Document Details
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Document Type |
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Thesis |
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Document Title |
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Validation of Novel Mutation in Familial Hypercholesterolemia in Saudi Arabia التحقق من طفرة نادرة في فرط كوليسترول الدم العائلي (FH)في المملكة العربية السعودية |
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Subject |
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Faculty of medicine |
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Document Language |
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Arabic |
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Abstract |
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Introduction: Familial hypercholesterolemia (FH) is a genetic condition that occurs globally associated with premature cardiovascular deaths. The genetic data on Arab FH patients is remains scarce. Therefore, this study was aimed at detecting the causative variants in clinically diagnosed FH patients from Saudi Arabia. Study Aim: This study aims at screening the mutations in two of the causative genes of FH in Saudi families with clinically diagnosed members with FH and 200 normolipidemic controls to study the genetic basis in Saudi families.
Method: Two Saudi families with one clinically diagnosed family member with FH were recruited for screening mutations in genes related to FH. Whole-exome sequencing (WES) was performed on the index cases, and the potential FH variants were validated in the index cases, family members, and 200 controls using the Sanger sequencing method. Moreover, a spectrum of bioinformatic tools were utilized to characterize the pathogenic impacts of the query variant on the secondary and tertiary structural features and ligand binding characteristics of the corresponding protein molecule.
Results: The identified mutation in the index case (A-II.2) was not found in the index case or in the screened family member with the sanger sequence. However, WES analysis detected a rare heterozygous c.1486C>T p. (Arg496Trp) missense variant in the exon 9 region of the PCSK9 gene in the index case (B-II.6) that was not found in the rest of the family or 200 controls upon screening the sequences with Sanger analysis. Moreover, this variant was not detected in Saudi and Middle Eastern regional and global population genetic databases. Based on American Collage of Medical Genetics and Genomics (ACMG) guidelines, this variant is classified as likely pathogenic. Computational functional characterization suggests that this variant destabilizes the wildtype protein, alters the secondary structure (loss of beta sheets, strands, helix, helix-helix interactions, and gain of beta-hairpins, gamma turns, and beta turns), tertiary structure (causes structural deviation), and ligand binding ability with LDLR and Alirocumab.
Conclusion: This study emphasizes the importance of genetic testing in identifying rare or novel FH mutations in underrepresented populations that are likely to have a positive impact on CVD burden reduction.
Key words: Familial Hypercholesterolemia, Genetic Screening, Cardiovascular Diseases, Genetic Risk Factors and Segregation Analysis |
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Supervisor |
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Dr. Zuhier Awan |
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Thesis Type |
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Master Thesis |
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Publishing Year |
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1445 AH
2023 AD |
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Co-Supervisor |
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Dr. Gehan Hegazy |
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Added Date |
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Saturday, October 21, 2023 |
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Researchers
| نجلاء حسن الشهري | Alshehri, Najla Hassan | Researcher | Master | |
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