A locus for autosomal dominant mitral valve prolapse on chromosome 11p15.4

Abstract

Mitral valve prolapse (MVP) is a common cardiovascular abnormality in the United States, occurring in approximately 2.4% of the general population. Clinically, patients with MVP exhibit fibromyxomatous changes in one or both of the mitral leaflets that result in superior displacement of the leaflets into the left atrium. Although often clinically benign, MVP can be associated with important accompanying sequelae, including mitral regurgitation, bacterial endocarditis, congestive heart failure, atrial fibrillation, and even sudden death. MVP is genetically heterogeneous and is inherited as an autosomal dominant trait that exhibits both sex- and age-dependent penetrance. In this report, we describe the results of a genome scan and show that a locus for MVP maps to chromosome 11p15.4. Multipoint parametric analysis performed by use of GENEHUNTER gave a maximum LOD score of 3.12 for the chromosomal region immediately surrounding the four-marker haplotype D11S4124-D11S2349-D11S1338-D11S1323, and multipoint nonparametric analysis (NPL) confirms this finding (NPL=38.59; P=.000397). Haplotype analysis across this region defines a 4.3-cM region between the markers D11S1923 and D11S1331 as the location of a new MVP locus, MMVP2, and confirms the genetic heterogeneity of this disorder. The discovery of genes involved in the pathogenesis of this common disease is crucial to understanding the marked variability in disease expression and mortality seen in MVP.

Figure 1

Pedigree of family with MVP showing chromosome 11 haplotypes. Affected, unaffected, and indeterminate individuals are shown as blackened, unblackened, and gray symbols, respectively. Patient ID codes are shown beneath the symbol. Symbols with a question mark (?) represent individuals who did not participate in the study. An asterisk (*) indicates individuals who were used in the GENEHUNTER analysis. Spouses of 25077 and 25065 were phenotyped, but DNA was unavailable. A black bar represents the disease chromosome, with the location of recombination events marked as “X.” The marker order for all haplotypes is shown next to individual 25067.

Figure 2

GENEHUNTER analysis of the MMVP2 locus. Distances between the markers correspond to the marker map in table 1. A, Graph of multipoint parametric LOD scores. B, Graph of multipoint NPL scores.