title: Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.
abstract: BACKGROUND
  Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation.
  
  
  RESULTS
  Exomes of 125 unrelated DFH patients were sequenced, as part of the UK10K project. First, analysis of known FH genes identified 23 LDLR and two APOB mutations, and patients with explained causes of FH were excluded from further analysis. Second, common and rare variants in genes associated with low-density lipoprotein cholesterol (LDL-C) levels in genome-wide association study (GWAS) meta-analysis were examined. There was no clear rare variant association in LDL-C GWAS hits; however, there were 29 patients with a high LDL-C SNP score suggestive of polygenic hypercholesterolaemia. Finally, a gene-based burden test for an excess of rare (frequency <0.005) or novel variants in cases versus 1926 controls was performed, with variants with an unlikely functional effect (intronic, synonymous) filtered out.
  
  
  CONCLUSIONS
  No major novel locus for FH was detected, with no gene having a functional variant in more than three patients; however, an excess of novel variants was found in 18 genes, of which the strongest candidates included CH25H and INSIG2 (p<4.3×10(-4) and p<3.7×10(-3), respectively). This suggests that the genetic cause of FH in these unexplained cases is likely to be very heterogeneous, which complicates the diagnostic and novel gene discovery process.
authors.affiliation: British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, the Rayne Building University College London, London, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Futema
authors.affiliation: Department of Genetics, Environment and Evolution, UCL Genetics Institute, University College London, London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, the Rayne Building University College London, London, UK.
authors.forename: KaWah
authors.initials: K
authors.lastname: Li
authors.affiliation: British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, the Rayne Building University College London, London, UK.
authors.forename: Ros A
authors.initials: RA
authors.lastname: Whittall
authors.affiliation: Department of Primary Care Health Sciences, NIHR School of Primary Care Research, University of Oxford, Oxford, UK.
authors.forename: H Andrew W
authors.initials: HA
authors.lastname: Neil
authors.affiliation: Department of Cardiology, Imperial College Health Services, Charing Cross Hospital, London, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Seed
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.affiliation: Centre de Recherche Médicale de Jolimont, Haine St-Paul, Belgium.
authors.forename: Olivier S
authors.initials: OS
authors.lastname: Descamps
authors.affiliation: Queens University Belfast & Regional Genetics Centre, Belfast Health and Social Care Trust/City Hospital Belfast BT9 7AB Northern Ireland UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Graham
authors.affiliation: Robarts Research Institute, London, Ontario, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.affiliation: OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.affiliation: Cardiology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel Department of Medicine, Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah Hebrew University Medical Centre, Jerusalem, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Durst
authors.affiliation: Department of Medicine, Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah Hebrew University Medical Centre, Jerusalem, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Leitersdorf
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lench
authors.affiliation: Consultant Lipidologist and Chemical Pathologist Director SAS Laboratory for Cardiac Biomarkers, Royal Free Hospital, London, UK.
authors.forename: Devaki R
authors.initials: DR
authors.lastname: Nair
authors.affiliation: Cardiovascular Trials Unit, University Department of Medicine, Central Manchester University Hospital NHS Foundation Trust, Manchester, UK.
authors.forename: Handrean
authors.initials: H
authors.lastname: Soran
authors.affiliation: Division of Laboratory Medicine, Department of Biochemistry, Royal Perth Hospital, Perth, Australia.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Van Bockxmeer
authors.affiliation: British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, the Rayne Building University College London, London, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics; D008078:Cholesterol, LDL / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Cardiovascular Medicine; Diagnosis; Genetics; Lipid Disorders