Genetic Bases of Bicuspid Aortic Valve: The Contribution of Traditional and High-Throughput Sequencing Approaches on Research and Diagnosis

Abstract

Bicuspid aortic valve (BAV) is a common (0.5–2.0% of general population) congenital heart defect with increased prevalence of aortic dilatation and dissection. BAV has an autosomal dominant inheritance with reduced penetrance and variable expressivity. BAV has been described as an isolated trait or associated with syndromic conditions [e.g., Marfan Marfan syndrome or Loeys-Dietz syndrome (MFS, LDS)]. Identification of a syndromic condition in a BAV patient is clinically relevant to personalize aortic surgery indication. A 4-fold increase in BAV prevalence in a large cohort of unrelated MFS patients with respect to general population was reported, as well as in LDS patients (8-fold). It is also known that BAV is more frequent in patients with thoracic aortic aneurysm (TAA) related to mutations in ACTA2, FBN1, and TGFBR2 genes. Moreover, in 8 patients with BAV and thoracic aortic dilation, not fulfilling the clinical criteria for MFS, FBN1 mutations in 2/8 patients were identified suggesting that FBN1 or other genes involved in syndromic conditions correlated to aortopathy could be involved in BAV. Beyond loci associated to syndromic disorders, studies in humans and animal models evidenced/suggested the role of further genes in non-syndromic BAV. The transcriptional regulator NOTCH1 has been associated with the development and acceleration of calcium deposition. Genome wide marker-based linkage analysis demonstrated a linkage of BAV to loci on chromosomes 18, 5, and 13q. Recently, a role for GATA4/5 in aortic valve morphogenesis and endocardial cell differentiation has been reported. BAV has also been associated with a reduced UFD1L gene expression or involvement of a locus containing AXIN1/PDIA2. Much remains to be understood about the genetics of BAV. In the last years, high-throughput sequencing technologies, allowing the analysis of large number of genes or entire exomes or genomes, progressively became available. The latter issue together with the development of “BigData” analysis methods improving their interpretation and integration with clinical data represents a promising opportunity to increase the disease knowledge and diagnosis in monogenic and multifactorial complex traits. This review summarized the main knowledge on the BAV genetic bases, the role of genetic diagnosis in BAV patient managements and the crucial challenges for the comprehension of genetics of BAV in research and diagnosis.

Piezo1 is required for outflow tract and aortic valve development

“…Similar to Pz1b morphants, the aortic valves in notch1b mutants are also highly dysmorphic compared to WT controls (Fig.2.C and Movie.S7). The epidermal growth factor receptor (EGFR) gene has also been implicated in the etiology of BAV 17 , furthermore previous research in zebrafish has indicated that chemical inhibition of EGFR using either PKI166 or AG1478 results in defective OFT development 18 . Based on this we treated zebrafish embryos with either inhibitor for 7 days and again assessed aortic valve development.…”

“…As with Pz1b morphants and notch1b mutants, inhibition of EGFR results in dysmorphic aortic valves (Fig.2.D,E). Lastly, Endothelial Nitric Oxide Synthase (eNOS) has also been linked to BAV in mice 17 , while treatment of zebrafish embryos with the NOS inhibitor 2-trifluoromethylphenyl imidazole (TRIM) results in defective cardiac development 19 . Therefore, we also treated zebrafish larvae with TRIM and analysed their aortic valves as before and found that TRIM treated larvae also display defective aortic valves (Fig.2.F).…”

The impact of the aortic cusps fusion pattern and valve disease severity on the aortic wall mechanics in patients with bicuspid aortic valve

“…Genetic abnormalities may also belong here, e.g. mutations in NOTCH1, GATA family and ACTA2 genes which lead to BAV formation and could contribute to structural abnormalities of ascending aortic wall [35].…”

Genetic testing for bicuspid aortic valve

“…Other likely candidate genes for BAV (12,14,16) AXIN2 Other research associates ZEB2 (OMIM gene 605802) with a complex syndrome manifesting with intellectual disability, facial dysmorphia, speech delay, hydronephrosis, bicuspid aortic valve and absence of corpus callosum (18) and MATR3 (OMIM gene 164015) with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus (19).…”