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Document Type |
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Thesis |
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Document Title |
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Genomic Screening of Non-syndromic Congenital Heart Defects in the Saudi Population الفحص الجيني لعيوب القلب الخلقية غير المتلازمية في الشعب السعودي |
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Subject |
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Faculty of Science |
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Document Language |
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Arabic |
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Abstract |
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Background: Previous studies have demonstrated that congenital heart disease (CHD) is a multifactorial disorder with both genetic and environmental components. However, the sequencing of the human genome and advancements in molecular techniques have provided compelling evidence that genetic predisposition plays a significant role in CHD development. Unraveling the genetic mutations implicated in the developmental pathway of the cardiovascular system strongly facilitates our understanding of the pathophysiology of such a complex disease. Consanguinity has major genetic implications for the offspring of an inbred population, including a higher risk for congenital defects such as CHD. It has been shown that consanguinity is significantly associated with the autosomal recessive inheritance of CHD. Molecular diagnosis of familial diseases is crucial for evaluating the recurrence risk and for addressing future prenatal diagnosis. In this study, we aimed to assess whether consanguinity is associated with an increased prevalence of CHD in Saudi families.
Methods: A couple of consanguineous families from Saudi Arabia presented with different clinical phenotypes of non-syndromic CHD were screened by whole-exome sequencing (WES). To characterize the identified variants, a series of in-silico analyses such as PolyPhen, SIFT, and 3D homology protein modeling were conducted after which a protein activity assay was performed to assess protein function.
Results: Molecular genetic screening has identified a novel PRKD1 variant, c.265-1G>T, in three CHD- affected sisters in family CHD01, and a rare monogenic TGFBR1 variant (R398H) in family CHD02, both variants showed an autosomal recessive mode of inheritance. According to pathogenicity predictions and 3D homology protein models, the PRKD1 variant is a splice site mutation that had a detrimental effect on the structural features of the protein. On the other hand, the TGBR1 variant had a minor effect on protein structure but functional analysis suggested it influenced protein activity in vitro.
Conclusions: Our research contributes to a better understanding of the molecular etiology of CHD and highlights the significance of genetic testing in clinical settings, especially for consanguineous families.
Keywords: congenital heart disease (CHD), non-syndromic, whole-exome sequencing (WES), consanguinity, autosomal recessive, non-syndromic |
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Supervisor |
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Prof. Dr. Sabah Mahmoud Hassan |
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Thesis Type |
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Doctorate Thesis |
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Publishing Year |
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1445 AH
2023 AD |
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Added Date |
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Wednesday, October 25, 2023 |
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Researchers
| نور حاتم البشر | Albesher, Nour | Researcher | Doctorate | |
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