Whole-genome sequencing of unexplained severe familial hypercholesterolaemia turns up a novel CETP deletion variant (Vavilovskii Zhurnal Genet Selektsii 2023)

Original title: Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning

Vavilovskii Zhurnal Genet Selektsii · 1 September 2023 · 4

Ivanoshchuk DE, Kolker AB, Timoshchenko OV, Semaev SE, Shakhtshneider EV

Familial hypercholesterolaemia (FH) has a known genetic cause in most patients, chiefly LDLR variants with APOB, PCSK9, LDLRAP1, ABCG5 and ABCG8 accounting for under 5%, but molecular genetic testing fails to find a cause in 20 to 40% of cases. This study used decision trees to flag five probands with the most severe FH phenotype and no pathogenic variant in the known genes, then applied whole-genome sequencing to them. Rare variants emerged in three of the five: a splicing-site variant in PLD1, a previously undescribed single-nucleotide deletion in SIDT1, a new missense variant in LRP1B, and a single-nucleotide deletion variant, rs753876598, in the CETP gene. All four variants were reported for the first time in patients with a clinical FH diagnosis. A small case series (n = 5) proposing candidate genes rather than confirming causality; the CETP finding is one of four novel variants identified.

Original abstract

One of the most common congenital metabolic disorders is familial hypercholesterolemia. Familial hypercholesterolemia is a condition caused by a type of genetic defect leading to a decreased rate of removal of low-density lipoproteins from the bloodstream and a pronounced increase in the blood level of total cholesterol. This disease leads to the early development of cardiovascular diseases of atherosclerotic etiology. Familial hypercholesterolemia is a monogenic disease that is predominantly autosomal dominant. Rare pathogenic variants in the LDLR gene are present in 75-85 % of cases with an identified molecular genetic cause of the disease, and variants in other genes (APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, and others) occur at a frequency of < 5 % in this group of patients. A negative result of genetic screening for pathogenic variants in genes of the low-density lipoprotein receptor and its ligands does not rule out a diagnosis of familial hypercholesterolemia. In 20-40 % of cases, molecular genetic testing fails to detect changes in the above genes. The aim of this work was to search for new genes associated with the familial hypercholesterolemia phenotype by modern high-tech methods of sequencing and machine learning. On the basis of a group of patients with familial hypercholesterolemia (enrolled according to the Dutch Lipid Clinic Network Criteria and including cases confirmed by molecular genetic analysis), decision trees were constructed, which made it possible to identify cases in the study population that require additional molecular genetic analysis. Five probands were identified as having the severest familial hypercholesterolemia without pathogenic variants in the studied genes and were analyzed by whole-genome sequencing on the HiSeq 1500 platform (Illumina). The whole-genome sequencing revealed rare variants in three out of five analyzed patients: a heterozygous variant (rs760657350) located in a splicing acceptor site in the PLD1 gene (c.2430-1G>A), a previously undescribed single-nucleotide deletion in the SIDT1 gene [c.2426del (p.Leu809CysfsTer2)], new missense variant c.10313C>G (p.Pro3438Arg) in the LRP1B gene, and single-nucleotide deletion variant rs753876598 [c.165del (p.Ser56AlafsTer11)] in the CETP gene. All these variants were found for the first time in patients with a clinical diagnosis of familial hypercholesterolemia. Variants were identified that may influence the formation of the familial hypercholesterolemia phenotype.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.