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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Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders
2023-09-01
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| Series: | Вавиловский журнал генетики и селекции |
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| Online Access: | https://vavilov.elpub.ru/jour/article/view/3868 |
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| author | D. E. Ivanoshchuk A. B. Kolker O. V. Timoshchenko S. E. Semaev E. V. Shakhtshneider |
| author_facet | D. E. Ivanoshchuk A. B. Kolker O. V. Timoshchenko S. E. Semaev E. V. Shakhtshneider |
| author_sort | D. E. Ivanoshchuk |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ea71e6866cde4052bdb646221d3a7b0b |
| institution | Kabale University |
| issn | 2500-3259 |
| language | English |
| publishDate | 2023-09-01 |
| publisher | Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders |
| record_format | Article |
| series | Вавиловский журнал генетики и селекции |
| spelling | doaj-art-ea71e6866cde4052bdb646221d3a7b0b2025-02-01T09:58:12ZengSiberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and BreedersВавиловский журнал генетики и селекции2500-32592023-09-0127552252910.18699/VJGB-23-631381Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learningD. E. Ivanoshchuk0A. B. Kolker1O. V. Timoshchenko2S. E. Semaev3E. V. Shakhtshneider4Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesNovosibirsk State Technical UniversityInstitute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesInstitute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesInstitute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesOne 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.https://vavilov.elpub.ru/jour/article/view/3868familial hypercholesterolemiawhole-genome sequencingmachine learning<i>sidt1</i><i>lrp1b</i><i>pld1</i><i>cetp</i> |
| spellingShingle | D. E. Ivanoshchuk A. B. Kolker O. V. Timoshchenko S. E. Semaev E. V. Shakhtshneider Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning Вавиловский журнал генетики и селекции familial hypercholesterolemia whole-genome sequencing machine learning <i>sidt1</i> <i>lrp1b</i> <i>pld1</i> <i>cetp</i> |
| title | Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning |
| title_full | Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning |
| title_fullStr | Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning |
| title_full_unstemmed | Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning |
| title_short | Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning |
| title_sort | searching for new genes associated with the familial hypercholesterolemia phenotype using whole genome sequencing and machine learning |
| topic | familial hypercholesterolemia whole-genome sequencing machine learning <i>sidt1</i> <i>lrp1b</i> <i>pld1</i> <i>cetp</i> |
| url | https://vavilov.elpub.ru/jour/article/view/3868 |
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