Background: Bicuspid aortic valve (BAV) is the most common cardiac malformation affecting 1-2% people worldwide. Despite its high prevalence, the pathogenesis of BAV is largely undetermined, although gene mutations leading to alterations in cell migration and signal transduction, in conjunction with non-genetic factors such as blood flow during valvulogenesis, may contribute to its formation prenatally. Objective: The determination of genetic factors contributing to the presentation of BAV in a family with three affected daughters. Methods: We applied next generation whole exome sequencing (>3Gigabases per individual) to high quality DNA from the blood samples of the three affected daughters and their unaffected parents. The >36.000.000 reads of each of the 5 individuals were analyzed with the bioinformatics tools Burrow-Wheeler Aligner, SOAPsnp, Sam tools, Varscan, and GATK to identify single nucleotide polymorphisms and insertions/deletions. Results: We identified over 38,000 SNPs and 3,400 Indels in each individual, of which >1,000 and >580, respectively, were novel. Forty one SNPs were detected in at least two of the affected siblings but neither parent, and only 3 of those were detected in all three BAV patients: HFM1 (ATP dependent DNA helicase), TSPAN2 (tetraspanin family member) and TTF2 (transcription termination factor, RNA polymerase II - pre-mRNA splicing regulator). All 3 genes carried exonic, non-synonymous SNVs, with highly significant pathogenicity prediction scores (SIFT, PhyloP, MutationTaster, LRT). Eight Indels were detected in at least two of the siblings, and only one of them was common across all three siblings: CCNL2 (cyclin L2). CCLN2 is a regulator of the pre-mRNA splicing process, as well as inducer of apoptosis, by modulating the expression of apoptotic and antiapoptotic proteins. In our patients it was found to carry a four base deletion affecting a splice site. None of the previously reported BAV-related genes were found to carry a common mutation across all, and unique to the BAV patients of this family. Conclusion: We have detected 4 genetic variants, shared by all three BAV patients but neither parent. These genes have not been associated with BAV to date. Of particular interest is the novel variant in TSPAN2, a gene of largely unexplored function, belonging to a transmembrane protein family known to mediate signal transduction events that play a role in the regulation of cell development, activation, growth, adhesion and motility.


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