealth Houston has established a connection between rare duplications and deletions in the 22q11.2 chromosome region and nonsyndromic bicuspid aortic valve disease. This area is known for its genes that play a crucial role in cardiac development.
Published in Heart, a journal of the BMJ, the study identified that 7.4% of participants with early-onset bicuspid aortic valve exhibited rare genetic variations within the 22q11.2 region. The findings suggest that these chromosomal changes may influence both the severity of the condition and the likelihood of experiencing complications.
Bicuspid aortic valve disease, characterized by having two leaflets instead of the typical three in the aortic valve, is identified as the most prevalent congenital heart defect, affecting approximately 2% of the global population. This condition is congenital, meaning it is present at birth, and often arises from single-gene mutations inherited from one parent. Complications associated with this disease can be severe, including thoracic aortic aneurysms, aortic wall weakening, and aortic stenosis, which is a narrowing of the valve. The term “nonsyndromic” implies that this condition does not form part of a broader syndrome.
While it is already established that certain genomic DNA variations in areas linked to cardiac development contribute to congenital defects, the specific relationship between the 22q11.2 region and nonsyndromic bicuspid aortic valve remained less understood. Medical students Sara Mansoorshahi and Catherina Tovar Pensa at McGovern Medical School, UTHealth Houston, undertook this important research to fill this knowledge gap.
“Our study aimed to explore the implications of variants in the 22q11.2 region for patients with early-onset bicuspid aortic valve,” stated Tovar Pensa, one of the co-first authors. “We sought to ascertain whether these genetic variants could aid in risk stratification and enhance predictive capabilities regarding potential complications.”
DiGeorge syndrome, which results from the deletion of a small segment of chromosome 22, can manifest through various complications from birth due to associated congenital heart or vascular anomalies, learning challenges, psychiatric disorders, immunodeficiencies, and abnormalities affecting the kidneys or urinary tract. This syndrome can arise in individuals with or without a family history of the deletion.
In their methodology, researchers employed whole genome microarray genotyping on samples from 272 patients diagnosed with early onset valve or aortic disease and 272 of their biological relatives. They scrutinized all copy number variations present in the 22q11.2 region, using questionnaires to gather comprehensive data regarding cardiovascular, endocrine, urogenital, musculoskeletal, developmental, and psychiatric histories of the participants. Copy number variation refers to a genomic condition wherein the number of copies of a specific DNA segment can differ among individuals.
Noteworthy genetic variants identified in this investigation were linked to the genes TBX1, CRKL, HIC2, and MAPK1, which are vital for proper vascular development, particularly in the left ventricular outflow tract that directs blood flow through the aorta. Importantly, the study found an explicit association between TBX1 variation and bicuspid aortic valve disease for the first time. Mutations in the TBX1 gene and other 22q11.2 genes may contribute not only to cardiac issues but also to learning and developmental disorders, psychiatric challenges, seizures, muscular hypotonia, and growth delays, highlighting the need for clinicians to consider genetic testing for this gene region in affected patients who display early-onset complications or have concurrent congenital heart defects.
“The statistically significant increase in genetic variants among the bicuspid aortic valve population was reassuring,” remarked Mansoorshahi, the other co-first author. “It indicates that further research in this domain could position this chromosome region as a key focus for future genetic testing.”
This research received partial funding from several National Institutes of Health grants, including R01HL137028, R21HL150383, R01HL114823, and R21HL150373.
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