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Document Type |
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Thesis |
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Document Title |
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Application of Genomic and Bioinformatic Tools to Search for Causal Variants in Laterality Defects of Major Organs استخدام الأدوات الجينومية والمعلوماتية الحيوية للبحث عن المتغيرات المسببة لعيوب الانعكاس الجذعي للأعضاء الداخلية |
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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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Cilia are essential for humans from breathing to reproduce and almost all body functions. Mutations impairing motile cilia result in a broad spectrum of diseases. Dysfunction of mucociliary cleaning mechanism result in Primary ciliary dyskinesia (PCD), while ciliary defects in early embryonic development leads to laterality defects (LD). Both are rare, heterogeneously inherited disorders with variable symptoms and severity. PCD is mainly inherited as a recessive disease, with ~40 causal genes identified so far, and only 70% are genetically explained. LD is more complex, and in most the causes are not known; with only ~20% have known causal variants in genes. Both PCD and LD overlap genetically and clinically, with more than 50% of PCD cases exhibit laterality defects. Arab societies with a high prevalence of consanguinity are expected to have an increased prevalence of autosomal recessive diseases. The limited number of studies in the Arab world reflects the lack of knowledge. This study aims to find genetic etiology of PCD/LD in consanguineous families residing in Saudi Arabia using whole-exome sequencing and a variety of bioinformatics tools to evaluate the damaging functional effect of these variants on the cilia. Through exome analysis, we identified variants with unusual inheritance: (a) novel or rare compound heterozygote in CCDC40, (b) two homozygotes in DNAH5 and (c) three homozygotes in DNAH1, DNAH5, and DNAH2 in 3 consanguineous families respectively with PCD/LD in Saudi Arabia. Targeted Sanger sequencing confirmed the autosomal recessive inheritance of all these rare/novel variants in the specified families. In the international and local exome databases these variants were extremely rare or absent. Damaging and destabilizing effect on the protein structure was predicted for these variants by multiple bioinformatics tools. This work provides insight into the genetic overlap between both diseases and complex inheritance in highly consanguineous society.
Key words: Cilia, Kartagener syndrome, Laterality defects, Primary ciliary dyskinesia, Exome sequencing. |
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Supervisor |
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Dr Ramu Elango |
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Thesis Type |
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Master Thesis |
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Publishing Year |
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1444 AH
2023 AD |
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Co-Supervisor |
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Dr Babajan Banaganapalli |
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Added Date |
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Tuesday, August 8, 2023 |
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Researchers
| نورا عدنان يوسف | Yousef, Nura Adnan | Researcher | Master | |
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