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J Med Genet. 2014 Aug;51(8):537-44. doi: 10.1136/jmedgenet-2014-102405. Epub 2014 Jul 1.

Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.

Author information

1
British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, the Rayne Building University College London, London, UK.
2
Department of Genetics, Environment and Evolution, UCL Genetics Institute, University College London, London, UK.
3
Department of Primary Care Health Sciences, NIHR School of Primary Care Research, University of Oxford, Oxford, UK.
4
Department of Cardiology, Imperial College Health Services, Charing Cross Hospital, London, UK.
5
Department of Internal Medicine, University of Genoa, Genoa, Italy.
6
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
7
Centre de Recherche Médicale de Jolimont, Haine St-Paul, Belgium.
8
Queens University Belfast & Regional Genetics Centre, Belfast Health and Social Care Trust/City Hospital Belfast BT9 7AB Northern Ireland UK.
9
Robarts Research Institute, London, Ontario, Canada.
10
OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
11
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.
12
Department of Medicine, Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah Hebrew University Medical Centre, Jerusalem, Israel.
13
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK.
14
Consultant Lipidologist and Chemical Pathologist Director SAS Laboratory for Cardiac Biomarkers, Royal Free Hospital, London, UK.
15
Cardiovascular Trials Unit, University Department of Medicine, Central Manchester University Hospital NHS Foundation Trust, Manchester, UK.
16
Division of Laboratory Medicine, Department of Biochemistry, Royal Perth Hospital, Perth, Australia.

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.

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.

KEYWORDS:

Cardiovascular Medicine; Diagnosis; Genetics; Lipid Disorders

PMID:
24987033
PMCID:
PMC4112429
DOI:
10.1136/jmedgenet-2014-102405
[Indexed for MEDLINE]
Free PMC Article

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