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Inheritance Impacts Mitral Valve Insufficiency
Daniel P. Judge, MD; Russell A. Norris, PhD
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s the field of cardiovascular genetics continues to evolve,
traditional Mendelian disorders are more readily characterized by clinical genetic testing. These conditions are
caused by rare DNA mutations with major effects for most, if
not all carriers. The newest frontiers for genetic investigation
include more common disorders in which the genetic variants are more prevalent and the effect sizes are smaller. The
spectrum extends from severe neonatal disorders with high
penetrance to more common diseases, such as familial mitral
valve prolapse (MVP). Pushing this envelope, investigators in
this issue of Circulation: Cardiovascular Genetics now report
heritability of mitral regurgitation (MR).1 Starting with the
well-characterized Framingham Heart Study participants in
whom second- and third-generation cardiac data were available, they identified 1062 with ≥mild MR among 5132 (21%),
in whom there was adequate parental and sibling information.
The odds ratio of MR was 1.42 if parental MR was present
after adjusting for age, sex, and risk factors and with restricting to ≥moderate MR. Likewise, the odds ratio of MR was
1.78 if sibling MR was present after adjusting for age, sex, and
risk factors and restricting to ≥moderate MR. Strengthening
their conclusions, the authors used the Swedish hospital
registry to validate these findings. In Sweden, 1.2% (239 of
18 891) of siblings with sibling MR had MR compared with
0.2% (n=8389/5 138 298) without sibling MR, corresponding
to a hazard ratio of 4.0 adjusted for age and sex. MR is more
commonly seen in the context of hypertrophic and dilated cardiomyopathy, each of which runs in families, but exclusion of
those individuals in both cohorts did not significantly change
the results. As the authors point out, further studies are needed
to elucidate the genetic factors involved with these interesting
worldwide, with consequences for MR, including arrhythmia,
endocarditis, heart failure, stroke, and sudden cardiac death.3,4
The causes are numerous, with a common pathway resulting
in either mitral valve leaflets that are too long and redundant
or too short in relation to the mitral annulus and left ventricle.
Numerous underlying conditions are associated with MR,
such as ischemic cardiomyopathy, hypertension, MVP, and
several heritable disorders of connective tissue.3 Most affected
individuals have a paucity of symptoms before severe mitral
insufficiency, resulting in left ventricular dilation, arrhythmia,
and heart failure. Surgery to repair the mitral leaflets is usually the best approach although valve replacement or catheterbased procedures are sometimes appropriate alternatives.3,5
Clues on the genetics of familial MR may be found in some
of the elegant studies performed previously on MVP. One of
the first answers about the genetic basis and pathogenesis of
MVP was based on its frequent occurrence in patients with
Marfan syndrome.6 After recognition of responsible mutations
in FBN1 encoding the extracellular matrix protein, fibrillin-1,
investigators focused on both the structural and regulatory
impacts that followed from its deficiency in patients with this
condition. Homology between fibrillin-1 and the family of
latent transforming growth factor-beta (TGF-beta)-binding
proteins suggested that FBN1 mutations cause impaired
latency (and more activity) of many TGF-beta proteins.
Consequently, increased mitral valve leaflet length and thickness were associated with increased activity of TGF-beta, and
neutralizing antibodies to TGF-beta normalized mitral valve
morphology in a murine model of Marfan syndrome.7
The next genetic cause for MVP was recognized with
traditional linkage analysis in male patients in France who
needed mitral valve surgery. Coincidentally, a subset of
these men had mildly elevated levels of their activated partial
thromboplastin time because of a linked mutation in their factor VIII gene on chromosome Xq28 with mild hemophilia A.8
Accordingly, after recognizing an X-linked pattern of inheritance, investigation of nearby genes identified novel missense
mutations in FLNA, encoding filamin A.9 Additional studies
have shown abnormal binding of a mutated form of filamin A
to the tyrosine phosphatase PTPN12, impaired activation of its
substrates, Src and RhoA,10 and altered serotonin signaling.11
Large families have previously been used for identification of other genetic contributions to MVP. In 2003, traditional linkage analysis found a locus on chromosome 11p15.4
to be associated with nonsyndromic MVP.12 After extensive
sequencing and genetic provocation of both murine and zebrafish models, mutations in DCHS1, encoding Dachsous-1, were
recognized as a cause for nonsyndromic MVP.13 Curiously,
this gene encodes a component of the primary cilium, and
another ciliopathy (polycystic kidney disease) is also associated with MVP.14 A recent study demonstrated that primary
cilia genes are expressed in valvular mesenchymal cells
See Article by Delling et al
Why is it useful or important to recognize genetic contributions for MR? There are many genes involved with
valvulogenesis, as well as the epigenetic, stochastic, and environmental factors, which impact valve homeostasis.2 Valve
disease is a common contributor to morbidity and mortality
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Department of Medicine/Cardiology (D.P.J.) and the
Department of Regenerative Medicine and Cell Biology (R.A.N.), Medical
University of South Carolina, Charleston; and Center for Inherited Heart
Disease, Johns Hopkins University, Baltimore, MD (D.P.J.).
Correspondence to Daniel P. Judge, MD, Center for Inherited Heart
Disease, Johns Hopkins University, 720 Rutland Ave, Ross 1049,
Baltimore, MD. E-mail
(Circ Cardiovasc Genet. 2017;10:e001920.
DOI: 10.1161/CIRCGENETICS.117.001920.)
© 2017 American Heart Association, Inc.
Circ Cardiovasc Genet is available at
DOI: 10.1161/CIRCGENETICS.117.001920
2 Judge and Norris Genetics of Mitral Regurgitation
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during embryonic development and that their loss with genetic
manipulation causes aortic valve malformations.15 Further
investigation is ongoing about the role of the primary cilium
in other forms of cardiac valve disease.
The largest investigation of MVP genetics took place
through a trans-Atlantic collaboration, with inclusion of several large cohorts and genome-wide association study with
global meta-analysis of 2864 individuals with MVP and 9218
controls.16 Overall, 6 chromosomal loci were linked and validated in this study. In the initial discovery meta-analysis on
2 independent genome-wide association study cohorts, the
locus with the strongest association was identified at chromosome 2q35 by virtue of having a tag single nucleotide
polymorphism (rs12465515) with P=1.08×10−8 in a genedesert region. Further investigation of the closest genes identified several candidates based on their patterns of expression
and response in zebrafish to morpholino knockdown studies. TNS1, encoding tensin-1, is a protein involved in focal
adhesion via its interaction with filamin A and integrins.16
Murine studies showed persistent expression of Tns1 during cardiac valve morphogenesis with persistence into adulthood. Furthermore, Tns1−/− mice and morpholino knockdown
studies in zebrafish demonstrated pathological responses in
the atrioventricular valves.16 Another interesting locus in this
study was chromosome 3p13 in an intron of LMCD1, encoding a transcription factor whose deficiency was subsequently
shown to cause valvular regurgitation in zebrafish morpholino
studies.16 These new mechanisms for MR suggest novel pathways for its pathogenesis and potential therapeutic strategies.
In the study by Delling et al,1 >mild MR was notably prevalent, but screening echocardiography for all adults would be
unnecessarily expensive. Thanks to improved recognition of
its heritability, clinicians should indeed be concerned about
MR developing in their patients who have a family history of
MR. As the Swedish component of this study demonstrates,
use of medical coding may help to convey this diagnosis for
affected individuals and their family members.1 Although the
mitral valve has sometimes been considered a passive structure, other studies show its dynamic nature, suggesting the
feasibility and potential benefit of medical therapies targeting
underlying pathogenic pathways. With a first step of recognizing its heritability, this work may lead to a more personalized
approach to valvular heart disease in the future.
1. Delling FN, Li X, Li S, Yang Q, Xanthakis V, Martinsson A, et al. Heritability of mitral regurgitation: observations from the Framingham Heart
Study and Swedish population. Circ Cardiovasc Genet. 2017;10:e001736.
doi: 10.1161/CIRCGENETICS.117.001736.
2. Padang R, Bagnall RD, Semsarian C. Genetic basis of familial valvular
heart disease. Circ Cardiovasc Genet. 2012;5:569–580. doi: 10.1161/
3. Levine RA, Hagége AA, Judge DP, Padala M, Dal-Bianco JP, Aikawa E, et
al; Leducq Mitral Transatlantic Network. Mitral valve disease–morphology and mechanisms. Nat Rev Cardiol. 2015;12:689–710. doi: 10.1038/
4. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, EnriquezSarano M. Burden of valvular heart diseases: a population-based study.
Lancet. 2006;368:1005–1011. doi: 10.1016/S0140-6736(06)69208-8.
5. Steinberg DH, Castillo-Sang M, Powers ER. Advances in transcatheter
valve therapies. J Cardiovasc Transl Res. 2014;7:375–386. doi: 10.1007/
6. Judge DP, Rouf R, Habashi J, Dietz HC. Mitral valve disease in Marfan
syndrome and related disorders. J Cardiovasc Transl Res. 2011;4:741–
747. doi: 10.1007/s12265-011-9314-y.
7. Ng CM, Cheng A, Myers LA, Martinez-Murillo F, Jie C, Bedja D, et al.
TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse
model of Marfan syndrome. J Clin Invest. 2004;114:1586–1592. doi:
8. Kyndt F, Schott JJ, Trochu JN, Baranger F, Herbert O, Scott V, et al. Mapping of X-linked myxomatous valvular dystrophy to chromosome Xq28.
Am J Hum Genet. 1998;62:627–632. doi: 10.1086/301747.
9. Kyndt F, Gueffet JP, Probst V, Jaafar P, Legendre A, Le Bouffant F, et
al. Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy. Circulation. 2007;115:40–49. doi: 10.1161/
10. Duval D, Labbé P, Bureau L, Le Tourneau T, Norris RA, Markwald RR,
et al. MVP-associated filamin A mutations affect FlnA-PTPN12 (PTPPEST) interactions. J Cardiovasc Dev Dis. 2015;2:233–247. doi: 10.3390/
11. Sauls K, de Vlaming A, Harris BS, Williams K, Wessels A, Levine RA,
et al. Developmental basis for filamin-A-associated myxomatous mitral valve disease. Cardiovasc Res. 2012;96:109–119. doi: 10.1093/cvr/
12. Freed LA, Acierno JS Jr, Dai D, Leyne M, Marshall JE, Nesta F, et al.
A locus for autosomal dominant mitral valve prolapse on chromosome
11p15.4. Am J Hum Genet. 2003;72:1551–1559. doi: 10.1086/375452.
13. Durst R, Sauls K, Peal DS, deVlaming A, Toomer K, Leyne M, et al. Mutations in DCHS1 cause mitral valve prolapse. Nature. 2015;525:109–113.
doi: 10.1038/nature14670.
14. Hossack KF, Leddy CL, Johnson AM, Schrier RW, Gabow PA. Echocardiographic findings in autosomal dominant polycystic kidney disease. N
Engl J Med. 1988;319:907–912. doi: 10.1056/NEJM198810063191404.
15. Toomer KA, Fulmer D, Guo L, Drohan A, Peterson N, Swanson P, et al.
A role for primary cilia in aortic valve development and disease. Dev Dyn.
2017;246:625–634. doi: 10.1002/dvdy.24524.
16. Dina C, Bouatia-Naji N, Tucker N, Delling FN, Toomer K, Durst R, et al;
PROMESA Investigators; MVP-France; Leducq Transatlantic MITRAL
Network. Genetic association analyses highlight biological pathways
underlying mitral valve prolapse. Nat Genet. 2015;47:1206–1211. doi:
Dr Judge has received payment as a scientific advisor to Alnylam,
Array Biopharma, Glaxo Smith Kline, Invitae, MyoKardia, and
Pfizer. The other author reports no conflicts.
KEY WORDS: Editorials ◼ cardiomyopathy, dilated ◼ heart failure ◼ genetics
◼ mitral valve ◼ risk factors
Inheritance Impacts Mitral Valve Insufficiency
Daniel P. Judge and Russell A. Norris
Downloaded from by guest on October 25, 2017
Circ Cardiovasc Genet. 2017;10:
doi: 10.1161/CIRCGENETICS.117.001920
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