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Open Access Highly Accessed Research article

Whole-exome sequencing in an extended family with myocardial infarction unmasks familial hypercholesterolemia

Ingrid Brænne12, Benedikt Reiz12, Anja Medack1, Mariana Kleinecke12, Marcus Fischer3, Salih Tuna6, Christian Hengstenberg45, Panos Deloukas678, Jeanette Erdmann12*, Heribert Schunkert45 and Cardiogenics consortium

Author Affiliations

1 Institute for Integrative and Experimental Genomics, University of Lübeck, 23562 Lübeck, Germany

2 DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany

3 Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany

4 Deutsches Herzzentrum München and Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany

5 DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80636 Munich, Germany

6 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK

7 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

8 Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia

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BMC Cardiovascular Disorders 2014, 14:108  doi:10.1186/1471-2261-14-108

Published: 26 August 2014

Abstract

Background

Familial hypercholesterolemia (FH) is an autosomal-dominant disease leading to markedly elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature myocardial infarction (MI). Mutation carriers display variable LDL cholesterol levels, which may obscure the diagnosis. We examined by whole-exome sequencing a family in which multiple myocardial infarctions occurred at a young age with unclear etiology.

Methods

Whole-exome sequencing of three affected family members, validation of the identified variant with Sanger-sequencing, and subsequent co-segregation analysis in the family.

Results

The index patient (LDL cholesterol 188 mg/dL) was referred for molecular-genetic investigations. He had coronary artery bypass graft (CABG) at the age of 59 years; 12 out of 15 1st, 2nd and 3rd degree relatives were affected with coronary artery disease (CAD) and/or premature myocardial infarction (MI). We sequenced the whole-exome of the patient and two cousins with premature MI. After filtering, we were left with a potentially disease causing variant in the LDL receptor (LDLR) gene, which we validated by Sanger-sequencing (nucleotide substitution in the acceptor splice-site of exon 10, c.1359-1G > A). Sequencing of all family members available for genetic analysis revealed co-segregation of the variant with CAD (LOD 3.0) and increased LDLC (>190 mg/dL), following correction for statin treatment (LOD 4.3). Interestingly, mutation carriers presented with highly variable corrected (183–354 mg/dL) and on-treatment LDL levels (116–274 mg/dL) such that the diagnosis of FH in this family was made only after the molecular-genetic analysis.

Conclusion

Even in families with unusual clustering of CAD FH remains to be underdiagnosed, which underscores the need for implementation of systematic screening programs. Whole-exome sequencing may facilitate identification of disease-causing variants in families with unclear etiology of MI and enable preventive treatment of mutation carriers in a more timely fashion.

Keywords:
Familial hypercholesterolemia; Myocardial infarction; Whole-exome sequencing