Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning
One of the most common congenital metabolic disorders is familial hypercholesterolemia. Familial hyper-cholesterolemia 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 leve...
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Published in | Vavilovskiĭ zhurnal genetiki i selekt͡s︡ii Vol. 27; no. 5; pp. 522 - 529 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Russia
The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
01.09.2023
Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders |
Subjects | |
Online Access | Get full text |
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Summary: | One of the most common congenital metabolic disorders is familial hypercholesterolemia. Familial hyper-cholesterolemia 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Correspondence to: D.E. Ivanoshchuk dinara2084@mail.ru |
ISSN: | 2500-3259 2500-0462 2500-3259 |
DOI: | 10.18699/VJGB-23-63 |