title: Whole-exome sequencing in an extended family with myocardial infarction unmasks familial hypercholesterolemia.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Brænne
authors.forename: Benedikt
authors.initials: B
authors.lastname: Reiz
authors.forename: Anja
authors.initials: A
authors.lastname: Medack
authors.forename: Mariana
authors.initials: M
authors.lastname: Kleinecke
authors.forename: Marcus
authors.initials: M
authors.lastname: Fischer
authors.forename: Salih
authors.initials: S
authors.lastname: Tuna
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, 23562 Lübeck, Germany. jeanette.erdmann@iieg.uni-luebeck.de.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D015415:Biomarkers / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D001026:Coronary Artery Bypass; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009203:Myocardial Infarction / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D015415:Biomarkers; D008078:Cholesterol, LDL; C573412:LDLR protein, human; D011973:Receptors, LDL