Recently published in Heart, a BMJ Journal, the research revealed that rare duplications and deletions within the 22q11.2 region, particularly involving genes associated with cardiac development, were identified in 7.4% of early-onset bicuspid aortic valve participants. The research demonstrated that variations in chromosome 22 may contribute to the individual severity of nonsyndromic bicuspid aortic valve disease and the risk for complications.

Bicuspid aortic valve disease, where the aortic valve has two leaflets instead of the normal three, is the most common congenital heart defect, affecting up to 2% of the population. The condition is present from birth and is usually caused by the dominant inheritance — meaning it can be inherited from just one parent — of many gene mutations. The condition can lead to complications as severe as thoracic aortic aneurysms, weakening of the aortic wall, and aortic stenosis, or narrowing of the aortic valve. Nonsyndromic means that the condition is not part of another syndrome.

Research has shown that duplications or deletions of genomic DNA in regions that regulate cardiac development contribute to congenital defects. But less is known about variants in the 22q11.2 region and nonsyndromic bicuspid aortic valve. Sara Mansoorshahi and Catherina Tovar Pensa, third-year medical students at McGovern Medical School at UTHealth Houston, are working to close that gap.

“Our study focused on assessing the role of variants in the 22q11.2 region in patients with early onset bicuspid aortic valve, and to determine if these variants could potentially be considered as part of risk stratification for bicuspid aortic valve patients and help predict complications and guide further management,” said Tovar Pensa, co-first author.

DiGeorge syndrome, a 22q11.2 deletion syndrome, is caused when a small portion of chromosome 22 is missing. The condition can occur in individuals born from a parent with the dominant contiguous gene or parents without the gene. Variants in 22q11.2 deletion syndrome can cause complications beginning at birth due to congenital heart or vascular malformations, learning difficulties, psychiatric conditions, immunodeficiencies, and kidney or urinary tract anomalies.

Researchers used whole genome microarray genotyping on 272 bicuspid aortic valve patients with early onset valve or aortic disease and 272 biological relatives. They analyzed all copy number variations in the 22q11.2 chromosome while participants completed a questionnaire about their cardiovascular, endocrine, urogenital, musculoskeletal, developmental, and psychiatric histories. Copy number variation refers to a circumstance where the number of copies of a specific segment of DNA varies in the genomes of different people.

Several variants identified in the research involved the genes TBX1, CRKL, HIC2, and MAPK1, which are required for vascular development, especially the left ventricular outflow tract, which passes blood through the aorta. Until now, a variation in TBX1 had not been explicitly associated with bicuspid aortic valve disease. Mutations in TBX1 and other 22q11.2 genes may cause learning differences, intellectual disabilities, psychiatric disease, seizures, muscular hypotonia, or stunted growth. These features may alert physicians to the need for genetic testing for 22q11.2 copy number variants in bicuspid aortic valve patients who present with early onset complications or have additional congenital heart malformations.

“It was reassuring to see it was not a small increase, but a statistically significant increase in these genetic variants among bicuspid aortic valve population, and to be able to show that with more research in this area, this region could be an important area of interest for future genetic testing,” said Mansoorshahi, a co-first author.

The research was funded in part by the National Institutes of Health (R01HL137028, R21HL150383, R01HL114823, and R21HL150373).