According to a recent study spearheaded by researchers at UTHealth Houston, significant and rare duplications and deletions in a specific chromosome region known as 22q11.2—home to genes that play a role in heart development—are associated with nonsyndromic bicuspid aortic valve disease.
Published in Heart, a BMJ Journal, the research indicates that 7.4% of participants with early-onset bicuspid aortic valve exhibited rare duplications and deletions within the 22q11.2 region, particularly affecting genes linked to cardiac development. The findings suggest that variations in chromosome 22 may influence the severity of nonsyndromic bicuspid aortic valve disease and its related complications.
Bicuspid aortic valve disease, characterized by an aortic valve having only two leaflets instead of the typical three, is the most prevalent congenital heart defect, with an occurrence rate of up to 2% in the general population. This condition is congenital, typically attributed to dominant inheritance patterns, meaning it can be passed down from just one parent through various gene mutations. It can lead to serious complications, including thoracic aortic aneurysms, aortic wall weakness, and aortic stenosis, which refers to the narrowing of the aortic valve. The term nonsyndromic indicates that this condition is not part of a broader syndrome.
Previous research has demonstrated that genomic duplications or deletions in areas impacting heart development can result in congenital heart defects. However, knowledge about the variants in the 22q11.2 region and their role in nonsyndromic bicuspid aortic valve is limited. Together, Sara Mansoorshahi and Catherina Tovar Pensa—third-year medical students at McGovern Medical School at UTHealth Houston—aim to fill this knowledge gap.
“Our study examined how variants in the 22q11.2 region affect patients with early-onset bicuspid aortic valve. We aimed to assess whether these variants could be used in risk assessment for patients with this condition, aiding in predicting future complications and improving management strategies,” stated Tovar Pensa, one of the co-first authors.
DiGeorge syndrome, which stems from a deletion in the 22q11.2 region, occurs when a small segment of chromosome 22 is absent. This condition can arise in individuals whose parents have the dominant contiguous gene or parents who lack it. Complications associated with 22q11.2 deletion syndrome may manifest at birth and can include congenital heart or vascular defects, cognitive challenges, psychiatric disorders, weakened immune systems, as well as kidney or urinary tract issues.
The research team applied whole genome microarray genotyping to analyze 272 patients with early-onset bicuspid aortic valve or aortic disease, along with 272 biological family members. They scrutinized all copy number variations present in the 22q11.2 region, while participants provided extensive background information regarding their cardiovascular, endocrine, urogenital, musculoskeletal, developmental, and psychiatric health histories. Copy number variation means that the quantity of DNA copies can differ among individuals’ genomes.
The study identified several variants affecting the genes TBX1, CRKL, HIC2, and MAPK1—key players in vascular development, particularly the left ventricular outflow tract, which channels blood through the aorta. Notably, this was the first time a variant in TBX1 was linked directly to bicuspid aortic valve disease. Mutations in TBX1 and other genes in the 22q11.2 region may lead to learning disabilities, intellectual impairments, psychiatric issues, seizures, muscle weakness, or growth restrictions, prompting physicians to consider genetic testing for 22q11.2 copy number variants in patients with early-onset complications or additional congenital heart abnormalities.
“It was encouraging to discover a substantial, statistically significant rise in these genetic variants within the bicuspid aortic valve population. This suggests that further research in this domain could establish the 22q11.2 region as a crucial focus for future genetic testing,” added Mansoorshahi, another co-first author.
The study received partial funding from several National Institutes of Health grants: R01HL137028, R21HL150383, R01HL114823, and R21HL150373.
