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(Circulation. 2005;112:2022-2030.)
© 2005 American Heart Association, Inc.

Valvular Heart Disease

New Locus for Autosomal Dominant Mitral Valve Prolapse on Chromosome 13

Clinical Insights From Genetic Studies

Francesca Nesta, MD^*; Maire Leyne, MS^*; Chaim Yosefy, MD; Charles Simpson, BS; Daisy Dai, BS; Jane E. Marshall, RDCS; Judy Hung, MD; Susan A. Slaugenhaupt, PhD; Robert A. Levine, MD

From the Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Department of Medicine, Harvard Medical School (F.N., C.Y., J.E.M, J.H., R.A.L.), and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School (M.L., C.S., D.D., S.A.S.), Boston, Mass.

Correspondence to Robert A. Levine, MD, Massachusetts General Hospital, Cardiac Ultrasound Laboratory, 55 Fruit St YWK5068, Boston, MA 02114. E-mail rlevine{at}partners.org

Received October 26, 2004; revision received June 3, 2005; accepted June 14, 2005.

Background— Mitral valve prolapse (MVP) is a common disorder associated with mitral regurgitation, endocarditis, heart failure, and sudden death. To date, 2 MVP loci have been described, but the defective genes have yet to be discovered. In the present study, we analyzed a large family segregating MVP, and identified a new locus, MMVP3. This study and others have enabled us to explore mitral valve morphological variations of currently uncertain clinical significance.

Methods and Results— Echocardiograms and blood samples were obtained from 43 individuals who were classified by the extent and pattern of displacement. Genotypic analyses were performed with polymorphic microsatellite markers. Evidence of linkage was obtained on chromosome 13q31.3-q32.1, with a peak nonparametric linkage score of 18.41 (P<0.0007). Multipoint parametric analysis gave a logarithm of odds score of 3.17 at marker D13S132. Of the 6 related individuals with mitral valve morphologies not meeting diagnostic criteria but resembling fully developed forms, 5 carried all or part of the haplotype linked to MVP.

Conclusions— The mapping of a new MVP locus to chromosome 13 confirms the observed genetic heterogeneity and represents an important step toward gene identification. Furthermore, the genetic analysis provides clinical lessons with regard to previously nondiagnostic morphologies. In the familial context, these may represent early expression in gene carriers. Early recognition of gene carriers could potentially enhance the clinical evaluation of patients at risk of full expression, with the ultimate aim of developing interventions to reduce progression.

Key Words: echocardiography • genetics • mitral valve

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