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Congenital Heart Valve Malformation Condition Linked to Rare NOTCH-Related Variants

NEW YORK – An international team led by investigators in Spain, France, and Israel has tracked down previously unappreciated ties between rare mutations in the E3-ubiquitin ligase-coding gene MIB1 and a congenital heart valve malformation condition known as bicuspid aortic valve (BAV).

"By deepening our understanding of the genetic basis and phenotypic variations of BAV, our results form the basis for future research aimed at tailoring risk stratification and clinical management to individual patients," Idit Tessler, a physician and public health and community medicine researcher at the Hebrew University of Jerusalem, said in an email.

For a paper appearing in JAMA Cardiology on Wednesday, she and her colleagues brought together multicenter exome sequence data for 69 individuals from more than two dozen families affected by non-syndromic BAV in France or Israel. Using a gene-prioritizing analytical pipeline, they searched for rare or common variants linked to nsBAV in the discovery group and in sequence or array-based genotyping profiles for 869 more individuals with nsBAV European or US replication cohorts.

The team's analyses highlighted rare, predicted-damaging MIB1 variants in around 2 percent of the nsBAV cases considered, potentially reflecting the gene's established role in heart development-related NOTCH signaling. In contrast, similar mutations in MIB1 turned up in just 0.1 percent of individuals from population matched controls from the Framingham Heart Study or gnomAD sequence database.

"This genetic association study identified the MIB1 gene as associated with nsBAV," the authors reported. "This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention."

The relatively common congenital malformation condition, marked by altered blood flow caused by aortic valve leaflet fusion, involves a range of patient phenotype or progression patterns that are still incompletely understood, Tessler explained. Despite the apparent heritability of BAV, autosomal dominant contributors detected so far seem to have low penetrance, and the condition remains overrepresented in males.

"A wide spectrum of clinical outcomes exists for the disorder ranging from serious childhood illnesses and sudden death to asymptomatic disease in the elderly," she said, noting that affected individuals "are at risk of developing aortic valve and cardiovascular complications, including aortic valve stenosis, aortic valve regurgitation, infective endocarditis, and acute aortic dissection (a medical emergency with above 50 percent mortality)."

In their current study, the researchers' follow-up experiments in mouse models suggested the presence of MIB1 variants coincided with BAV-related physical features or symptoms in animals that were missing one copy of NOTCH1, a gene implicated in nsBAV in humans in the past.

"MIB1 has a crucial role in the NOTCH pathway, which is well known to be involved in heart development," Tessler explained. "Our findings highlight this pathway's role as a potential future target."