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Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations

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Abstract

The aim of this study was to identify regions of the genome that harbor genes influencing inheritance of bicuspid aortic valve (BAV) and/or associated cardiovascular malformation (CVM). Aortic valve disease is an important clinical problem, which often results in valve replacement, the second most common cardiac surgery in the United States. In every age group, a majority of cases of valve disease involves a BAV. BAV is the most common CVM with a reported prevalence of 1–2%. Heritability studies indicate that BAV determination is almost entirely genetic. We used a family-based genome-wide linkage analysis with microsatellite markers. Parametric and nonparametric analyses were performed with the software GENEHUNTER and SOLAR (Sequential Oligogenic Linkage Analysis Routines). Thirty-eight families (353 subjects) with BAV and/or associated CVM were assessed. Each participant underwent a standardized echocardiographic examination. The highest LOD score, 3.8, occurred on chromosome 18q between markers D18S68 and D18S1161. Two other chromosomal regions, 5q15–21 (between D5S644 and D5S2027) and 13q33-qter (between D13S1265 and 13qter), exhibited suggestive evidence of linkage (LOD > 2.0). Further, two previously reported linkage peaks on 9q34 and 17q24 were replicated in family specific analyses. No significant X chromosome linkage peaks were identified. In this genome-wide scan we demonstrate for the first time, that BAV and/or associated CVM exhibit linkage to chromosomes 18q, 5q and 13q. These regions likely contain genes whose mutation results in BAV and/or associated CVM indicating their important role in valvulogenesis and cardiac development.

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Acknowledgments

The authors are grateful to the families who participated in this study. The echocardiographic studies would not have been possible without the assistance of the sonographers in the Cardiovascular Imaging Core Research Laboratory, Betty Glascock, Fred Jones, Vickie Moore and Sandy Witt. This work was supported by grants from National Institutes of Health HD43005 (RBH), HL085122 (RBH), HL069712 (DWB), and HL074728 (DWB, LJM, LHC).

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Author notes

  1. Gregor Andelfinger

    Present address: Department of Pediatrics, Hospital Ste-Justine and University of Montreal, Montreal, QC, Canada

Authors and Affiliations

  1. Center for Epidemiology and Biostatistics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Lisa J. Martin & Meredith Tabangin

  2. Division of Human Genetics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Lisa J. Martin & Mehdi Keddache

  3. Department of Pediatrics, Division of Cardiology, MLC 7042, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA

    Vijaya Ramachandran, Linda H. Cripe, Robert B. Hinton, Gregor Andelfinger, Kerry Shooner & D. Woodrow Benson

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  1. Lisa J. Martin
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Correspondence to D. Woodrow Benson.

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Lisa J. Martin and Vijaya Ramachandran have contributed equally to this work.

Electronic supplementary material

439_2006_316_MOESM1_ESM.doc

Supplemental Table 1. Family specific LOD scores for QTLs on chromosome 18q22.1 (D18S61), 5q21.2 (D5S4333) and 13q34 (D13S285). (DOC 55 kb)

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Martin, L.J., Ramachandran, V., Cripe, L.H. et al. Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. Hum Genet 121, 275–284 (2007). https://doi.org/10.1007/s00439-006-0316-9

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