Genetic bases of bicuspid aortic valve: the contribution of traditional and high-throughput sequencing approaches on research and diagnosis

Genetic bases of bicuspid aortic valve: the contribution of traditional and
high-throughput sequencing approaches on research and diagnosis

Elena Sticchi ^{1, 2, 3, 4 §}, Rosina De Cario ^{1, 2, §}, Betti Giusti ^{1, 2, 3, 4}, Andrea Volta ^{1, 3}, Ada Kura ^{1, 3},
Guglielmina Pepe ^{1, 2, 4}, Stefano Nistri ^{4, 5}

¹ Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Florence, Italy
² Marfan Syndrome and Related Disorders Regional (Tuscany) Referral Center, Careggi Hospital, Florence, Italy
³ Advanced Molecular Genetics Laboratory, Atherothrombotic Diseases Center, Careggi Hospital, Florence, Italy
⁴ Center of excellence for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, DENOTHE Center, University of Florence, Florence, Italy
⁵ Cardiology Service, CMSR Veneto Medica, Altavilla Vicentina, Italy
^§ These Authors equally contributed to this work

Abstract

Bicuspid aortic valve (BAV) is a congenital heart defect inherited as an autosomal dominant trait with reduced penetrance and variable expressivity, affecting 1.3% of general population. BAV is characterized by an increased prevalence of aortic dilatation (> 50%) and dissection. BAV can be present as an isolated entity or in combination with other clinical manifestations in syndromic disorders [e.g. Marfan or Loeys-Dietz syndrome (MFS, LDS)]. The presence of BAV in syndromic patients determines an earlier indication to aortic surgery with respect to isolated BAV patients. Consistent evidences exist indicating that genetic variants in different genes are responsible for BAV. Several genes have been demonstrated or suspected to be associated or contributing to BAV or BAV complications: the transcriptional regulator NOTCH1 (BAV development and acceleration of calcium deposition); loci on chromosomes 18q, 5q and 13q; GATA4 and GATA5 (aortic valve morphogenesis and endocardial cell differentiation); reduced UFD1L gene expression; ACTA2; a locus containing AXIN1 and PDIA2, and FBN1. The availability of high-throughput sequencing technologies, allowing analysis of large panels of genes or entire exomes/genomes, and development of data analysis methods able to manage and integrate large set of experimental and clinical data represents a promising opportunity to rapidly improve the disease knowledge and diagnosis in monogenic as well as polygenic complex multifactorial traits. This review aims to address the genetic bases of BAV, genetic diagnosis role in BAV patient management and the impact of high-throughput sequencing technologies and data analysis approaches on BAV genetic bases research and diagnosis.

Key words: Bicuspid aortic valve; Genetics; High-throughput sequencing; Next generation sequencing; Gene; Modifier gene; Mendelian inheritance; Multifactorial inheritance.