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Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations
  1. Marta Futema1,
  2. Vincent Plagnol2,
  3. KaWah Li1,
  4. Ros A Whittall1,
  5. H Andrew W Neil3,
  6. Mary Seed4,
  7. on behalf of the Simon Broome Consortium,
  8. Stefano Bertolini5,
  9. Sebastiano Calandra6,
  10. Olivier S Descamps7,
  11. Colin A Graham8,
  12. Robert A Hegele9,
  13. Fredrik Karpe10,
  14. Ronen Durst11,12,
  15. Eran Leitersdorf12,
  16. Nicholas Lench13,
  17. Devaki R Nair14,
  18. Handrean Soran15,
  19. Frank M Van Bockxmeer16,
  20. UK10K Consortium17,
  21. Steve E Humphries1
  1. 1British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, the Rayne Building University College London, London, UK
  2. 2Department of Genetics, Environment and Evolution, UCL Genetics Institute, University College London, London, UK
  3. 3Department of Primary Care Health Sciences, NIHR School of Primary Care Research, University of Oxford, Oxford, UK
  4. 4Department of Cardiology, Imperial College Health Services, Charing Cross Hospital, London, UK
  5. 5Department of Internal Medicine, University of Genoa, Genoa, Italy
  6. 6Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
  7. 7Centre de Recherche Médicale de Jolimont, Haine St-Paul, Belgium
  8. 8Queens University Belfast & Regional Genetics Centre, Belfast Health and Social Care Trust/City Hospital Belfast BT9 7AB Northern Ireland UK
  9. 9Robarts Research Institute, London, Ontario, Canada
  10. 10OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
  11. 11Cardiology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  12. 12Department of Medicine, Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah Hebrew University Medical Centre, Jerusalem, Israel
  13. 13North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK
  14. 14Consultant Lipidologist and Chemical Pathologist Director SAS Laboratory for Cardiac Biomarkers, Royal Free Hospital, London, UK
  15. 15Cardiovascular Trials Unit, University Department of Medicine, Central Manchester University Hospital NHS Foundation Trust, Manchester, UK
  16. 16Division of Laboratory Medicine, Department of Biochemistry, Royal Perth Hospital, Perth, Australia
  17. 17The University of Western Australia, Perth, Australia
  1. Correspondence to Professor Steve E Humphries, Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, The Rayne Building University College London, London WC1E 6JF, UK; steve.humphries{at}, rmhaseh{at}


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.

Methods and 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.

  • Genetics
  • Lipid Disorders
  • Diagnosis
  • Cardiovascular Medicine

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