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

Autor: Mariana Kleinecke, Jeanette Erdmann, Benedikt Reiz, Ingrid Braenne, Panos Deloukas, Marcus Fischer, Anja Medack, Salih Tuna, Christian Hengstenberg, Heribert Schunkert
Rok vydání: 2014
Předmět:
Adult
Male
medicine.medical_specialty
DNA Mutational Analysis
Familial hypercholesterolemia
Myocardial Infarction
030204 cardiovascular system & hematology
Hyperlipoproteinemia Type II
Coronary artery disease
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Predictive Value of Tests
Internal medicine
medicine
Humans
Exome
Genetic Predisposition to Disease
Genetic Testing
Myocardial infarction
Age of Onset
Coronary Artery Bypass
Exome sequencing
Aged
030304 developmental biology
0303 health sciences
business.industry
Cholesterol
Cholesterol
LDL
Middle Aged
medicine.disease
Pedigree
3. Good health
Phenotype
Receptors
LDL
chemistry
Whole-exome sequencing
Mutation
LDL receptor
Cardiology
Female
Myocardial infarction diagnosis
Cardiology and Cardiovascular Medicine
business
Biomarkers
Research Article
Zdroj: BMC Cardiovascular Disorders
ISSN: 1471-2261
Popis: 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.
Databáze: OpenAIRE
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