Whole exome sequencing of familial hypercholesterolaemia patients negative forLDLR/APOB/PCSK9mutations

Abstract

BackgroundFamilial 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 resultsExomes 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.ConclusionsNo 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.

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom

“…PCSK9 mutations therefore occur in about 1% of this population. In a Dutch population [29] reported gene frequencies were LDLR, 95% and APOB, 5% with no gain of function PCSK9 discovered and in the UK LDL-R, 93%, APOB about 5% and gain of function PCSK9 1.7% [30]. Although the presence of a gain of function PCSK9 allele, which increases PCSK9 levels, in HoFH predicts a good response to PCSK9 inhibitors, response in the HoFH population is mainly determined by residual receptor activity [31].…”

Clinical Management of Familial Hypercholesterolemia: New Insights from International Guidelines and Recent Studies

“…21 The causes of the remaining cases of clinical FH remain obscure though some seem to be caused by mutations in apoB outside exon 26 or in other genes. 22 However studies of FH in children suggest that 95% of FH is potentially identifiable with the remainder of cases being caused by phenocopies of FH such as familial combined hyperlipidemia which share many clinical features with FH. 23 Analyses of the health economics of FH show that cascade screening is the optimal strategy to find cases of FH 24 and that comprehensive genetic typing allied with cascade family screening by genetic techniques is best 25 but value is also gained from lipid-related screening in those where mutations are not identified.…”

Evaluation of polygenic cause in Korean patients with familial hypercholesterolemia – A study supported by Korean Society of Lipidology and Atherosclerosis

“…Researchers have been actively searching for a mutation in an additional gene that could explain the genetic cause of mutationnegative FH cases [4e8]. Nevertheless, novel FH-causing genes still account for only fractional portions of genetically undefined FH patients, possibly due to allelic rarity or heterogeneity [4,9]. Recently, studies of European patients demonstrated that a subset of mutation-negative FH patients may have a polygenic cause [10,11].…”