Genetics of syndromic and non-syndromic mitral valve prolapse

Abstract

Mitral valve prolapse (MVP) is a common condition that affects 2%-3% of the general population. MVP is thought to include syndromic forms such as Marfan syndrome and non-syndromic MVP, which is the most frequent form. Myxomatous degeneration and fibroelastic deficiency (FED) are regarded as two different forms of non-syndromic MVP. While FED is still considered a degenerative disease associated with ageing, frequent familial clustering has been demonstrated for myxomatous MVP. Familial and genetic studies led to the recognition of reduced penetrance and large phenotypic variability, and to the identification of prodromal or atypical forms as a part of the complex spectrum of the disease. Whereas autosomal dominant mode is the common inheritance pattern, an X linked form of non-syndromic MVP was recognised initially, related to Filamin-A gene, encoding for a cytoskeleton protein involved in mechanotransduction. This identification allowed a comprehensive description of a new subtype of MVP with a unique association of leaflet prolapse and paradoxical restricted motion in diastole. In autosomal dominant forms, three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31-32. Although deciphering the underlying genetic defects is still a work in progress, DCHS1 mutations have been identified (11p15.4) in typical myxomatous disease, highlighting new molecular pathways and pathophysiological mechanisms leading to the development of MVP. Finally, a large international genome-wide association study demonstrated the implication of frequent variants in MVP development and opened new directions for future research. Hence, this review focuses on phenotypic, genetic and pathophysiological aspects of MVP.

Keywords: Dachsous; Filamin-A; animal model; genetic; mitral valve prolapse; myxomatous disease.

Figure 1

Mitral valve prolapse (MVP) with no or moderate regurgitation in patients with (A) Marfan syndrome, (B) myxomatous disease, (C) Filamin-A disease and (D) fibroelastic deficiency (FED). Of note, the echocardiographic presentation of MVP is often similar in Marfan syndrome and myxomatous disease, and Filamin-A MVP can be confused with myxomatous MVP. In addition, myxomatous degeneration of mitral leaflets has been described in Marfan syndrome, myxomatous disease and Filamin-A disease, whereas the histological aspect is quite different in FED. White arrows: prolapse/billowing, black head arrows: mitral annular disjunction.

Figure 2

Filamin A: a hub protein involved in mechanotransduction pathways. Dimers of Filamin A protein organise the filamentous actin network and participate, through their interactions with >80 binding partners, to many signalling pathways including: transforming growth factor (TGF)-β and tyrosine kinase receptors, integrin macromolecular complex, mechanosensitive channels (Piezzo) and actin/actomyosin homeostasis. All these signalling pathways are modulated by mechanical stress symbolised by red marks. The location of mitral valve prolapse (MVP)-associated Filamin-A mutations is indicated by yellow stars.