Authors

• Katica Cvitkušić Lukenda — General Hospital dr. Josip Benčević, Slavonski Brod, Croatia — ORCID: 0000-0001-6188-0708
• Domagoj Vučić — General Hospital dr. Josip Benčević, Slavonski Brod, Croatia — ORCID: 0000-0003-3169-3658
• Marijana Knežević Praveček — General Hospital dr. Josip Benčević, Slavonski Brod, Croatia — ORCID: 0000-0002-8727-7357
• Krešimir Gabaldo — General Hospital dr. Josip Benčević, Slavonski Brod, Croatia — ORCID: 0000-0002-0116-5929
• Domagoj Mišković — General Hospital dr. Josip Benčević, Slavonski Brod, Croatia — ORCID: 0000-0003-4600-0498
• Blaženka Miškić — General Hospital dr. Josip Benčević, Slavonski Brod, Croatia — ORCID: 0000-0001-6568-3306
• Ana Livun — University Hospital Dubrava, Zagreb, Croatia — ORCID: 0000-0002-6758-1677

Abstract

Valve diseases have a large share in the total morbidity and mortality of the adult population, and can be congenital or acquired. The last few decades have seen a predominance of degenerative (calcified) heart valve diseases due to a prolonged life expectancy in economically developed countries. The therapeutic approach has remained unchanged and in the case of severe dysfunction, the valve is replaced with a mechanical or biological prosthesis, balloon valvuloplasty or valve reconstruction. The findings in understanding the development of heart valves along with human genome sequencing have led to the discovery of a genetic basis in valvular diseases (1). Also, there are numerous evidence to suggest that heart valve diseases which develop in adulthood has its source in embryonic development. In this review authors will display the genetic basis of the two most common inherited valvular diseases: bicuspid aortic valve and mitral valve prolapse, as well as a review of the findings suggesting a genetic contribution to calcified aortic valve disease (2). In addition, this review will include a review of the guidelines and benefits of genetic testing, as well as highlight the need to include genetic counseling in families with proven or suspected malformations. Linking genetic information to the clinical phenotype (**Table 1**) and potential outcomes of surgical treatment leads to a personalized approach to each patient (3). ### TABLE 1: Gene mutations associated with valvular heart disease. | | **Location** | **Gene** | **Inheritance** | **Phenotype** | | --- | --- | --- | --- | --- | | **Bicuspid aortic valve** | | | | | | **Syndromic** | 17q24.3 | *KCNJ2* | AD | Andersen syndrome | | **Nonsyndromic** | 9q34.3 20q13.33 15q22.31 11q24.2 | *NOTCH1* *GATA5* *SMAD6* *ROBO4* | AD AD, AR AD AD | AOVD1 CHTD5 AOVD2 AOVD3 | | **Mitral valve prolapse** | | | | | | **Syndromic** | 15q21.1 9q22.33 3p24.1 7q21.3, 12q13.1, 2q32.2,9q34.3 | *FBN1* *TGFBR1* *TGFBR2* *Collagen types I–III, V/ XI* | AD AD AD AR,AD AD,AD | Marfan syndrome Loeys-Dietz syndrome 1 Loeys-Dietz syndrome2 OI 1,Ehlers-Danlos syndrome, cardiac valvular type | | **Nonsyndromic** | Xq28 | *Filamin A* | XL | Cardiac valvular dysplasia | | **Aortic valve stenosis** | | | | | | **CAVD** | 9q34.3 | *NOTCH1* | AD | AOVD1 | [†] AD – autosomal dominant, AR – autosomal recessive, AOVD – aortic valve disease, CHTD – congenital heart disease, OI – osteogenesis imperfecta, XL – X-linked, CAVD - calcified aortic valve disease.

Keywords

bicuspid aortic valve, calcified aortic valve disease, genetic testing, mitral valve prolapse

DOI

Literature

1. Blue GM, Kirk EP, Giannoulatou E, Sholler GF, Dunwoodie SL, Harvey RP, et al. Advances in the Genetics of Congenital Heart Disease: A Clinician’s Guide. J Am Coll Cardiol. 2017 February 21;69(7):859–70. https://doi.org/10.1016/j.jacc.2016.11.060
2. Koenig SN, Lincoln J, Garg V. Genetic basis of aortic valvular disease. Curr Opin Cardiol. 2017 May;32(3):239–45. https://doi.org/10.1097/HCO.0000000000000384
3. Diz OM, Toro R, Cesar S, Gomez O, Sarquella-Brugada G, Campuzano O. Personalized Genetic Diagnosis of Congenital Heart Defects in Newborns. J Pers Med. 2021 June 16;11(6):562. https://doi.org/10.3390/jpm11060562