Brnne, Ingrid and Reiz, Benedikt and Medack, Anja and Kleinecke, Mariana and Fischer, Marcus and Tuna, Salih and Hengstenberg, Christian and Deloukas, Panos and Erdmann, Jeanette and Schunkert, Heribert (2014) Whole-exome sequencing in an extended family with myocardial infarction unmasks familial hypercholesterolemia. BMC CARDIOVASCULAR DISORDERS, 14: 108. ISSN 1471-2261,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LDL RECEPTOR GENE; DISEASE; MUTATIONS; GENOME; PREVALENCE; STRATEGIES; GUIDANCE; Familial hypercholesterolemia; Myocardial infarction; Whole-exome sequencing |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Aug 2019 14:21 |
| Last Modified: | 29 Aug 2019 14:21 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9725 |
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