Journal of Cardiovascular Translational Research

, Volume 4, Issue 6, pp 748–756

Filamin-A-Related Myxomatous Mitral Valve Dystrophy: Genetic, Echocardiographic and Functional Aspects

Authors

  • Aurélie Lardeux
    • l’institut du thoraxClinique Cardiologique and Inserm
  • Florence Kyndt
    • l’institut du thoraxClinique Cardiologique and Inserm
  • Simon Lecointe
    • l’institut du thoraxClinique Cardiologique and Inserm
  • Hervé Le Marec
    • l’institut du thoraxClinique Cardiologique and Inserm
  • Jean Merot
    • l’institut du thoraxClinique Cardiologique and Inserm
  • Jean-Jacques Schott
    • l’institut du thoraxClinique Cardiologique and Inserm
  • Thierry Le Tourneau
    • l’institut du thoraxClinique Cardiologique and Inserm
    • l’institut du thoraxClinique Cardiologique and Inserm
    • Service de cardiologie du CHU de Nantes
Article

DOI: 10.1007/s12265-011-9308-9

Cite this article as:
Lardeux, A., Kyndt, F., Lecointe, S. et al. J. of Cardiovasc. Trans. Res. (2011) 4: 748. doi:10.1007/s12265-011-9308-9

Abstract

Myxomatous dystrophy of the cardiac valves is a heterogeneous group of disorders, including syndromic diseases such as Marfan syndrome and isolated valvular diseases. Mitral valve prolapse, the most common form of this disease, is presumed to affect approximately 2% to 3% of the population and remains one of the most common causes of valvular surgery. During the past years, important effort has been made to better understand the pathophysiological basis of mitral valve prolapse. Autosomal-dominant transmission is the usual inheritance with reduced penetrance and variable expressivity. Three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31-32, but the underlying genetic defects are not currently known. An X-linked recessive form has been originally described by Monteleone and Fagan in 1969. Starting from one large French family and three smaller other families in which MVP was transmitted with an X-linked pattern, we have been able to identify three filamin A mutations p.Gly288Arg and p.Val711Asp and a 1,944-bp genomic deletion coding for exons 16 to 19. In this review, we describe the genetic, echocardiographic and functional aspects of the filamin-A-related myxomatous mitral valve dystrophy.

Keywords

Filamin AMitral valve prolapseGeneticPathophysiology

Introduction

During the past years, important effort has been made to better understand the pathophysiological basis of mitral valve prolapse [1]. One of the most efficient ways to go inside the understanding of a disease is to identify the underlying genetic basis. This strategy has already been proved successful for other cardiac diseases like hypertrophic cardiomyopathy or long QT syndrome. Often, once the first gene is identified, it becomes easier to identify the other genetic defects as most of the diseases follow a final common pathway meaning that the different genes involved in a disease are finally only a part of a same pathophysiological cascade [2]. For these different reasons, the identification of the filamin A (FLNA) gene as the first gene of non-syndromic mitral valve prolapse represents the first step to a new field of knowledge and perhaps at term, to new therapeutic strategies.

In this review, we will present the current knowledge on the role of FLNA mutations on mitral valve prolapse and valve disease at both cellular and clinical level.

Genetics of Mitral Valve Prolapse

Myxomatous dystrophy of the cardiac valves is a heterogeneous group of disorders, including syndromic diseases such as Marfan syndrome and isolated valvular diseases. Mitral valve prolapse, the most common form of this disease, is presumed to affect approximately 2% to 3% of the population and remains one of the most common causes of valvular surgery [35].

Typical histopathological features of myxomatous valvular dystrophy include fragmentation of collagenous bundles within the valve fibrosa and accumulation of proteoglycans causing excessive valve tissue that leads to billowing of the valve leaflets, with or without prolapse and regurgitation. The causes of these histological changes remain unknown [6, 7] although recent studies suggest a role of the transforming growth factor-β in these changes at least in specific form of the disease [8].

Initially, MVP has been reported in syndromic form in association with many genetic connective tissue disorders, including Marfan syndrome [9] caused by mutations in the gene fibrillin-1 FBN1, Loeys–Dietz syndrome caused by mutations in transforming growth factor beta receptor 1 TGFBR1 and 2 TGFBR2 [10], Ehlers–Danlos syndrome [11, 12], osteogenesis imperfecta [13] which are associated with collagen mutations in most patients and pseudoxanthoma elasticum [14, 15], which is caused by mutations in the ATP-binding cassette protein ABCC6 [16]. Despite the association of MVP with these connective tissue disorders, linkage of non-syndromic MVP to fibrillin-1 and several collagen genes has been excluded [17].

Recently MVP has been described co-segregating with aortic dilation and Juvenile polyposis syndrome (JPS) in a family with mutation in SMAD4, another gene implicated in the TGFβ network [18].

Non-syndromic Forms of Mitral Valve Prolapse

Familial inheritance has been clearly demonstrated for mitral valve prolapse and a familial screening of the first degree relatives is recommended after the identification of an index patient affected by mitral valve prolapse [19]. Autosomal-dominant transmission is the usual inheritance with reduced penetrance and variable expressivity [1]. Three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31-32 but the underlying genetic defects are not currently known [2022]. A X-linked recessive form has been originally described by Monteleone and Fagan in 1969 [23].

Filamin A Mutations in X-linked Myxomatous Valvular Dystrophy

Familial Description

The proband of the large French family underwent aortic replacement for severe regurgitation at age 17 (Fig. 1). He was of normal size and morphology, and a physical examination found no connective tissue or joint abnormalities. Cardiac auscultation suggested aortic regurgitant murmur, and echocardiography showed severe aortic regurgitation. Aortic root dimensions were normal as confirmed by a nuclear magnetic resonance study of the thoracic aorta. Histological examination of the excised valve showed typical features of myxomatous valvular disease (thickness was superior to 4 mm), with marked thickening of the free edge of the valve. Light microscopy using blue alcyan, hemalun–eosin–safran and Weigert stains was performed, showing extensive accumulation of proteoglycan and fragmentation of the collagenous bundle. Aortic root analysis was strictly normal without any aspect of Marfan or Ehlers–Danlos syndrome. His cousin underwent mitral valve repair for severe mitral regurgitation due to mitral valve dystrophy several weeks later. The identification of a mild haemophilia A in these two patients and the familial study led to the identification of a very large family of more than 300 individuals.
https://static-content.springer.com/image/art%3A10.1007%2Fs12265-011-9308-9/MediaObjects/12265_2011_9308_Fig1_HTML.gif
Fig. 1

Pedigree tree of the French family that led to the identification of the FLNA gene as responsible for myxoïde valve disease. Female family members are indicated by circles; male family members are indicated by squares. Affected status is indicated by filled symbols; patients with no clinical manifestations of XMVD by unfilled symbols; and patients with undetermined status by hatched symbols. Obligatory carriers are designated by a dot inside an open circle. Slashes denote deceased family members. Positive symbol indicates the WT allele, and m indicates the mutated allele

In this family, among 44 males, ten suffered from progressive mitral valve prolapse (leaflet displacement relative to the high points of the saddle-shaped mitral annulus) associated in four cases with moderate to severe aortic regurgitation and four had undergone valvular surgery. Among 47 women, ten were considered as affected with mitral and/or aortic valve abnormalities although all were asymptomatic. One child diagnosed at age 10, showed severe aortic regurgitation with aortic stenosis. In all affected members, the valvular disease was associated with a mild haemophilia A (FVIII activity between 15% and 50%). In order to increase the size of this family to facilitate the identification of the gene responsible for the disease, we have screened our database to identify patients affected by mild haemophilia A and operated for valvulopathy. This led us to identify a new patient operated at age 52 for severe aortic regurgitation and who had also a mild haemophilia A. This patient was deceased at the time of the study but as he originated from the same geographic location than the initial family, we considered that he should be linked to this family and genealogic approach allows us to link the two kindred to a common ancestor born in the eighteenth century. We then performed a familial study. His mother had moderate mitral and aortic regurgitation. Three other males presented with moderate mitral valvular dystrophy and moderate to mild aortic regurgitation. All of them had mild haemophilia A except for one individual whose FVIII activity was normal (>50%) demonstrating that mild haemophilia and the myxomatous valvulopathy are two separated entities in the family. Five females were considered as affected with variable mitral and/or aortic regurgitation.

The second family (family 2) was a British family with X-linked myxomatous valvular dystrophy (XMVD) described by Newbury-Ecob R.A. et al. in 1993 [24]. The proband was born with severe congenital valvular disease and died at 24 h of age with severe cardiac failure (Fig. 2). Necropsy showed dystrophy of all four valves and an atrial septal defect. His grandfather underwent a triple valve replacement and closure of a persistent foramen ovale at age 41. At surgery, the mitral and aortic valves showed myxomatous dystrophy. His brother was diagnosed as having mitral and aortic valvular disease at age 30.
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Fig. 2

a Pedigree of the three other FLNA families and localisation of the mutation within the filamin A gene. b Schematic representation of filamin’s actin-binding domain (ABD) and the 24 repeats. The location of three interacting partners discussed in the text (vimentin, R-Ras and Syk) are indicated together with the XMVD-associated FLNA mutations

Male infant (family 3) was the first child of healthy black African parents (Fig. 2). He was diagnosed antenatally with abnormally thickened cardiac valves by ultrasound and fetal echocardiography and was born at 38 weeks in good condition. Postnatal echocardiography confirmed moderate tricuspid incompetence, trivial mitral and pulmonary incompetence and mild aortic incompetence. All valves were thickened and dystrophic. At 4 months of age, his growth and developmental assessment were within normal limits and he showed no signs of cardiac failure. An echocardiogram showed excellent ventricular function. The mitral valve remained dystrophic without evidence of regurgitation and only very mild aortic regurgitation. His mother was examined clinically and showed no evidence of cardiac involvement.

Family 4 was of Hong Kong Chinese origin. The two boys, 12 and 4 years old, had both mitral and aortic dystrophy. A heart murmur was identified in the first boy at age 4 months on a routine check. Subsequent echocardiography revealed he had polyvalvular disease with myxomatous thickening of the mitral tricuspid and aortic valves. He had significant mitral and tricuspid regurgitation with mild aortic regurgitation. His brother was shown to have polyvalvular disease with mitral incompetence and stenosis, tricuspid regurgitation and mild aortic regurgitation. Their mother had an essentially normal echocardiogram at age 38 years with mild aortic and pulmonary incompetence.

All four families presented no clinically apparent extracardiac abnormalities, no dysmorphic features and no epileptic seizures.

Genetic

Using linkage analysis, we first mapped the gene on chromosome Xq28 in the large French family [25]. A standard positional cloning approach identified a first mutation (p.Pro637Gln) in the FLNA gene in all affected members of this French family (Fig. 1). Three other FLNA mutations p.Gly288Arg and p.Val711Asp and a 1,944-bp genomic deletion coding for exons 16 to 19, were identified in the three other families (Fig. 2).

The FLNA gene encodes a large cytoskeletal protein, FLNA, that crosslinks actin filaments into a dynamic three-dimensional structure network and links these to the cell membrane. Filamin proteins have an N-terminal actin-binding domain, followed by 24 immunoglobulin-like filamin repeats that fold into antiparallel beta sheets that function as interfaces for protein interactions [26].

Three of the XMVD mutations cause missense changes in highly conserved amino acid residues and alter repeat consensus sequences, which probably leads to significant conformational changes in the protein. The fourth mutation leads to an in-frame deletion of repeats 5 through 7 [27].

Echographic Analysis of the FLNA Gene Carriers in the French Family

The first finding of our echocardiographic examinations was the preponderance of mitral valve lesions in males compared with female patients (Table 1) in agreement with an X-linked transmission [28]. Indeed, male patients are hemizygous while female patients are heterozygous for filamin A mutation. Mitral leaflets were clearly dystrophic in all male patients as demonstrated by an increase in anterior and posterior leaflet thickness and leaflet length. Mitral annulus was enlarged in diastole and systole compared with control male patients [28]. Mitral valve billowing was present in all but one male with a moderate backward displacement of the anterior leaflet into the left atrium of 3.1 ± 1.5 mm on average [28]. Mitral regurgitation was graded as moderate or severe in the nine males according to a semi-quantitative criterion (left atrial regurgitant jet area to left atrium ratio). However, only one patient underwent mitral valve repair at 18 years old for severe mitral regurgitation.
Table 1

Main echocardiographic characteristics in mutation carriers of the large family (family 1)

 

Males (n = 14)

Females (n = 31)

P

Age (years)

32 ± 16

32 ± 20

0.79

AML billowing (n (%))

12 (85.7)

4 (12.9)

<0.0001

PML billowing (n (%))

8 (57.1)

1 (3.2)

<0.0001

AML thickness (mm)

5.3 ± 1.2

3.4 ± 0.6

<0.0001

PML thickness (mm)

4.5 ± 0.9

2.8 ± 0.7

<0.0001

Mitral regurgitation (n (%))

  

<0.0001

 Mild

0

20 (64.5)

 Moderate

12 (85.7)

4 (12.9)

 Severe

2 (14.3)

0

Aortic regurgitation (n (%))

  

0.006

 Mild

6 (42.8)

9 (29.0)

 Moderate

3 (21.4)

3 (9.7)

 Severe

4 (28.6)

1 (3.2)

Tricuspid regurgitation (n (%))

  

<0.0001

 Mild

9 (64.3)

9 (29.0)

 Moderate

2 (14.3)

1 (3.2)

 Severe

0

0

Pulmonary regurgitation (n (%))

  

<0.0001

 Mild

4 (28.6)

2 (6.4)

 Moderate

0

1 (3.2)

 Severe

0

0

Billowing of the mitral leaflets is defined as the systolic displacement of mitral leaflet at ≥2 mm into the left atrium, relative to a line connecting the mitral annular hinge points in the parasternal long-axis view (i.e. above the superior part of the saddle-shaped mitral annulus)

AML anterior mitral leaflet, PML posterior mitral leaflet

By contrast, females had less severe mitral valve dystrophy (Fig. 3) without significant difference in leaflet thickness or length compared with controls. Annulus diameter did not differ from controls. Among 17 heterozygous females, eight had moderate mitral regurgitation and only one had moderate mitral leaflet billowing [28]. None of them underwent cardiac surgery.
https://static-content.springer.com/image/art%3A10.1007%2Fs12265-011-9308-9/MediaObjects/12265_2011_9308_Fig3_HTML.gif
Fig. 3

Filamin A mitral valve dystrophy (P637Q mutation). a Thickening of anterior leaflet tip (arrow). b Marked posterior leaflet prolapse or billowing (arrow) and mild anterior leaflet billowing. Dash line, annulus line

The second finding was the frequent involvement of the aortic valve with aortic regurgitation. In males aortic regurgitation was found in six of nine carrier patients and was the main reason to refer patients to surgery in three cases. In the three other male patients, aortic regurgitation was considered mild or moderate based on a semi-quantitative approach. Aortic regurgitation was the main aortic valve finding as aortic valve dystrophy is more difficult to ascertain compared with mitral valve dystrophy.

Tricuspid valve and pulmonary valves of males and females were not considered affected by the dystrophic process in this first evaluation. However, a young female had moderate pulmonary regurgitation without left valve defect.

Based on our recent data (Table 1) comprising more patients, mitral regurgitation was moderate in 12 of 14 carrier male patients and severe in two of 14 [27]. Aortic regurgitation was mild in six, moderate in three and severe in four of 14 male patients. Moreover, tricuspid regurgitation was mild in nine and moderate in two of 14 male patients. Finally, pulmonary regurgitation was absent or only of mild grade in males. In females, mitral regurgitation was absent or mild in 27 and moderate in four of 31 carrier patients. Aortic regurgitation was absent or mild in 28 and moderate in only three of 31 female patients. Tricuspid regurgitation was moderate in only one female and pulmonary regurgitation in only one carrier female patient.

To conclude, FLNA mutations can result in various cardiac defects with or without other organ involvement. Filamin-A-related mitral valve dystrophy has been described in a few families around the world; mitral valve lesions predominate in male patients owing to X-linked FLNA inheritance but females can also be affected with minor lesions. The precise mechanism of the development of the disease remains unclear. However, like other X-linked diseases, X chromosome inactivation (XCI) might be a key component of how the disease develops. Disorders caused by defects in the FLNA gene often show a skewed XCI pattern [29]. Primarily, the XCI choice is random, but when most of the normal X chromosomes are preferentially inactivated in the target tissues, the carriers will show typical features of X-linked diseases usually observed in male patients. Skewed XCI is known to vary in different tissues and to correlate with age under the pressure of secondary selection [30]. Several mechanisms may contribute to the skewing, including stochastic effects, a selective growth advantage of the cell that carries either the mutated or the normal allele (secondary cell selection) and genetic processes yielding preferential inactivation of specific alleles. During cell proliferation, either in all cells or in a tissue specific manner, cells that carry an active mutated allele may have a significant disadvantage, are gradually lost or selected against, and are thus less represented in the adult female.[31]. Therefore, it is important to investigate the XCI patterns to understand the pathogenesis of the disease in female carriers. Mitral valve lesions are characterized by leaflet thickening, leaflet elongation and moderate billowing in male patients. Polyvalvular involvement associating mitral valve dystrophy and aortic regurgitation is a frequent finding in these patients but the tricuspid and pulmonary valves can also be affected by the dystrophic process. Further investigations are warranted to determine the overall valvular phenotype of this specific aetiology of valve dystrophy.

Functional Consequences of the FLNA Mutations

The human FLNA molecule consists in 24 immunoglobulin-like domains preceded by an N-terminal actin-binding domain of 275 residues, which includes two calponin homology domains that are characteristic of actin-binding proteins. Filamin A stabilizes cortical three-dimensional F-actin networks and links them to cellular membranes thereby conferring membranes integrity and protecting cells against mechanical stress [26]. In addition to actin, FLNA binds to >70 cellular proteins including transmembrane receptors and signalling molecules. FLNA thus exhibits essential scaffolding functions and integrates multiple cellular behaviours during embryonic development, cellular migration or mechanical stress response [3234].

Not surprisingly, FLNA mutations cause a wide spectrum of congenital anomalies including: Melnick–Needles syndrome (MNS), otopalatodigital syndrome (OPD) and periventricular heterotopia (PVH) [35, 36]. However, although FLNA null mutations causing PVH were associated with neuronal migration failure during fetal development [37] and many mutations causing MNS and OPD were linked to gain of function in actin-binding domain [29], to date, the molecular mechanisms by which FLNA mutations affect cellular behaviours remain largely unknown. The same holds for the mutations which result in XMVD.

Functional analyses through FLNA gene knockout studies have provided important information on the role of FLNA during cardiac morphogenesis [38]. Indeed, complete loss of FLNA results in embryonic lethality with pleomorphic array of cardiac malformations involving ventricles, atria and outflow tracts, as well as widespread aberrant vascular patterning [39]. Abnormal epithelial and endothelial organization and aberrant adherent junctions in developing blood vessels in heart and other tissues support the essential roles for FLNA in intercellular junctions and provide possible mechanism for the valvular defects seen in patients [40]. In fact, valvulogenesis is a complex process in which growth factors signal the process of endocardium-to-mesenchyme transformation (EMT) resulting in formation of pre-valvular cushions [41]. The spatio-temporal distribution of FLNA during cardiac morphogenesis supports its key role in this developmental process. Indeed, FLNA is found in the endothelium and mesenchyme of atrioventricular and outflow tract cushions, the epicardium and the endothelium of the ventricular trabeculae, supporting the idea that, in the developing valves, FLNA participates in endothelial integrity and promotes maturation of the valvular interstitium after EMT [4244]. However, how FLNA mutations affect valve development remains unresolved.

FLNA appears as a functional hub in many signalling pathway that may contribute to the development of the valvular disease. For example, FLNA is known to modulate TGF-β signalling and physically interacts with its intracellular mediators Smads [45]. It may, thus, interfere with the TGF-β signalling pathways which are known to contribute to the molecular machinery essential for collagen deposition, and matrix remodelling in the myxomatous valve associated to mitral valve prolapse as this is the case in the Marfan syndrome [8, 46, 47]. However, it is worth noting that most of FLNA binding partners identified to date (including Smads) interact with the C-terminal repeats of the protein whereas XMVD mutations are clustered in the N-terminal 1–8 repeats [3234], suggesting their pathological effects may arise from interactions with new, yet unknown binding partners or more remote defects in the signalling pathway.

Interestingly, recent studies identified new FLNA binding partners interacting through the N-terminal repeats of the protein that could potentially have physiopathological consequences. These include the small GTPase R-Ras, the spleen tyrosine kinase (Syk) and the intermediate filament protein vimentin (Fig. 2b).

R-Ras is a small GTPase of the Ras family known to regulate many cell functions including apoptosis, cell adhesion, cell spreading, and phagocytosis through the activation of integrin. In a recent study Griffiths and colleagues demonstrated the role of FLNA/R-Ras interactions in cadherin organization at endothelial cell–cell adherens junctions and the regulation of endothelium permeability [48, 49]. Whether the XMV-associated mutations affect FLNA/R-Ras interactions and impact valvulogenesis through abnormal endothelial function and endothelial-mesenchymal transformation as discussed above will require future studies.

Falet and colleagues identified the Syk as a new binding partner of FLNA N-terminal repeats 1–3 and 5 [50]. They showed Syk/FLNA interaction participates in immunoreceptor tyrosine-based activation motif (ITAM) response. In their inducible FLNA knock out model, the ITAM response is severely compromised. FLNA null platelets exhibit decreased α-granule secretion, integrin αIIbβ3 activation, and protein–tyrosine phosphorylation and, in particular, that of the protein–tyrosine kinase Syk. This study indicates that FLNA contributes to Syk spatial distribution to the cytoplasmic surface of the platelet plasma membrane and facilitates Syk phosphorylation and activation. Interestingly, Syk participates in the regulation of serotonin transporter activity (SERT) which has been widely involved in the development of cardiac fibrosis and valvulopathy [5157]. Here again, whether XMVD-associated FLNA mutations alter Syk activation, SERT activity and valvular serotonin signalling should be clarified.

The last FLNA binding partner recently identified is vimentin [58]. Vimentin is a member of the intermediate filament family of proteins which is expressed in quiescent valvular interstitial cells and activated myofibroblasts [40]. Vimentin shares several functional features in common with FLNA, including regulation of cell adhesion and motility, enrichment in β1 integrin-containing focal adhesions, reorganization of collagen fibrils, contraction of collagen lattices and mechanical stabilization of cells [59]. One can speculate that a functional defect of vimentin may participate to the pathological portrait of FLNA associated XMVD. Interestingly recent studies described FLNA–vimentin–protein kinase C (PKCε) interaction and localized their binding site in the N-terminal repeats of FLNA (repeats 1–8) [60, 61]. They showed FLNA–vimentin interactions modulate cell adhesion to collagen through the regulation of β1 integrin trafficking. Deficient FLNA–vimentin–PKCε interaction limits vimentin phosphorylation that increases β1 integrin endocytosis and degradation which finally results in reduced β1 integrin plasma membrane expression [62]. Given the crucial role of β1 integrin signalling pathways in cell migration, extracellular matrix remodelling, chemokin signalling pathway (including TGF-β) in response to mechanical stress, makes vimentin–FLNA an interesting duo to consider in XMVD [63].

Conclusions

MVP appears to be the result of multiple genetic pathways, as illustrated by the identification of several genes in syndromic MVP and three loci for non-syndromic MVP. The identification of FLNA mutations in an X-linked form of valvular dystrophy highlight the importance of the cytoskeleton not only in providing structural integrity but also in critical cellular signalling pathways, specifically the TGF-β pathway. As FLNA interacts with a large number of partners involved in several different pathways it is currently difficult to draw a clear picture of the major pathophysiological mechanism involved in the occurrence of mitral valve prolapse. Why the FLNA mutations identified in the MVP lead to a phenotype restricted to the cardiac valves whereas the FLNA is widely expressed remains unresolved? Interaction with protein partners mainly expressed or functionally important in cardiac valves; and the presence of a pulsatile stretch on the valves not present in the other tissues appears to be the most probable explanations. Advances in DNA sequencing technologies should lead to the identification of the MMVP1, MMVP2 and MMVP3 genes in the near future. Large-scale collections of MVP patients and genome wide association studies will allow identification of additional MVP genes and finally allow to understand the complete pathway (unique or not) leading to the occurrence of mitral valve prolapse.

Identification of the genes involved in the development of MVP is important because the disease typically manifests later in life, and earlier intervention in susceptible individuals could potentially prevents progression to a clinically severe stage. Studies in murine models of Marfan syndrome have shown for the first time that the myxomatous changes characteristic of MVP are pharmacologically preventable, which offers great hope for the development of therapies based on future genetic discoveries.

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