RT Journal Article
SR Electronic
T1 Whole exome sequencing of familial hypercholesterolaemia patients negative for <em>LDLR</em>/<em>APOB</em>/<em>PCSK9</em> mutations
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 537
OP 544
DO 10.1136/jmedgenet-2014-102405
VO 51
IS 8
A1 Futema, Marta
A1 Plagnol, Vincent
A1 Li, KaWah
A1 Whittall, Ros A
A1 Neil, H Andrew W
A1 Seed, Mary
A1 ,
A1 Bertolini, Stefano
A1 Calandra, Sebastiano
A1 Descamps, Olivier S
A1 Graham, Colin A
A1 Hegele, Robert A
A1 Karpe, Fredrik
A1 Durst, Ronen
A1 Leitersdorf, Eran
A1 Lench, Nicholas
A1 Nair, Devaki R
A1 Soran, Handrean
A1 Van Bockxmeer, Frank M
A1 ,
A1 Humphries, Steve E
YR 2014
UL http://jmg.bmj.com/content/51/8/537.abstract
AB 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 &lt;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&lt;4.3×10−4 and p&lt;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.