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DC Field | Value | Language |
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dc.contributor.author | MUMTAZ, SARA | - |
dc.date.accessioned | 2018-04-11T15:36:20Z | - |
dc.date.available | 2018-04-11T15:36:20Z | - |
dc.date.issued | 2017 | - |
dc.identifier.uri | http://hdl.handle.net/123456789/4366 | - |
dc.description.abstract | ABSTRACT Mendelian diseases have been difficult to study due to various limitations including difficulty in ascertainment of subjects/families with rare phenotypes, inadequate data, and laborious molecular methods. However, the recent advances in genetic technologies have made it possible to accurately identify the molecular bases of such disorders. By studying such disorders and identifying their underlying molecular causes, it becomes possible to control recurrence of such disorders by proper genetic counselling for affected families. Furthermore, the discovery of each new gene of a genetic disorder tells us about basic cellular processes, which is important for basic science. Linkage analysis employing genome-wide SNP markers by using large pedigrees is a powerful tool for locus identification. After locus identification, exome sequencing and Sanger sequencing are used for finding the pathogenic mutation in the gene. Large families suitable for genetic studies are relatively abundant in Pakistan, because of its cultural setup that promotes large families, consanguineous marriages, and stable communities. In the framework of this study, eight Pakistani families afflicted with rare diseases were explored for disease gene loci and causative mutations by using SNP based linkage analysis and exome sequencing and/or Sanger sequencing. The diseases were Intellectual Disability with Speech Problem and Dysmorphic Facial Features (IDSD), Autosomal Recessive Primary Microcephaly (MCPH), Microcephaly,Intellectual Disability, Short Stature and Brachydactyly (MIDSB), Autosomal Dominant Postaxial Polydactyly, Camptodactyly and Zygodactyly (ADPCZ), Tooth agenesis manifested as Oligodontia/Hypodontia (TAOH), Seckel-like syndrome (SLS), and Syndactyly type IX (MSSD). The first family (IDSD) was with syndromic intellectual disability manifesting with impaired intelligence along with other problems. Three affected siblings and their cousin were subjected to linkage mapping and exome sequencing, and a novel homozygous missense PDIA3 mutation was identified in these patients. The second family (MCPH) was suffering from autosomal recessive primary microcephaly (MCPH). It is characterized by a marked decrease in the brain volume and nonprogressive intellectual disability. However, the architecture of the brain remains normal. In this family linkage analysis was performed and the disease locus was found on chromosome 1q31 harboring ASPM gene of primary microcephaly. This family was not studied further as many mutations were already reported in this gene from the Pakistani population. The third family (MIDSB) was a consanguineous family suffering from yet another syndrome, primary microcephaly and a unique combination of skeletal, limb and skin abnormities. The disease gene locus was mapped to 18q11.2, and a homozygous RBBP8 mutation was detected. The family is the fifth family reported with RBBP8 mutation. The fourth family (ADPCZ) was a large autosomal dominant family with a highly variable polydactyly phenotype. We were expecting a new condition since the postaxial polydactyly manifested with a combination of synpolydactyly I or syndactyly type II. After subjecting the family to linkage analysis and whole-exome sequencing (WES), a novel mutation was discovered in GLI3. The fifth family (TAOH) was a large autosomal dominant familywith tooth agenesis. Whole genome SNP genotyping yielded several candidate loci. Mutation screening in the WNT10A gene did not reveal any pathogenic variants. It was concluded that there is still an uncharacterized gene in one of the candidate intervals. In the sixth family with Seckel-like syndrome (SLS), the whole genome SNP genotyping excluded all the known loci for hypodontia/oligodontia as the candidate loci segregating with the phenotype. There were several regions that were homozygous among the affected subjects but no possibly damaging variant in a gene relevant to the phenotype was found. It was concluded that there is still an uncharacterized gene in one of the candidate homozygous regions. In seventh and eighth families with syndactyly type IX (MSSD), two novel homozygous mutations were detected in BHLHA9. In conclusion, in five families causative mutations were identified. In three families there were several regions segregating with the phenotypes and no pathogenic variants were detected in any gene relevant to the malformations. This research adds useful data to the scientific literature and furthers our understanding of the studied disorders. The scientific findings of this study would be highly beneficial for the recruited families in genetic counseling and genetic testing. | en_US |
dc.language.iso | en | en_US |
dc.publisher | Quaid-i-Azam University | en_US |
dc.relation.ispartofseries | Faculty of Biological Sciences; | - |
dc.subject | Animal Sciences | en_US |
dc.title | Linkage Analysis and Gene Hunt in Families with Inherited Disorders | en_US |
dc.type | Thesis | en_US |
Appears in Collections: | Ph.D |
Files in This Item:
File | Description | Size | Format | |
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BIO 4565.pdf | BIO 4565 | 6.75 MB | Adobe PDF | View/Open |
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