subject:(exome sequencing)

1. Carswell, Shaun. Exome sequence analysis of siblings affected with Niemann-Pick type C disease.

Degree: 2017, Victoria University of Wellington; Victoria University of Wellington

► Mutations in either the Niemann-Pick type C1 or C2 (NPC1/NPC2) gene result in a fatal lysosomal storage disorder, Niemann-Pick type C (NP-C) disease, for which… (more)

▼ Mutations in either the Niemann-Pick type C1 or C2 (NPC1/NPC2) gene result in a fatal lysosomal storage disorder, Niemann-Pick type C (NP-C) disease, for which there is no effective cure. The disease is characterized by systemic and neurodegenerative symptoms arising from toxic accumulation of unesterified cholesterol within the late endosome and lysosome, with a common cause of death for patients being respiratory failure or recurrent infection of pulmonary tissue. Interestingly, the disease symptoms are heterogeneous, with age of onset and severity varied, even among siblings with the same mutations in the NPC1 or NPC2 gene causing this monogenic disease. To date there is no clear explanation for disease severity in siblings with the same mutation. As siblings are raised in the same environment, the major hypothesis of this thesis is that there are genetic modifiers that explain variation in disease severity within siblings. To determine if there are genetic variants associated with disease severity, exomes were sequenced from five sibling pairs exhibiting divergent onset and progression of NPC disease. Out of 23,105 genes, 26 variants were identified that were predicted to have functional consequences in NP-C patients, of which homozygous MUC5B and MARCH8 variants segregated across siblings that exhibited increased and decreased severity of disease, respectively. A cluster of variants was discovered on chromosome 11 belonging to the matrix metalloproteinase (MMP) family. Further investigation of one of these variants, a frameshift insertion in MMP-12, confirmed that this locus regulates the accumulation of unesterified cholesterol in primary neurons derived from a murine model of NPC disease. However, this region on chromosome 11 did not have any statistically significant copy number alteration detectable through a depth of coverage analysis. Overall, these results provide groundwork into the sequence variants mediating disease severity, which with further investigations, may be novel pharmacological targets to treat NPC disease. Advisors/Committee Members: Munkacsi, Andrew.

Subjects/Keywords: Niemann-Pick; Exome; Sequencing; Bioinformatics

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APA (6^th Edition):

Carswell, S. (2017). Exome sequence analysis of siblings affected with Niemann-Pick type C disease. (Masters Thesis). Victoria University of Wellington; Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/9391

Chicago Manual of Style (16^th Edition):

Carswell, Shaun. “Exome sequence analysis of siblings affected with Niemann-Pick type C disease.” 2017. Masters Thesis, Victoria University of Wellington; Victoria University of Wellington. Accessed April 14, 2021. http://hdl.handle.net/10063/9391.

MLA Handbook (7^th Edition):

Carswell, Shaun. “Exome sequence analysis of siblings affected with Niemann-Pick type C disease.” 2017. Web. 14 Apr 2021.

Vancouver:

Carswell S. Exome sequence analysis of siblings affected with Niemann-Pick type C disease. [Internet] [Masters thesis]. Victoria University of Wellington; Victoria University of Wellington; 2017. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/10063/9391.

Council of Science Editors:

Carswell S. Exome sequence analysis of siblings affected with Niemann-Pick type C disease. [Masters Thesis]. Victoria University of Wellington; Victoria University of Wellington; 2017. Available from: http://hdl.handle.net/10063/9391

University of Cincinnati

2. Tolusso, Leandra K. Parental understanding of whole exome sequencing: A comparison of perceived and actual understanding.

Degree: MS, Medicine: Genetic Counseling, 2016, University of Cincinnati

URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1458814771

► Whole exome sequencing (WES), a genetic test that sequences the protein-coding DNA, is an integral tool in the diagnosis of suspected genetic conditions in pediatric… (more)

▼ Whole exome sequencing (WES), a genetic test that sequences the protein-coding DNA, is an integral tool in the diagnosis of suspected genetic conditions in pediatric patients. Healthcare providers and families have expressed concerns about the informed consent process for WES due to the complexity of the information and the possibility for secondary findings. There has been little research into parental understanding about WES. We developed a survey to assess perceived (subjective) and actual (objective) understanding of WES in parents/guardians who consented to WES for their child between July 2013 and May 2015. The survey questions were divided into eight overall domains of informed consent and seventeen subdomains, which each addressed one specific aspect of WES. We surveyed 99 parents/guardians and received 55 completed surveys (56.7% response rate). We performed paired t-tests to compare overall mean subjective and objective understanding scores, and scores by domain and subdomain, to identify areas where perceptions of understanding did not match actual understanding. There was no significant difference in overall mean subjective (83.1/100) and objective understanding (82.5/100). However, subjective and objective understanding differed significantly in four domains (scope, description, voluntary nature, and benefits) and seven subdomains (purpose, analysis, reporting of results, benefits of WES, reinterpretation, and implications of secondary findings). As a secondary aim, we compared mean subjective and objective understanding scores between parents/guardians who consented to WES in a genetics clinic (n=41) versus a non-genetics specialty clinic (n=12). There were no significant differences in overall subjective or objective understanding or by domain in participants from the different clinics. However, a genetic counselor was involved in 9 (75%) of the pre-test counseling sessions in the speciality clinics. Our findings suggest that parents/guardians understood the majority of the information about WES that we assessed and that their perceptions of their understanding corresponded to their actual understanding. Concepts participants understood less well that may warrant further attention were the possibility of insurance discrimination based on results and the methods of WES analysis. Since a genetic counselor was involved in the majority of pre-test counseling sessions in genetics and speciality clinics, additional research into the impact on understanding of WES without involvement of genetics professionals is also warranted. Advisors/Committee Members: Myers, Melanie (Committee Chair).

Subjects/Keywords: Genetics; Whole exome sequencing; Informed consent; Exome; Secondary findings; Incidental findings

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APA (6^th Edition):

Tolusso, L. K. (2016). Parental understanding of whole exome sequencing: A comparison of perceived and actual understanding. (Masters Thesis). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1458814771

Chicago Manual of Style (16^th Edition):

Tolusso, Leandra K. “Parental understanding of whole exome sequencing: A comparison of perceived and actual understanding.” 2016. Masters Thesis, University of Cincinnati. Accessed April 14, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1458814771.

MLA Handbook (7^th Edition):

Tolusso, Leandra K. “Parental understanding of whole exome sequencing: A comparison of perceived and actual understanding.” 2016. Web. 14 Apr 2021.

Vancouver:

Tolusso LK. Parental understanding of whole exome sequencing: A comparison of perceived and actual understanding. [Internet] [Masters thesis]. University of Cincinnati; 2016. [cited 2021 Apr 14]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1458814771.

Council of Science Editors:

Tolusso LK. Parental understanding of whole exome sequencing: A comparison of perceived and actual understanding. [Masters Thesis]. University of Cincinnati; 2016. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1458814771

University of Toronto

3. Kanji, Zaheer Shamshudin. Somatic Copy Number Aberrations in Familial Pancreatic Cancer: Integrative Genomics and Gene Discovery.

Degree: 2013, University of Toronto

URL: http://hdl.handle.net/1807/42995

►

Familial Pancreatic Cancer (FPC) is an autosomal dominant condition with greater then 80% of genetic causes unknown. We hypothesize that an integrative approach employing germline… (more)

Subjects/Keywords: Cancer; Pancreatic; CNV; Genomics; Exome; Sequencing; 0564

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APA (6^th Edition):

Kanji, Z. S. (2013). Somatic Copy Number Aberrations in Familial Pancreatic Cancer: Integrative Genomics and Gene Discovery. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/42995

Chicago Manual of Style (16^th Edition):

Kanji, Zaheer Shamshudin. “Somatic Copy Number Aberrations in Familial Pancreatic Cancer: Integrative Genomics and Gene Discovery.” 2013. Masters Thesis, University of Toronto. Accessed April 14, 2021. http://hdl.handle.net/1807/42995.

MLA Handbook (7^th Edition):

Kanji, Zaheer Shamshudin. “Somatic Copy Number Aberrations in Familial Pancreatic Cancer: Integrative Genomics and Gene Discovery.” 2013. Web. 14 Apr 2021.

Vancouver:

Kanji ZS. Somatic Copy Number Aberrations in Familial Pancreatic Cancer: Integrative Genomics and Gene Discovery. [Internet] [Masters thesis]. University of Toronto; 2013. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/1807/42995.

Council of Science Editors:

Kanji ZS. Somatic Copy Number Aberrations in Familial Pancreatic Cancer: Integrative Genomics and Gene Discovery. [Masters Thesis]. University of Toronto; 2013. Available from: http://hdl.handle.net/1807/42995

University of Toronto

4. Rajendram, Rageen. Identification of Causal Rare Variants in an Extended Pedigree with Obsessive-compulsive Disorder.

Degree: 2014, University of Toronto

URL: http://hdl.handle.net/1807/68833

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Obsessive-Compulsive Disorder (OCD) is a common, heritable and etiologically heterogeneous neuropsychiatric disorder. Despite twin and family studies supporting genetic determinants in OCD, the discovery of… (more)

Subjects/Keywords: Exome; Genetics; Linkage; OCD; Sequencing; 0369

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APA (6^th Edition):

Rajendram, R. (2014). Identification of Causal Rare Variants in an Extended Pedigree with Obsessive-compulsive Disorder. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/68833

Chicago Manual of Style (16^th Edition):

Rajendram, Rageen. “Identification of Causal Rare Variants in an Extended Pedigree with Obsessive-compulsive Disorder.” 2014. Masters Thesis, University of Toronto. Accessed April 14, 2021. http://hdl.handle.net/1807/68833.

MLA Handbook (7^th Edition):

Rajendram, Rageen. “Identification of Causal Rare Variants in an Extended Pedigree with Obsessive-compulsive Disorder.” 2014. Web. 14 Apr 2021.

Vancouver:

Rajendram R. Identification of Causal Rare Variants in an Extended Pedigree with Obsessive-compulsive Disorder. [Internet] [Masters thesis]. University of Toronto; 2014. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/1807/68833.

Council of Science Editors:

Rajendram R. Identification of Causal Rare Variants in an Extended Pedigree with Obsessive-compulsive Disorder. [Masters Thesis]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/68833

KTH

5. Andeer, Robin. Coverage analysis and visualization in clinical exome sequencing.

Degree: Biotechnology (BIO), 2013, KTH

URL: http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-149941

► Motivation: The advent of clinical exome sequencing will require new tools to handlecoverage data and making it relevant to clinicians. That means genes over… (more)

Subjects/Keywords: Exome; clinical sequencing; software; GC content

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APA (6^th Edition):

Andeer, R. (2013). Coverage analysis and visualization in clinical exome sequencing. (Thesis). KTH. Retrieved from http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-149941

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Andeer, Robin. “Coverage analysis and visualization in clinical exome sequencing.” 2013. Thesis, KTH. Accessed April 14, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-149941.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Andeer, Robin. “Coverage analysis and visualization in clinical exome sequencing.” 2013. Web. 14 Apr 2021.

Vancouver:

Andeer R. Coverage analysis and visualization in clinical exome sequencing. [Internet] [Thesis]. KTH; 2013. [cited 2021 Apr 14]. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-149941.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Andeer R. Coverage analysis and visualization in clinical exome sequencing. [Thesis]. KTH; 2013. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-149941

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

6. HUANG KIE KYON. CLINICAL APPLICATION OF CANCER EXOME SEQUENCING.

Degree: 2016, National University of Singapore

URL: http://scholarbank.nus.edu.sg/handle/10635/135189

Subjects/Keywords: exome sequencing; biomarker

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APA (6^th Edition):

KYON, H. K. (2016). CLINICAL APPLICATION OF CANCER EXOME SEQUENCING. (Thesis). National University of Singapore. Retrieved from http://scholarbank.nus.edu.sg/handle/10635/135189

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

KYON, HUANG KIE. “CLINICAL APPLICATION OF CANCER EXOME SEQUENCING.” 2016. Thesis, National University of Singapore. Accessed April 14, 2021. http://scholarbank.nus.edu.sg/handle/10635/135189.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

KYON, HUANG KIE. “CLINICAL APPLICATION OF CANCER EXOME SEQUENCING.” 2016. Web. 14 Apr 2021.

Vancouver:

KYON HK. CLINICAL APPLICATION OF CANCER EXOME SEQUENCING. [Internet] [Thesis]. National University of Singapore; 2016. [cited 2021 Apr 14]. Available from: http://scholarbank.nus.edu.sg/handle/10635/135189.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

KYON HK. CLINICAL APPLICATION OF CANCER EXOME SEQUENCING. [Thesis]. National University of Singapore; 2016. Available from: http://scholarbank.nus.edu.sg/handle/10635/135189

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Iowa

7. Cox, Allison Jeanne. Whole exome analysis of individuals and families with chronic recurrent multifocal osteomyelitis (CRMO).

Degree: PhD, Genetics, 2016, University of Iowa

URL: https://ir.uiowa.edu/etd/2199

► Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by… (more)

Subjects/Keywords: bone; inflammation; whole exome sequencing; Genetics

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APA (6^th Edition):

Cox, A. J. (2016). Whole exome analysis of individuals and families with chronic recurrent multifocal osteomyelitis (CRMO). (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/2199

Chicago Manual of Style (16^th Edition):

Cox, Allison Jeanne. “Whole exome analysis of individuals and families with chronic recurrent multifocal osteomyelitis (CRMO).” 2016. Doctoral Dissertation, University of Iowa. Accessed April 14, 2021. https://ir.uiowa.edu/etd/2199.

MLA Handbook (7^th Edition):

Cox, Allison Jeanne. “Whole exome analysis of individuals and families with chronic recurrent multifocal osteomyelitis (CRMO).” 2016. Web. 14 Apr 2021.

Vancouver:

Cox AJ. Whole exome analysis of individuals and families with chronic recurrent multifocal osteomyelitis (CRMO). [Internet] [Doctoral dissertation]. University of Iowa; 2016. [cited 2021 Apr 14]. Available from: https://ir.uiowa.edu/etd/2199.

Council of Science Editors:

Cox AJ. Whole exome analysis of individuals and families with chronic recurrent multifocal osteomyelitis (CRMO). [Doctoral Dissertation]. University of Iowa; 2016. Available from: https://ir.uiowa.edu/etd/2199

University of Helsinki

8. Hinterding, Helena. Novel disease genes for childhood-onset cardiomyopathy.

Degree: Medicinska fakulteten, 2018, University of Helsinki

URL: http://hdl.handle.net/10138/236385

► Early-onset cardiomyopathies (CMPs) are disorders that bring a heavy burden for families as they often lead to early death among children. CMP may be defined… (more)

▼ Early-onset cardiomyopathies (CMPs) are disorders that bring a heavy burden for families as they often lead to early death among children. CMP may be defined as a disease affecting the myocardium and its ability to pump blood efficiently. While CMPs can be both of acquired and hereditary origin, heterogeneous genetics often explain the early onset of such diseases with varying phenotypes. This study aimed to offer molecular diagnoses to three patients within the ‘KidCMP cohort’ (n=74, University Hospital Helsinki) and characterize their disease-causing genes in early-onset CMPs. Additionally; it aimed to develop patient-specific tools to study disease mechanisms in more detail. While candidate pathogenic variants were identified through whole-exome sequencing, the validation of these variants was approached through experimental work at RNA and protein level as well as molecular modeling. Using whole-exome sequencing data, we identified novel candidate disease genes in three patients from the ‘KidCMP’ cohort: TMOD1, NRAP and PGM5. While NRAP has been previously reported in a family with autosomal dominant transmission of adult dilated CMP and incomplete penetrance, TMOD1 and PGM5 have not been previously associated with disease. TMOD1 (Tropomodulin-1) presented a homozygous missense mutation in our patient, and the conservation in species and molecular modeling of the identified variant further supported its underlying role in teenage-onset dilated CMP. Cytoskeletal stability and sarcomeric force transmission are likely to be disrupted as a result of the mutation in this actin-binding protein. NRAP (Nebulin-related-anchoring protein) presented a homozygous nonsense mutation in the second patient and RNA analysis from cells and heart tissue revealed mRNA to escape nonsense-mediated decay. This gene occupies an important role in myofibril assembly and anchoring actin filaments to the cell membrane. Based on the induced premature stop codon we judged this variant to lead to a loss of function and to underlie severe early-onset dilated CMP in our patient. PGM5 (Phosphoglucomutase-like protein 5) presented a compound heterozygous missense mutation in the third patient and protein analysis revealed the affected protein to be present in reduced form. PGM5 interacts with actin filaments and occupies an important role in myofibril formation as well as cell-cell contact. Homology modeling showed the variants to cluster in the disease-associated region of the homologous PGM1 gene. Based on this, we judge this variant to underlie early-onset dilated CMP in our patient. Overall, these findings suggest a valuable role of whole-exome sequencing in disclosing the heterogeneous genetic background of this field of diseases. By identifying and characterizing novel disease genes as presented here, we offer important knowledge for targeted treatment options and further research.

Subjects/Keywords: Cardiomyopathy; whole-exome sequencing; TMOD1; NRAP; PGM5; Cardiomyopathy; whole-exome sequencing; TMOD1; NRAP; PGM5

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APA (6^th Edition):

Hinterding, H. (2018). Novel disease genes for childhood-onset cardiomyopathy. (Masters Thesis). University of Helsinki. Retrieved from http://hdl.handle.net/10138/236385

Chicago Manual of Style (16^th Edition):

Hinterding, Helena. “Novel disease genes for childhood-onset cardiomyopathy.” 2018. Masters Thesis, University of Helsinki. Accessed April 14, 2021. http://hdl.handle.net/10138/236385.

MLA Handbook (7^th Edition):

Hinterding, Helena. “Novel disease genes for childhood-onset cardiomyopathy.” 2018. Web. 14 Apr 2021.

Vancouver:

Hinterding H. Novel disease genes for childhood-onset cardiomyopathy. [Internet] [Masters thesis]. University of Helsinki; 2018. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/10138/236385.

Council of Science Editors:

Hinterding H. Novel disease genes for childhood-onset cardiomyopathy. [Masters Thesis]. University of Helsinki; 2018. Available from: http://hdl.handle.net/10138/236385

Boston University

9. Dougherty, Kristen Elizabeth. Evaluation of Next-Generation Sequencing as a clinical and research modality in the diagnosis of hereditary breast cancer.

Degree: MS, Medical Sciences, 2015, Boston University

URL: http://hdl.handle.net/2144/16120

► Next-Generation Sequencing has opened the doors to nearly limitless amounts of genomic data, but the clinical utility of this data is not yet clear. From… (more)

▼ Next-Generation Sequencing has opened the doors to nearly limitless amounts of genomic data, but the clinical utility of this data is not yet clear. From examining at sequencing data of known familial cancer genes in hereditary cancer patients, the NCGENES study found a clear molecular diagnosis in about 5% of patients and an uncertain molecular result in about 15% of patients. The remaining 80% of hereditary cancer patients received a negative result for the screening of known cancer genes. These latter patients were followed up by whole exome sequencing analysis, and the data was used to perform a research sweep to potentially identify mutation(s) in gene(s) that have yet to be clearly associated with their phenotype. Hereditary breast cancer has a relatively well-established set of susceptibility genes, yet a large percentage of the molecular etiology is still unknown. There are many genes that are good candidates for breast cancer genes based on their protein's function, but they may not actually contribute to breast cancer susceptibility. The ClinGen consortium is aiming to establish the clinical validity of gene-disease associations so that clinicians and patients can better interpret and utilize sequencing results. Six breast cancer susceptibility genes were evaluated using the ClinGen clinical validity framework with the goal of both evaluating the genes already on hereditary breast cancer panels and evaluating genes not yet widely tested to determine if there is enough evidence to support their role in disease to warrant widespread testing. These genes have varying levels of evidence supporting their role in breast cancer susceptibility. The variants in each of the six genes were compared between a cancer patient cohort and a non-cancer patient cohort enrolled in the NCGENES whole exome sequencing study. One likely pathogenic variant and several variants of unknown significance were identified in various genes, and the burden of variants in cancer cases versus controls was evaluated, although the controls were not matched to the cancer cohort in any way. Research sweeps were performed for patients with VUSs to ensure that there were no other mutations in genes that would better fit the phenotype. This thesis presents a method for evaluating gene-disease associations and for utilizing whole exome sequencing data to pinpoint a molecular diagnosis in hereditary breast cancer patients. Overall, it was found that the ClinGen method of evaluating clinical validity of gene-disease associations could be helpful when determining if variants are pathogenic or benign. A new gene, RINT1, was found to have enough evidence to be moderately associated with hereditary breast cancer and it was subsequently added to the diagnostic list so that all cancer patients will now be screened for RINT1 variants. In addition, it was found that two of the genes currently on the diagnostic list, RAD51C and RAD51D, have "disputed" evidence with respect to breast cancer susceptibility. Interestingly, they have much more evidence for…

Subjects/Keywords: Genetics; Breast cancer; Hereditary cancer; Whole exome sequencing; Next generation sequencing

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APA (6^th Edition):

Dougherty, K. E. (2015). Evaluation of Next-Generation Sequencing as a clinical and research modality in the diagnosis of hereditary breast cancer. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/16120

Chicago Manual of Style (16^th Edition):

Dougherty, Kristen Elizabeth. “Evaluation of Next-Generation Sequencing as a clinical and research modality in the diagnosis of hereditary breast cancer.” 2015. Masters Thesis, Boston University. Accessed April 14, 2021. http://hdl.handle.net/2144/16120.

MLA Handbook (7^th Edition):

Dougherty, Kristen Elizabeth. “Evaluation of Next-Generation Sequencing as a clinical and research modality in the diagnosis of hereditary breast cancer.” 2015. Web. 14 Apr 2021.

Vancouver:

Dougherty KE. Evaluation of Next-Generation Sequencing as a clinical and research modality in the diagnosis of hereditary breast cancer. [Internet] [Masters thesis]. Boston University; 2015. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/2144/16120.

Council of Science Editors:

Dougherty KE. Evaluation of Next-Generation Sequencing as a clinical and research modality in the diagnosis of hereditary breast cancer. [Masters Thesis]. Boston University; 2015. Available from: http://hdl.handle.net/2144/16120

Harvard University

10. Xu, Liwen. Targeted Next Generation Sequencing Approach Towards Improving Genetic Diagnosis of Limb Girdle Muscular Dystrophy.

Degree: Doctor of Medicine, 2018, Harvard University

URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973492

►

Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of rare muscle disorders in which progressive skeletal muscle weakness and wasting affect primarily the shoulders, hips… (more)

Subjects/Keywords: Limb Girdle Muscular Dystrophies; Next Generation Sequencing; Whole Exome Sequencing

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APA (6^th Edition):

Xu, L. (2018). Targeted Next Generation Sequencing Approach Towards Improving Genetic Diagnosis of Limb Girdle Muscular Dystrophy. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973492

Chicago Manual of Style (16^th Edition):

Xu, Liwen. “Targeted Next Generation Sequencing Approach Towards Improving Genetic Diagnosis of Limb Girdle Muscular Dystrophy.” 2018. Doctoral Dissertation, Harvard University. Accessed April 14, 2021. http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973492.

MLA Handbook (7^th Edition):

Xu, Liwen. “Targeted Next Generation Sequencing Approach Towards Improving Genetic Diagnosis of Limb Girdle Muscular Dystrophy.” 2018. Web. 14 Apr 2021.

Vancouver:

Xu L. Targeted Next Generation Sequencing Approach Towards Improving Genetic Diagnosis of Limb Girdle Muscular Dystrophy. [Internet] [Doctoral dissertation]. Harvard University; 2018. [cited 2021 Apr 14]. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973492.

Council of Science Editors:

Xu L. Targeted Next Generation Sequencing Approach Towards Improving Genetic Diagnosis of Limb Girdle Muscular Dystrophy. [Doctoral Dissertation]. Harvard University; 2018. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973492

Washington University in St. Louis

11. Bailey, Matthew Hawkins. A tail of two PanCancer projects: Somatic variant identification and driver gene discovery using TCGA.

Degree: PhD, Biology & Biomedical Sciences (Human & Statistical Genetics), 2018, Washington University in St. Louis

URL: https://openscholarship.wustl.edu/art_sci_etds/1691

► The implementation of next-generation genomic sequencing has exploded over the past dozen years. Large consortia, such as The Cancer Genome Atlas (TCGA); the International… (more)

▼ The implementation of next-generation genomic sequencing has exploded over the past dozen years. Large consortia, such as The Cancer Genome Atlas (TCGA); the International Cancer Genetics Consortium (ICGC); and the Pediatric Cancer Genome Projects (PCGP), made great strides in democratizing big data for the scientific community. These data sets provide a rich resource to build tools for somatic variant discovery and exploratory analysis. Public repositories hold the answer to many novel biological and clinical revelations i.e., the discovery of complex indels, splice creating mutations, alternative super enhancer binding sites, machine learning models to predict mutation impact, and cancer subtype classification and identification. At the end of 2014, seven additional cancer types and 11 different pediatric tumor cohorts were publicly available when compared to the Ding lab’s first PanCancer effort [Kandoth et al., 2013]. Motivated by the possibility of novel cancer driver gene discovery, we launched a new PanCan2 effort. We assembled sequence data from 8,018 cancer cases representing a combined 30 pediatric and adult cancer types from 8 organ systems. Analysis of the resulting data corpus identified 270 cancer-associated genes, 107 of which have not been previously reported in Pan- Cancer studies. Pediatric-enriched mutant genes (e.g., IL7R, PAX5, and H3F3A) were found in tumors from the hematopoietic and central nervous systems, consistent with their roles in early development. Distinctive mutational architectures were identified for each of the 8 organ sys- tems, reflecting the tissue of origin and likely exposure to similar environmental factors. TP53 mutant vs. TP53 wild-type tumors had largely distinct patterns of co-occurring mutations, suggesting a pivotal role of TP53 in shaping the mutational network. Cis-activation of receptor tyrosine kinases at mutational, expression, and phosphorylation levels, as well as trans-activation of hormone-related transcription factors, were identified through the integration of multiple data types. In the end, this effort did not result in a publication because we did not perform uniform variant calling across all samples and relied primarily on publicly available data sets. Armed with the knowledge that reviewers would require a complete reboot of the TCGA variant calls before another PanCancer paper would be considered, Dr. Li Ding thoughtfully sub- mitted a proposal to acquire funding necessary for the recalling of all TCGA exome sequencing bams using many different calls. This effort is referred to as the Multi-center Mutation Calling in Multiple Cancers (MC3). TCGA cancer genomics data set includes over 10,000 tumor-normal exome pairs across 33 different cancer types, in total >400 TB of raw data files required re- analysis. A comprehensive encyclopedia of somatic mutation calls for the TCGA data was created to enable robust cross-tumor-type analyses. Our approach accounts for variance and batch effects introduced by the rapid advancement of DNA… Advisors/Committee Members: Li Ding, Ron Bose, Michael Province, Govindan Ramaswamy, John Rice.

Subjects/Keywords: Genomics, PanCancer, Whole exome sequencing, Whole genome sequencing; Bioinformatics; Genetics; Oncology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bailey, M. H. (2018). A tail of two PanCancer projects: Somatic variant identification and driver gene discovery using TCGA. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/art_sci_etds/1691

Chicago Manual of Style (16^th Edition):

Bailey, Matthew Hawkins. “A tail of two PanCancer projects: Somatic variant identification and driver gene discovery using TCGA.” 2018. Doctoral Dissertation, Washington University in St. Louis. Accessed April 14, 2021. https://openscholarship.wustl.edu/art_sci_etds/1691.

MLA Handbook (7^th Edition):

Bailey, Matthew Hawkins. “A tail of two PanCancer projects: Somatic variant identification and driver gene discovery using TCGA.” 2018. Web. 14 Apr 2021.

Vancouver:

Bailey MH. A tail of two PanCancer projects: Somatic variant identification and driver gene discovery using TCGA. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2018. [cited 2021 Apr 14]. Available from: https://openscholarship.wustl.edu/art_sci_etds/1691.

Council of Science Editors:

Bailey MH. A tail of two PanCancer projects: Somatic variant identification and driver gene discovery using TCGA. [Doctoral Dissertation]. Washington University in St. Louis; 2018. Available from: https://openscholarship.wustl.edu/art_sci_etds/1691

Universidade Estadual de Campinas

12. Borges, Murilo Guimarães, 1989-. Metodologias em bioinformática aplicadas à análise de dados de sequenciamento de alto desempenho em genética médica.

Degree: Faculdade de Ciências Médicas; Programa de Pós-Graduação em Fisiopatologia Médica, 2019, Universidade Estadual de Campinas

URL: http://repositorio.unicamp.br/jspui/handle/REPOSIP/334837

►

Orientador: Iscia Teresinha Lopes Cendes

Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas

Made available in DSpace on 2019-09-02T14:53:58Z (GMT). No. of… (more)

▼

Orientador: Iscia Teresinha Lopes Cendes

Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas

Made available in DSpace on 2019-09-02T14:53:58Z (GMT). No. of bitstreams: 1 Borges_MuriloGuimaraes_D.pdf: 10371458 bytes, checksum: 8271dadd980bcff52977acc8b4ea4684 (MD5) Previous issue date: 2019

Resumo: O sequenciamento de nova geração é cada vez mais incorporado na prática clínica, trazendo consigo desafios. Para propósitos diagnósticos, são priorizados os métodos de alta resolução de sequenciamento: seja pela delimitação de uma região-alvo de um painel de genes, ou pela definição de uma região de interesse constituída pelos exons. Neste sentido, bancos de dados públicos ajudam a entender de que forma variações genéticas se relacionam a um dado fenótipo, ou simplesmente refletirem uma variabilidade normal da população. A influência de variantes comuns com alta frequência e qualidade na população brasileira em métodos de chamada de variantes ainda é desconhecida. No outro extremo, encontram-se as variantes com impacto clínico comprovado, cuja identificação, acreditamos ser dependente de fatores metodológicos. Perfis de herança genética mais complexos e variações em mais de uma linhagem celular geneticamente distinta de um mesmo organismo são de relevância para as epilepsias. Acredita-se que as mutações em mosaico sejam causais em alguns tipos de displasias corticais focais, e que um perfil poligênico seja mais realista para diversas manifestações epileptogênicas não-familiares. Assim, nosso objetivo foi aplicar e avaliar ferramentas e protocolos em bioinformática para análise de sequenciamento de exomas e painéis no contexto da medicina genômica. Fomos capazes de identificar variantes somáticas e em mosaico em pacientes com displasia cortical focal sequenciados por WES e por um painel de genes empregando nosso protocolo baseado no GATK. Realizamos controles de qualidade pré e pós alinhamento, chamada e anotação das variantes com diversos programas como FastQC, Rqc, Picard, entre outros. Tivemos uma correspondência de 92,4% entre as variantes do painel com o exoma. Com relação as ferramentas utilizadas para a chamada das variantes em mosaico, 85,7% das variantes foram exclusivas de uma das ferramentas, evidenciando uma baixa concordância metodológica para estes algoritmos. Como resultado da chamada de variantes do exoma de 122 pacientes do grupo de encefalopatias epilépticas do desenvolvimento, foram identificadas um total de 608634 variantes. As variantes foram anotadas com VEP e priorizadas com o VVP para possibilitar a filtragem posterior com BrowseVCF. Como resultados preliminares para a descrição de um perfil poligênico, identificamos 32 variantes como possíveis alvos em 24 genes relacionados ao sistema nervoso central pela aplicação de métodos de aprendizado de máquina com RapidMiner. Com relação a aplicação de variantes comuns da população brasileira em protocolos de chamada de variantes, identificamos um alto potencial de sua utilização, aumentando a descoberta de variantes…

Advisors/Committee Members: UNIVERSIDADE ESTADUAL DE CAMPINAS, Lopes-Cendes, Íscia Teresinha, 1964-, Godard, Ana Lúcia Brunialti, Junior, Wilson Araujo da Silva, Melo, Mônica Barbosa de, Yasuda, Clarissa Lin.

Subjects/Keywords: Bioinformática; Sequenciamento completo de exoma; Exoma; Herança multifatorial; Bioinformatics; Whole exome sequencing; Exome; Polygenic inheritance

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Borges, Murilo Guimarães, 1. (2019). Metodologias em bioinformática aplicadas à análise de dados de sequenciamento de alto desempenho em genética médica. (Doctoral Dissertation). Universidade Estadual de Campinas. Retrieved from http://repositorio.unicamp.br/jspui/handle/REPOSIP/334837

Chicago Manual of Style (16^th Edition):

Borges, Murilo Guimarães, 1989-. “Metodologias em bioinformática aplicadas à análise de dados de sequenciamento de alto desempenho em genética médica.” 2019. Doctoral Dissertation, Universidade Estadual de Campinas. Accessed April 14, 2021. http://repositorio.unicamp.br/jspui/handle/REPOSIP/334837.

MLA Handbook (7^th Edition):

Borges, Murilo Guimarães, 1989-. “Metodologias em bioinformática aplicadas à análise de dados de sequenciamento de alto desempenho em genética médica.” 2019. Web. 14 Apr 2021.

Vancouver:

Borges, Murilo Guimarães 1. Metodologias em bioinformática aplicadas à análise de dados de sequenciamento de alto desempenho em genética médica. [Internet] [Doctoral dissertation]. Universidade Estadual de Campinas; 2019. [cited 2021 Apr 14]. Available from: http://repositorio.unicamp.br/jspui/handle/REPOSIP/334837.

Council of Science Editors:

Borges, Murilo Guimarães 1. Metodologias em bioinformática aplicadas à análise de dados de sequenciamento de alto desempenho em genética médica. [Doctoral Dissertation]. Universidade Estadual de Campinas; 2019. Available from: http://repositorio.unicamp.br/jspui/handle/REPOSIP/334837

Queensland University of Technology

13. Maksemous, Neven. Development of high through-put neurogenetics diagnostics.

Degree: 2016, Queensland University of Technology

URL: http://eprints.qut.edu.au/101097/

► This project was an effort to improve the speed and affordability of genetic testing for neurological disorders. The research involved the development of a genetic… (more)

Subjects/Keywords: Next generation sequencing; Familial hemiplegic migraine; Episodic Ataxia Type 2; CADASIL; Whole Exome Sequencing

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Maksemous, N. (2016). Development of high through-put neurogenetics diagnostics. (Thesis). Queensland University of Technology. Retrieved from http://eprints.qut.edu.au/101097/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Maksemous, Neven. “Development of high through-put neurogenetics diagnostics.” 2016. Thesis, Queensland University of Technology. Accessed April 14, 2021. http://eprints.qut.edu.au/101097/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Maksemous, Neven. “Development of high through-put neurogenetics diagnostics.” 2016. Web. 14 Apr 2021.

Vancouver:

Maksemous N. Development of high through-put neurogenetics diagnostics. [Internet] [Thesis]. Queensland University of Technology; 2016. [cited 2021 Apr 14]. Available from: http://eprints.qut.edu.au/101097/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Maksemous N. Development of high through-put neurogenetics diagnostics. [Thesis]. Queensland University of Technology; 2016. Available from: http://eprints.qut.edu.au/101097/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Ottawa

14. Wagner, Justin. Whole Exome Sequencing to Identify Disease-Causing Mutations in Lower Motor Neuron Disease and Peripheral Neuropathy .

Degree: 2016, University of Ottawa

URL: http://hdl.handle.net/10393/34124

► Lower motor neuron diseases and peripheral neuropathies are two groups of diseases that include multiple rare disorders where many causes are unknown and definitive treatments… (more)

Subjects/Keywords: Charcot-Marie-Tooth; Next Generation Sequencing; Whole-Exome Sequencing; Peripheral Neuropathy; Lower Motor Neuron Disease

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wagner, J. (2016). Whole Exome Sequencing to Identify Disease-Causing Mutations in Lower Motor Neuron Disease and Peripheral Neuropathy . (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/34124

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Wagner, Justin. “Whole Exome Sequencing to Identify Disease-Causing Mutations in Lower Motor Neuron Disease and Peripheral Neuropathy .” 2016. Thesis, University of Ottawa. Accessed April 14, 2021. http://hdl.handle.net/10393/34124.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Wagner, Justin. “Whole Exome Sequencing to Identify Disease-Causing Mutations in Lower Motor Neuron Disease and Peripheral Neuropathy .” 2016. Web. 14 Apr 2021.

Vancouver:

Wagner J. Whole Exome Sequencing to Identify Disease-Causing Mutations in Lower Motor Neuron Disease and Peripheral Neuropathy . [Internet] [Thesis]. University of Ottawa; 2016. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/10393/34124.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wagner J. Whole Exome Sequencing to Identify Disease-Causing Mutations in Lower Motor Neuron Disease and Peripheral Neuropathy . [Thesis]. University of Ottawa; 2016. Available from: http://hdl.handle.net/10393/34124

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

15. G.E.M. Melloni. COMPUTATIONAL FRAMEWORKS FOR THE IDENTIFICATION OF SOMATIC AND GERMLINE VARIANTS CONTRIBUTING TO CANCER PREDISPOSITION AND DEVELOPMENT.

Degree: 2017, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/462986

► The most recent cancer classification from NIH includes ~200 types of tumor that originates from several tissue types (http://www.cancer.gov/types). Although macroscopic and microscopic characteristics varies… (more)

▼ The most recent cancer classification from NIH includes ~200 types of tumor that originates from several tissue types (http://www.cancer.gov/types). Although macroscopic and microscopic characteristics varies significantly across subtypes, the starting point of every cancer is believed to be a single cell that acquires DNA somatic alterations that increases its fitness over the surrounding cells and makes it behave abnormally and proliferate uncontrollably. Somatic mutations are the consequence of many possible defective processes such as replication deficiencies, exposure to carcinogens, or DNA repair machinery faults. Mutation development is a random and mostly natural process that frequently happens in every cell of an individual. Only the acquisition of a series of subtype-specific alterations, including also larger aberrations such as translocations or deletions, can lead to the development of the disease and this is a long process for the majority of adult tumor types. However, genetic predisposition for certain cancer types is epidemiologically well established. In fact, several cancer predisposing genes where identified in the last 30 years with various technologies but they characterize only a small fraction of familial cases. This work will therefore cover two main steps of cancer genetics and genomics: the identification of the genes that somatically changes the behavior of a normal human cell to a cancer cell and the genetic variants that increase risk of cancer development. The use of publicly available datasets is common to all the three results sections that compose this work. In particular, we took advantage of several whole exome sequencing databases (WES) for the identification of both driver mutations and driver variants. In particular, the use of WES in cancer predisposition analysis represents one of the few attempts of performing such analysis on genome-wide sequencing germline data. Advisors/Committee Members: supervisor: Pelicci Pier Giuseppe, co-supervisor: Riva, Laura, internal advisor: Bagnardi, Vincenzo, external advisor: Markowetz, Florian, PELICCI, PIER GIUSEPPE.

Subjects/Keywords: Somatic Mutations; Germline Mutations; Next Generation Sequencing; Whole Exome Sequencing; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Melloni, G. (2017). COMPUTATIONAL FRAMEWORKS FOR THE IDENTIFICATION OF SOMATIC AND GERMLINE VARIANTS CONTRIBUTING TO CANCER PREDISPOSITION AND DEVELOPMENT. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/462986

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Melloni, G.E.M.. “COMPUTATIONAL FRAMEWORKS FOR THE IDENTIFICATION OF SOMATIC AND GERMLINE VARIANTS CONTRIBUTING TO CANCER PREDISPOSITION AND DEVELOPMENT.” 2017. Thesis, Università degli Studi di Milano. Accessed April 14, 2021. http://hdl.handle.net/2434/462986.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Melloni, G.E.M.. “COMPUTATIONAL FRAMEWORKS FOR THE IDENTIFICATION OF SOMATIC AND GERMLINE VARIANTS CONTRIBUTING TO CANCER PREDISPOSITION AND DEVELOPMENT.” 2017. Web. 14 Apr 2021.

Vancouver:

Melloni G. COMPUTATIONAL FRAMEWORKS FOR THE IDENTIFICATION OF SOMATIC AND GERMLINE VARIANTS CONTRIBUTING TO CANCER PREDISPOSITION AND DEVELOPMENT. [Internet] [Thesis]. Università degli Studi di Milano; 2017. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/2434/462986.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Melloni G. COMPUTATIONAL FRAMEWORKS FOR THE IDENTIFICATION OF SOMATIC AND GERMLINE VARIANTS CONTRIBUTING TO CANCER PREDISPOSITION AND DEVELOPMENT. [Thesis]. Università degli Studi di Milano; 2017. Available from: http://hdl.handle.net/2434/462986

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Sydney

16. Ghaoui, Roula. The application of whole exome sequencing for the diagnosis of limb-girdle muscular dystrophies .

Degree: 2016, University of Sydney

URL: http://hdl.handle.net/2123/16358

► The limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of inherited muscle disorders characterized by progressive weakness and wasting that primarily affects the proximal muscle… (more)

▼ The limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of inherited muscle disorders characterized by progressive weakness and wasting that primarily affects the proximal muscle of the upper and lower extremities. By definition, disease onset occurs after the age of 2 years and varies from early childhood to adulthood with a spectrum of clinical severity. The LGMDs typically show dystrophic changes on muscle biopsy. To date, 33 different genetic forms of LGMD have been described and are grouped according to inheritance pattern; LGMD1 refers to dominantly inherited forms whilst LGMD2 refers to recessively inherited forms. As the genetic basis of the various subtypes within LGMD have been identified, it has become clear that the clinical presentations and histopathology overlap, and predicting the genetic form of LGMD based on clinical examination or histological appearances alone is difficult. In Australia, the rate of genetic diagnosis of LGMD remains low at approximately 24%, despite traditional approaches of histopathological findings to triage genetic screening of known LGMD genes. The aim of my PhD project was to improve the genetic diagnoses of LGMDs by translating whole-exome sequencing (WES) to clinical practice. I initially ascertained LGMD families retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank (INMR) between 2006 and 2014 to determine the frequency of the LGMD subtypes in Australia. By collecting this data, I determined that 65% of patients have remained undiagnosed at our centre despite previous extensive investigations. At the outset of my PhD project, and in collaboration with Associate Professor Daniel MacArthur at the Broad Institute of Harvard, WES was the NGS technology available to screen my LGMD families and also provided the opportunity to identify new disease genes. 60 LGMD families were initially recruited for WES but with ongoing collaboration with Australian and New Zealand Neurologist colleagues, a total of 90 LGMD families were enrolled for the study. I also investigated whether the WES platform provides adequate coverage of known LGMD-related genes by performing Neurogenetic Subexomic Supercapture (NSES)(also referred to as targeted neuromuscular disease gene panel) on all undiagnosed LGMDs after WES. NSES did not identify any variants missed by WES. Using NGS, I achieved 45% diagnostic rate for this patient cohort who remained undiagnosed after extensive investigations (biochemistry and candidate gene sequencing). Inclusion of family members increased the diagnostic efficacy of WES, with a diagnostic rate of 60% for “trios” (an affected proband with both parents) versus 40% for single probands. Common causes of phenotypic overlap with LGMD were due to mutations in genes associated with congenital muscular dystrophy and Bethlem myopathy. The most common causes of LGMD in an Australasian population were due to the recessive LGMD genes, specifically FKRP, DYSF and CAPN3. During the course of this work, I also expanded the clinical…

Subjects/Keywords: muscular dystrophy; myopathy; limb girdle; genetics; whole exome sequencing; next generation sequencing

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ghaoui, R. (2016). The application of whole exome sequencing for the diagnosis of limb-girdle muscular dystrophies . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/16358

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ghaoui, Roula. “The application of whole exome sequencing for the diagnosis of limb-girdle muscular dystrophies .” 2016. Thesis, University of Sydney. Accessed April 14, 2021. http://hdl.handle.net/2123/16358.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ghaoui, Roula. “The application of whole exome sequencing for the diagnosis of limb-girdle muscular dystrophies .” 2016. Web. 14 Apr 2021.

Vancouver:

Ghaoui R. The application of whole exome sequencing for the diagnosis of limb-girdle muscular dystrophies . [Internet] [Thesis]. University of Sydney; 2016. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/2123/16358.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ghaoui R. The application of whole exome sequencing for the diagnosis of limb-girdle muscular dystrophies . [Thesis]. University of Sydney; 2016. Available from: http://hdl.handle.net/2123/16358

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Sydney

17. O'Grady, Gina Louise. Improving the Diagnosis of Congenital Muscular Dystrophy with Next Generation Sequencing Technology .

Degree: 2016, University of Sydney

URL: http://hdl.handle.net/2123/16490

► The congenital muscular dystrophies (CMDs) are inherited disorders of skeletal muscle characterized by early onset muscle weakness and dystrophic changes on muscle biopsy. The traditional… (more)

▼ The congenital muscular dystrophies (CMDs) are inherited disorders of skeletal muscle characterized by early onset muscle weakness and dystrophic changes on muscle biopsy. The traditional approach to diagnosis included muscle biopsy, protein-based studies of muscle specimens, and Sanger sequencing of candidate genes. The diagnostic yield was less than 25%. As Next Generation Sequencing (NGS) moves rapidly into clinical practice, this thesis evaluates the efficacy of NGS in the diagnosis of CMD, identifies new genetic causes of congenital myopathy, evaluates the cost efficacy of a NGS approach, and re-evaluates the diagnostic algorithm. 123 CMD patients were investigated with a traditional approach, yielding a genetic diagnosis in 32% of patients. Undiagnosed patients available for further testing, were investigated using NGS techniques. Of the 85 patients who presented in the last 20 years, 28 of the 51 who lacked a confirmed genetic diagnosis consented to NGS studies. This confirmed diagnoses in a further 11 patients. Using the combination of approaches, a genetic diagnosis was achieved in 51% (43/85). In the cohort three new genetic causes of disease were identified: Early onset myopathy due to variants in PYROXD1; multisystem disease, including congenital muscular dystrophy, due to variants in PIGY; and pre-synaptic congenital myasthenic syndrome due to variants in SLC18A3. The spectrum of ACTA1, CHD7 and COL1A1-related disease was expanded. A detailed cost benefit analysis was performed on a combined CMD and nemaline myopathy cohort. Compared with the traditional diagnostic algorithm, both the NMD panel and WES, had significantly increased diagnostic yields (from 46% to 75% for the NMD panel, and 79% for WES), reduced the cost per diagnosis from AUD22,596 to AUD5,077 for the NMD panel and AUD7,734 for WES. This thesis supports NGS as an effective, non-invasive first-tier investigation which can be performed in patients of any age. Muscle biopsy should be reserved as a second-tier investigation for patients undiagnosed by a NGS neuromuscular gene panel. The challenge of neuromuscular genetic research now lies with families undiagnosed after first tier NGS investigations.

Subjects/Keywords: Congenital muscular dystrophy; Congenital myopathy; Neuromuscular disease; Next generation sequencing; Whole exome sequencing

Record Details Similar Records Cite « Share

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

O'Grady, G. L. (2016). Improving the Diagnosis of Congenital Muscular Dystrophy with Next Generation Sequencing Technology . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/16490

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

O'Grady, Gina Louise. “Improving the Diagnosis of Congenital Muscular Dystrophy with Next Generation Sequencing Technology .” 2016. Thesis, University of Sydney. Accessed April 14, 2021. http://hdl.handle.net/2123/16490.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

O'Grady, Gina Louise. “Improving the Diagnosis of Congenital Muscular Dystrophy with Next Generation Sequencing Technology .” 2016. Web. 14 Apr 2021.

Vancouver:

O'Grady GL. Improving the Diagnosis of Congenital Muscular Dystrophy with Next Generation Sequencing Technology . [Internet] [Thesis]. University of Sydney; 2016. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/2123/16490.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

O'Grady GL. Improving the Diagnosis of Congenital Muscular Dystrophy with Next Generation Sequencing Technology . [Thesis]. University of Sydney; 2016. Available from: http://hdl.handle.net/2123/16490

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

UCLA

18. Gupta, Pritha. Translating Mouse Systems Genetics to Discovery in Human Disease.

Degree: Molec, Cell, & Integ Physiology, 2017, UCLA

URL: http://www.escholarship.org/uc/item/9g93k63j

► This dissertation is the culmination of my graduate studies in the laboratory of Jake Lusis at UCLA. The research presented here utilizes systems genetics studies… (more)

▼ This dissertation is the culmination of my graduate studies in the laboratory of Jake Lusis at UCLA. The research presented here utilizes systems genetics studies performed in mice to aid in discovery in human disease in three separate studies. A significant portion of disease-oriented research is performed in mice, but a major criticism from the medical community is that laboratory mice are generally inbred and thus have no genetic variation among individuals. Almost 15 years ago, the Lusis lab developed a novel genetic resource for association analysis in the mouse called the Hybrid Mouse Diversity Panel (HMDP). The HMDP is a panel of inbred mouse strains that was developed for performing association studies with adequate statistical power and resolution for mapping of complex traits. Mouse genome wide association studies (GWAS) studies are a powerful tool and can be performed relatively easily, but translating the data obtained from these studies to human disease is still in its infancy. My dissertation work reveals three different novel approaches to the utilization of data from GWAS studies performed on the HMDP for translation into human disease processes, namely cardiovascular disease. The first study utilizes novel genetic signatures in murine macrophages to predict disease incidence and survival in humans. The second study utilizes a traditional GWAS to candidate gene discovery to elucidate the mechanisms underlying cardiac remodeling in humans. Lastly, the third study utilizes mouse GWAS data for novel heart failure biomarker discovery in humans. As an introduction to this dissertation, Chapter 1 briefly summarizes the history of GWAS in mice using the HMDP and GWAS in humans. Chapter 2 is a completed and accepted first-author manuscript entitled “Natural diversity reveals macrophage activation spectra predictive of inflammation and cancer survival.” Chapter 3 explores the role of CD200, a candidate gene obtained from a large heart failure GWAS study in mice, and it’s receptor, CD200R1 in cardiac homeostasis and injury. Chapter 4 describes a novel approach to biomarker discovery for human heart failure using data from a large heart failure GWAS study. Chapter 5 is a departure from mouse systems genetics. In this chapter, I describe the strengths and pitfalls of exome sequencing. In addition, I describe two cases of rare cardiovascular disease in which exome sequencing is utilized to find causal variants of disease. Ultimately, I’d like to use what I’ve learned in my studies of mouse genetics and translate this to discovery in human disease. In conclusion, this dissertation work contributes significant findings to the expanding knowledge of utilizing mouse GWAS for discovery in human disease.

Subjects/Keywords: Genetics; Cardiovascular Disease; Exome Sequencing; Macrophage; Mouse Genetics

Record Details Similar Records Cite « Share

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gupta, P. (2017). Translating Mouse Systems Genetics to Discovery in Human Disease. (Thesis). UCLA. Retrieved from http://www.escholarship.org/uc/item/9g93k63j

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Gupta, Pritha. “Translating Mouse Systems Genetics to Discovery in Human Disease.” 2017. Thesis, UCLA. Accessed April 14, 2021. http://www.escholarship.org/uc/item/9g93k63j.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Gupta, Pritha. “Translating Mouse Systems Genetics to Discovery in Human Disease.” 2017. Web. 14 Apr 2021.

Vancouver:

Gupta P. Translating Mouse Systems Genetics to Discovery in Human Disease. [Internet] [Thesis]. UCLA; 2017. [cited 2021 Apr 14]. Available from: http://www.escholarship.org/uc/item/9g93k63j.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Gupta P. Translating Mouse Systems Genetics to Discovery in Human Disease. [Thesis]. UCLA; 2017. Available from: http://www.escholarship.org/uc/item/9g93k63j

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of California – Irvine

19. Bevilacqua, Jennifer Ann. Exome Sequencing Reveals Gene Variants Involved in Methylation, Acetylation, and Chromatin Remodeling in Patients with Autism.

Degree: Genetic Counseling, 2014, University of California – Irvine

URL: http://www.escholarship.org/uc/item/4br5n3vx

► Autism is a complex and both genetically and phenotypically heterogeneous neurodevelopmental condition. Some clear genetic causes have been identified but for most cases of autism… (more)

Subjects/Keywords: Genetics; autism; chromatin; epigenetics; exome sequencing; methylation; variant

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bevilacqua, J. A. (2014). Exome Sequencing Reveals Gene Variants Involved in Methylation, Acetylation, and Chromatin Remodeling in Patients with Autism. (Thesis). University of California – Irvine. Retrieved from http://www.escholarship.org/uc/item/4br5n3vx

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Bevilacqua, Jennifer Ann. “Exome Sequencing Reveals Gene Variants Involved in Methylation, Acetylation, and Chromatin Remodeling in Patients with Autism.” 2014. Thesis, University of California – Irvine. Accessed April 14, 2021. http://www.escholarship.org/uc/item/4br5n3vx.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Bevilacqua, Jennifer Ann. “Exome Sequencing Reveals Gene Variants Involved in Methylation, Acetylation, and Chromatin Remodeling in Patients with Autism.” 2014. Web. 14 Apr 2021.

Vancouver:

Bevilacqua JA. Exome Sequencing Reveals Gene Variants Involved in Methylation, Acetylation, and Chromatin Remodeling in Patients with Autism. [Internet] [Thesis]. University of California – Irvine; 2014. [cited 2021 Apr 14]. Available from: http://www.escholarship.org/uc/item/4br5n3vx.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Bevilacqua JA. Exome Sequencing Reveals Gene Variants Involved in Methylation, Acetylation, and Chromatin Remodeling in Patients with Autism. [Thesis]. University of California – Irvine; 2014. Available from: http://www.escholarship.org/uc/item/4br5n3vx

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Vanderbilt University

20. McElroy, Jude James. Genetics of spontaneous idiopathic preterm birth: exploration of maternal and fetal genomes.

Degree: PhD, Human Genetics, 2013, Vanderbilt University

URL: http://hdl.handle.net/1803/12685

► Preterm birth (PTB), defined as live birth before 37 weeks’ completed gestation, is the leading cause of infant mortality worldwide. Despite this major public health… (more)

▼ Preterm birth (PTB), defined as live birth before 37 weeks’ completed gestation, is the leading cause of infant mortality worldwide. Despite this major public health concern, little is known about the pathogenesis of PTB. The limited insight into PTB is contributed to by the fact that the mechanism for normal parturition is not known in humans. A number of lines of evidence suggest that PTB has a genetic component such as PTB aggregating in families, segregation analysis and genetic modeling. Primarily through candidate gene studies, there have been a number of single nucleotide polymorphisms (SNPs) associated with PTB; however, contradictory evidence from replication studies exists, and none of these have large effect sizes or have implicated novel insight into the mechanism of birth timing and parturition. The primary objective of this dissertation was to identify unidentified or unappreciated genetic variants responsible for the predisposition or pathogenesis of PTB. In order to investigate this hypothesis, we performed studies using a number of complementary approaches, which included genome-wide association studies (GWAS), exome array association, whole-exome sequence and pathway analysis. In addition to using a group of complementary methods, we also interrogated both maternal and fetal genomes for their potential role. Our GWAS in mothers identified several SNPs associated with the dichotomous trait, PTB, and the quantitative trait gestational age. Additionally, when we used whole-exome sequencing and exome array association in mothers we identified the Kyoto Encyclopedia of Genes and Genomes (KEGG) complement and coagulation cascade to be implicated in PTB and found a robust association with coding region SNPs in complement receptor 1 (CR1). Finally, when we switched our interrogation to infant samples we observed a handful of robust associations with PTB and the quantitative traits gestational age and birth weight z-scores. Advisors/Committee Members: Michael R. DeBaun (committee member), Louis J. Muglia (committee member), Dan M. Roden (committee member), Scott M. Williams (committee member), Dana C. Crawford (Committee Chair).

Subjects/Keywords: birth weight; GWAS; exome sequencing; preterm birth; gestational age

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APA (6^th Edition):

McElroy, J. J. (2013). Genetics of spontaneous idiopathic preterm birth: exploration of maternal and fetal genomes. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12685

Chicago Manual of Style (16^th Edition):

McElroy, Jude James. “Genetics of spontaneous idiopathic preterm birth: exploration of maternal and fetal genomes.” 2013. Doctoral Dissertation, Vanderbilt University. Accessed April 14, 2021. http://hdl.handle.net/1803/12685.

MLA Handbook (7^th Edition):

McElroy, Jude James. “Genetics of spontaneous idiopathic preterm birth: exploration of maternal and fetal genomes.” 2013. Web. 14 Apr 2021.

Vancouver:

McElroy JJ. Genetics of spontaneous idiopathic preterm birth: exploration of maternal and fetal genomes. [Internet] [Doctoral dissertation]. Vanderbilt University; 2013. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/1803/12685.

Council of Science Editors:

McElroy JJ. Genetics of spontaneous idiopathic preterm birth: exploration of maternal and fetal genomes. [Doctoral Dissertation]. Vanderbilt University; 2013. Available from: http://hdl.handle.net/1803/12685

Vanderbilt University

21. Jorge, Benjamin S. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.

Degree: PhD, Neuroscience, 2014, Vanderbilt University

URL: http://hdl.handle.net/1803/14387

► Epilepsy is a common neurological disease characterized by an enduring predisposition to generate seizures. Although multiple factors contribute to epilepsy, the majority of cases are… (more)

Subjects/Keywords: potassium channel; epileptic encephalopathy; mouse model; genetics; whole-exome sequencing; epilepsy

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APA (6^th Edition):

Jorge, B. S. (2014). Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14387

Chicago Manual of Style (16^th Edition):

Jorge, Benjamin S. “Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed April 14, 2021. http://hdl.handle.net/1803/14387.

MLA Handbook (7^th Edition):

Jorge, Benjamin S. “Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.” 2014. Web. 14 Apr 2021.

Vancouver:

Jorge BS. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/1803/14387.

Council of Science Editors:

Jorge BS. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14387

Stellenbosch University

22. Drogemoller, Britt Ingrid. Investigation of genetic variation contributing to antipsychotic treatment response in a South African first episode schizophrenia cohort.

Degree: PhD, Biology and Human Genetics, 2013, Stellenbosch University

URL: http://hdl.handle.net/10019.1/95473

► ENGLISH ABSTRACT: Schizophrenia is a debilitating disorder that occurs the world over. Although antipsychotics are largely effective in treating the positive symptoms of schizophrenia, the… (more)

▼ ENGLISH ABSTRACT: Schizophrenia is a debilitating disorder that occurs the world over. Although antipsychotics are largely effective in treating the positive symptoms of schizophrenia, the outcomes are non-optimal in many patients. As antipsychotic treatment response has been shown to be heritable, it is expected that the implementation of antipsychotic pharmacogenomics should aid in the optimization of antipsychotic treatments, however to date clinically applicable results are limited. Therefore this study utilized exome sequencing in a cohort of well characterized first episode schizophrenia patients to identify the genetic factors contributing to antipsychotic treatment response. The utility of exome sequencing for antipsychotic pharmacogenomic applications in the African context was assessed through examination of the literature and publically available data. Thereafter, a cohort of 104 well characterized South African first episode schizophrenia patients who were treated with flupenthixol decanoate for twelve months was collected. From this cohort, subsets of patients on extreme ends of the treatment response spectrum were identified for exome sequencing. Thereafter a bioinformatics pipeline was used to call and annotate variants. These variants and those that have previously been associated with antipsychotic response, along with a panel of ancestry informative markers, were prioritized for genotyping in the entire cohort of patients. After genotyping of the 393 variants, statistical analyses were performed to identify associations with treatment response outcomes. Examination of the literature revealed a need for exome sequencing in Africa. However, critical analyses of next generation sequencing data demonstrated that complex regions of the genome may not be well suited to these technologies. Thus, it may be necessary to combine exome sequencing with knowledge obtained from past research, as was done in this study to identify the genetic factors contributing to antipsychotic treatment response. Using this strategy, the current study highlighted the potential role that rare variants play in antipsychotic treatment response and additionally detected 11 variants that were significantly associated with antipsychotic treatment response outcomes (P=2.19x10-5). Nine of these variants were predicted to alter the function of the genes in which they occurred; of which eight were novel with regards to antipsychotic treatment response. The remaining two variants have been associated with antipsychotic treatment outcomes in previous GWAS. Examination of the function of the genes in which the variants occurred revealed that the variants associated with (i) positive symptom improvement were involved in the folate metabolism pathway and (ii) negative and general pathological symptoms improvement had potential links to neuronal development and migration. To our knowledge this study is the first to utilize exome sequencing for antipsychotic pharmacogenomic purposes. The ability of this study… Advisors/Committee Members: Warnich, Louise, Emsley, Robin, Niehaus, Dana, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biology and Human Genetics. Molecular Biology and Human Genetics..

Subjects/Keywords: Antipsychotics; Schizophrenia; Pharmacogenetics; Exome sequencing; Department of Genetics

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APA (6^th Edition):

Drogemoller, B. I. (2013). Investigation of genetic variation contributing to antipsychotic treatment response in a South African first episode schizophrenia cohort. (Doctoral Dissertation). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/95473

Chicago Manual of Style (16^th Edition):

Drogemoller, Britt Ingrid. “Investigation of genetic variation contributing to antipsychotic treatment response in a South African first episode schizophrenia cohort.” 2013. Doctoral Dissertation, Stellenbosch University. Accessed April 14, 2021. http://hdl.handle.net/10019.1/95473.

MLA Handbook (7^th Edition):

Drogemoller, Britt Ingrid. “Investigation of genetic variation contributing to antipsychotic treatment response in a South African first episode schizophrenia cohort.” 2013. Web. 14 Apr 2021.

Vancouver:

Drogemoller BI. Investigation of genetic variation contributing to antipsychotic treatment response in a South African first episode schizophrenia cohort. [Internet] [Doctoral dissertation]. Stellenbosch University; 2013. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/10019.1/95473.

Council of Science Editors:

Drogemoller BI. Investigation of genetic variation contributing to antipsychotic treatment response in a South African first episode schizophrenia cohort. [Doctoral Dissertation]. Stellenbosch University; 2013. Available from: http://hdl.handle.net/10019.1/95473

23. Jouenne, Fanélie. Apport du séquençage d’exomes constitutionnels dans l’identification de nouveaux gènes de prédisposition aux cancers, sarcomes et mélanomes pédiatriques. : Constitutional Exome Sequencing contribution for identification of new cancer predisposing genes, sarcoma and pediatric melanoma.

Degree: Docteur es, Sciences de la vie et de la santé, 2017, Université Paris-Saclay (ComUE)

URL: http://www.theses.fr/2017SACLS224

►

Le but de ce travail de thèse a été d’identifier par séquençage d’exomes, de nouveaux gènes de prédisposition dans 2 pathologies rares dont l’étiologie est… (more)

▼

Le but de ce travail de thèse a été d’identifier par séquençage d’exomes, de nouveaux gènes de prédisposition dans 2 pathologies rares dont l’étiologie est peu connue. Le 1er projet a porté sur une famille à 3 cas de sarcomes, sans mutation du gène TP53. Nous avons identifié une mutation pathogénique du gène CDKN2A, dans les 3 cas. Le gène CDKN2A étant le gène majeur de prédisposition au mélanome, nous avons recherché parmi 3 collections différentes des cas de sarcomes associés à une mutation du gène CDKN2A. Nous avons identifié 8 cas de sarcomes indépendants, porteurs d’une mutation du gène CDKN2A et montré une perte d’hétérozygotie au niveau du site de la mutation constitutionnelle CDKN2A dans 5/7 cas, montrant ainsi une perte de fonction complète. Les sarcomes étant rares chez les porteurs de mutations CDKN2A, nous avons recherché des variants rares modificateurs potentiels, par séquençages d’exomes constitutionnels des 8 cas index, et identifié 3 variants du gène PDGFRA. Des études de modélisation ont montré que 2 de ces variants, pourraient avoir un impact sur la structure du domaine extracellulaire de la protéine PDGFRA. Nous avons ainsi démontré que le gène CDKN2A peut prédisposer aux sarcomes et identifié PDGFRA comme gène modificateur potentiel.Dans le second projet nous avons travaillé sur les mélanomes de l’enfant, d’apparence sporadique. Notre hypothèse de travail était que ces mélanomes surviennent suite à un accident génétique de novo. Nous avons analysé des exomes constitutionnels de 41 trios (enfant atteint et ses 2 parents sains). Nos analyses bio-informatiques ont montré l’existence de mutations de novo post-zygotiques de gènes impliqués dans le développement de la crête neurale ou le cancer, dans 5 cas. Les analyses plus complètes des exomes tumoraux sont en cours, ainsi que des études fonctionnelles des gènes et de leurs mutations, dans un modèle d’embryon de poulet. Ce travail permettra d’accroitre la compréhension des mécanismes moléculaires et cellulaires dérégulés dans ces maladies, ouvrant ainsi, de nouvelles perspectives thérapeutiques.

The aim of this thesis was to identify by sequencing of exomes new predisposing genes in 2 rare pathologies whose etiology is not well known.The first project involved a family with 3 cases of sarcomas, without mutation of TP53 gene. We identified a pathogenic mutation of the CDKN2A gene, in the 3 cases. Since CDKN2A gene is the major melanoma predisposing gene, we have searched in 3 different collections, sarcoma cases link to CDKN2A mutations. In total, we have identified 8 independent sarcomas cases, carrying a germline mutation of the CDKN2A gene and showed a loss of heterozygosity at the site of the constitutional mutation of CDKN2A in 5/7 cases, thus proving a complete loss of function. Since sarcomas are rare in carriers of CDKN2A mutations, we looked for potential modifying rare variants, by sequencing constitutional exomes of the 8 index cases, and identified 3 variants of the PDGFRA gene. Modeling studies have shown that 2 of these variants could…

Advisors/Committee Members: Bressac, Brigitte (thesis director).

Subjects/Keywords: Prédisposition; Séquençage d'exomes; Mélanome; Sarcome; Predisposition; Exome sequencing; Melanoma; Sarcoma

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APA (6^th Edition):

Jouenne, F. (2017). Apport du séquençage d’exomes constitutionnels dans l’identification de nouveaux gènes de prédisposition aux cancers, sarcomes et mélanomes pédiatriques. : Constitutional Exome Sequencing contribution for identification of new cancer predisposing genes, sarcoma and pediatric melanoma. (Doctoral Dissertation). Université Paris-Saclay (ComUE). Retrieved from http://www.theses.fr/2017SACLS224

Chicago Manual of Style (16^th Edition):

Jouenne, Fanélie. “Apport du séquençage d’exomes constitutionnels dans l’identification de nouveaux gènes de prédisposition aux cancers, sarcomes et mélanomes pédiatriques. : Constitutional Exome Sequencing contribution for identification of new cancer predisposing genes, sarcoma and pediatric melanoma.” 2017. Doctoral Dissertation, Université Paris-Saclay (ComUE). Accessed April 14, 2021. http://www.theses.fr/2017SACLS224.

MLA Handbook (7^th Edition):

Jouenne, Fanélie. “Apport du séquençage d’exomes constitutionnels dans l’identification de nouveaux gènes de prédisposition aux cancers, sarcomes et mélanomes pédiatriques. : Constitutional Exome Sequencing contribution for identification of new cancer predisposing genes, sarcoma and pediatric melanoma.” 2017. Web. 14 Apr 2021.

Vancouver:

Jouenne F. Apport du séquençage d’exomes constitutionnels dans l’identification de nouveaux gènes de prédisposition aux cancers, sarcomes et mélanomes pédiatriques. : Constitutional Exome Sequencing contribution for identification of new cancer predisposing genes, sarcoma and pediatric melanoma. [Internet] [Doctoral dissertation]. Université Paris-Saclay (ComUE); 2017. [cited 2021 Apr 14]. Available from: http://www.theses.fr/2017SACLS224.

Council of Science Editors:

Jouenne F. Apport du séquençage d’exomes constitutionnels dans l’identification de nouveaux gènes de prédisposition aux cancers, sarcomes et mélanomes pédiatriques. : Constitutional Exome Sequencing contribution for identification of new cancer predisposing genes, sarcoma and pediatric melanoma. [Doctoral Dissertation]. Université Paris-Saclay (ComUE); 2017. Available from: http://www.theses.fr/2017SACLS224

Harvard University

24. Lim, Teng Ting. Exploring the genetic landscape of complex diseases using the recessive model.

Degree: PhD, Biology: Medical Sciences, Division of, 2014, Harvard University

URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274464

► High-throughput sequencing technologies have changed the way we identify, study and understand the role of rare variation in Mendelian diseases. Sequencing in complex diseases have… (more)

Subjects/Keywords: Genetics; complex disease; exome sequencing; rare variant; recessive

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APA (6^th Edition):

Lim, T. T. (2014). Exploring the genetic landscape of complex diseases using the recessive model. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274464

Chicago Manual of Style (16^th Edition):

Lim, Teng Ting. “Exploring the genetic landscape of complex diseases using the recessive model.” 2014. Doctoral Dissertation, Harvard University. Accessed April 14, 2021. http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274464.

MLA Handbook (7^th Edition):

Lim, Teng Ting. “Exploring the genetic landscape of complex diseases using the recessive model.” 2014. Web. 14 Apr 2021.

Vancouver:

Lim TT. Exploring the genetic landscape of complex diseases using the recessive model. [Internet] [Doctoral dissertation]. Harvard University; 2014. [cited 2021 Apr 14]. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274464.

Council of Science Editors:

Lim TT. Exploring the genetic landscape of complex diseases using the recessive model. [Doctoral Dissertation]. Harvard University; 2014. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274464

Harvard University

25. Sathirapongsasuti, Jarupon Fah. Post-Genomic Approaches to Personalized Medicine: Applications in Exome Sequencing, Microbiome, and COPD.

Degree: PhD, Biostatistics, 2013, Harvard University

URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274187

► Since the completion of the sequencing of the human genome at the turn of the century, genomics has revolutionized the study of biology and medicine… (more)

Subjects/Keywords: Bioinformatics; Genetics; Statistics; COPD; eQTL; Exome sequencing; Integrative genomics; Microbiome; Network

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APA (6^th Edition):

Sathirapongsasuti, J. F. (2013). Post-Genomic Approaches to Personalized Medicine: Applications in Exome Sequencing, Microbiome, and COPD. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274187

Chicago Manual of Style (16^th Edition):

Sathirapongsasuti, Jarupon Fah. “Post-Genomic Approaches to Personalized Medicine: Applications in Exome Sequencing, Microbiome, and COPD.” 2013. Doctoral Dissertation, Harvard University. Accessed April 14, 2021. http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274187.

MLA Handbook (7^th Edition):

Sathirapongsasuti, Jarupon Fah. “Post-Genomic Approaches to Personalized Medicine: Applications in Exome Sequencing, Microbiome, and COPD.” 2013. Web. 14 Apr 2021.

Vancouver:

Sathirapongsasuti JF. Post-Genomic Approaches to Personalized Medicine: Applications in Exome Sequencing, Microbiome, and COPD. [Internet] [Doctoral dissertation]. Harvard University; 2013. [cited 2021 Apr 14]. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274187.

Council of Science Editors:

Sathirapongsasuti JF. Post-Genomic Approaches to Personalized Medicine: Applications in Exome Sequencing, Microbiome, and COPD. [Doctoral Dissertation]. Harvard University; 2013. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274187

26. C. Tiloca. EXOME SEQUENCING APPROACH TO IDENTIFY CAUSATIVE GENES FOR AMYOTROPHIC LATERAL SCLEROSIS.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/253040

► Introduzione: La Sclerosi laterale amiotrofica (SLA) è una malattia neurodegenerativa progressiva e fatale caratterizzata dalla perdita selettiva dei motoneuroni nella corteccia cerebrale, nel tronco cerebrale… (more)

▼ Introduzione: La Sclerosi laterale amiotrofica (SLA) è una malattia neurodegenerativa progressiva e fatale caratterizzata dalla perdita selettiva dei motoneuroni nella corteccia cerebrale, nel tronco cerebrale e midollo spinale. La maggior parte dei casi è costituita da forme sporadiche, mentre solo il 5-10% dei casi è rappresentato da forme familiari, causate da geni con modalità di trasmissione mendeliana, generalmente autosomica dominante. Sono stati identificati più di 20 geni causativi delle forme familiari, che hanno contribuito a comprendere meglio i meccanismi patogenetici coinvolti e sottolineano la grande eterogeneità genetica della malattia. Nonostante i numerosi progressi raggiunti, in circa il 40% dei casi familiari la causa genetica non è stata ancora identificata, mentre la componente genetica delle forme sporadiche è in gran parte sconosciuta. L’ applicazione delle tecniche di sequenziamento di nuova generazione ed in particolare il sequenziamento della porzione codificante del genoma o esoma rappresenta un approccio innovativo e promettente per gli studi genetici sulla SLA. Lo scopo del presente progetto di ricerca di Dottorato è stato quello di identificare nuovi geni associati alle forme familiari e sporadiche di SLA mediante sequenziamento dell’esoma come metodo alternativo per superare i limiti delle tecniche genetiche tradizionali. Metodi: Sono state utilizzate tre diverse strategie per l’identificazione di geni causativi: I) sequenziamento dell’esoma in combinazione con analisi di linkage in due grandi famiglie SLA a trasmissione dominante; II) analisi per varianti rare degli esomi di 363 casi familiari singoli; III) sequenziamento dell’esoma in 32 casi di SLA sporadica e dei loro genitori non affetti (approccio dei trios). Risultati: I) Attraverso l’approccio combinato di sequenziamento dell’esoma ed analisi di linkage, abbiamo identificato il gene PFN1 (profilina-1), codificante per una proteina implicata nella regolazione dell’actina, come nuovo gene causativo di SLA. Mutazioni a carico del gene PFN1 sono state osservate nel 2,6% dei pazienti SLA familiari e gli studi funzionali condotti sui mutanti hanno dimostrato una maggiore tendenza all’aggregazione, una riduzione del legame all’actina ed un effetto inibitorio sulla crescita assonale. II) L’analisi delle varianti rare tra casi e controlli, applicata su un totale di 12.495 geni, ha portato all’identificazione di TUBA4A (codificante per lalfa-tubulina 4a) come gene candidato caratterizzato da un eccesso significativo di varianti rare potenzialmente dannose nei 363 casi familiari analizzati. L’analisi funzionale ha dimostrato per i mutanti di TUBA4A una capacità ridotta di dimerizzazione con la beta-tubulina in vitro ed un’alterata incorporazione nei microtubuli in vivo. Inoltre, il mutante tronco TUBA4A p.W407X ha mostrato una maggiore tendenza all’aggregazione. III) Infine, analizzando l’esoma di 32 pazienti con SLA sporadica e dei loro… Advisors/Committee Members: tutore: G. P. Comi, co-tutore: V. Silani, coordinatore: M. Clerici, COMI, GIACOMO PIETRO, CLERICI, MARIO SALVATORE.

Subjects/Keywords: Amyotrophic lateral sclerosis; neurodegenerative disease; exome-sequencing; Settore MED/26 - Neurologia

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APA (6^th Edition):

Tiloca, C. (2015). EXOME SEQUENCING APPROACH TO IDENTIFY CAUSATIVE GENES FOR AMYOTROPHIC LATERAL SCLEROSIS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/253040

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tiloca, C.. “EXOME SEQUENCING APPROACH TO IDENTIFY CAUSATIVE GENES FOR AMYOTROPHIC LATERAL SCLEROSIS.” 2015. Thesis, Università degli Studi di Milano. Accessed April 14, 2021. http://hdl.handle.net/2434/253040.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tiloca, C.. “EXOME SEQUENCING APPROACH TO IDENTIFY CAUSATIVE GENES FOR AMYOTROPHIC LATERAL SCLEROSIS.” 2015. Web. 14 Apr 2021.

Vancouver:

Tiloca C. EXOME SEQUENCING APPROACH TO IDENTIFY CAUSATIVE GENES FOR AMYOTROPHIC LATERAL SCLEROSIS. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/2434/253040.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tiloca C. EXOME SEQUENCING APPROACH TO IDENTIFY CAUSATIVE GENES FOR AMYOTROPHIC LATERAL SCLEROSIS. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/253040

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Virginia Commonwealth University

27. Rymer, Karen. Identification of Candidate Genes for Craniosynostosis.

Degree: MS, Human Genetics, 2015, Virginia Commonwealth University

URL: https://doi.org/10.25772/84CF-M543 ; https://scholarscompass.vcu.edu/etd/3782

► Craniosynostosis is a disorder characterized by the premature fusing of cranial sutures in an infant. Premature closure of these sutures can lead to detrimental… (more)

Subjects/Keywords: craniosynostosis; skull; whole exome sequencing; suture; Diseases; Medicine and Health Sciences

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APA (6^th Edition):

Rymer, K. (2015). Identification of Candidate Genes for Craniosynostosis. (Thesis). Virginia Commonwealth University. Retrieved from https://doi.org/10.25772/84CF-M543 ; https://scholarscompass.vcu.edu/etd/3782

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Rymer, Karen. “Identification of Candidate Genes for Craniosynostosis.” 2015. Thesis, Virginia Commonwealth University. Accessed April 14, 2021. https://doi.org/10.25772/84CF-M543 ; https://scholarscompass.vcu.edu/etd/3782.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Rymer, Karen. “Identification of Candidate Genes for Craniosynostosis.” 2015. Web. 14 Apr 2021.

Vancouver:

Rymer K. Identification of Candidate Genes for Craniosynostosis. [Internet] [Thesis]. Virginia Commonwealth University; 2015. [cited 2021 Apr 14]. Available from: https://doi.org/10.25772/84CF-M543 ; https://scholarscompass.vcu.edu/etd/3782.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Rymer K. Identification of Candidate Genes for Craniosynostosis. [Thesis]. Virginia Commonwealth University; 2015. Available from: https://doi.org/10.25772/84CF-M543 ; https://scholarscompass.vcu.edu/etd/3782

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

28. 조, 현우. Analysis of Exome Sequencing in Hepatocellular Carcinoma.

Degree: 2013, Ajou University

URL: http://repository.ajou.ac.kr/handle/201003/8583 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000013484

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Hepatocellular carcinoma (HCC) is the type of cancer difficult to classify and analyze despite the high occurrence, because it displays a high level of tumor… (more)

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Hepatocellular carcinoma (HCC) is the type of cancer difficult to classify and analyze despite the high occurrence, because it displays a high level of tumor heterogeneity with complex etiology. For unbiased analysis of HCC with diverse tumorigenic backgrounds, a genomewide study that does not target any specific target genes is needed. The mutation of known oncogenes was found from previous sequencing studies. The samples from HCC and surrounding liver samples were dissected from twelve HCC patients to investigate the pattern of tumor heterogeneity and analyze by subgroups, to be used in the integrated analysis including the whole exome sequencing to identify mutations and the gene expression profiling using microarray to identify differentially expressed genes. Two subgroups were obtained from gene expression studies, and divided according to the clinically diagnosed tumor stages. Class 1, showing low aggressiveness, displayed the high expression of metabolic activity, while Class 2, with high aggressiveness, displayed the high expression of genes modulating epigenetic regulation. From the mutation analysis 144 genes contained exonic, novel, and nonsynonymous somatic mutations in total. Two recurrently mutated genes, HMCN1 from immunoglobulin family and UNC80 comprising sodium ion channel, were found, and validated by Sanger sequencing. By the functional analysis of the set of mutated genes using gene ontology, genes regulating cell adhesion were mutated in both Class 1 and Class 2. Class 1 specifically included mutations in the genes regulating cellular development, while Class 2 genes for epigenetic regulations. As a result of determining the association between the cancer-specific mutations from exome sequencing and the chromosomal region with high epigenetic modifications, the mutated genes in the region with high histone H3k09 trimethylation displayed enrichment in the G-protein coupled receptor signaling and cell adhesion, and those with high histone H3k04 dimethylation had mutations in noncoding RNA processing and RNA metabolism in common. By the functional analysis from mutation studies of liver cancer, the profile of each subgroup was compared, and the functions related to tumor malignancy could be found.

간암 (hepatocellular carcinoma, 간세포암)은 높은 발병자 수에도 불구하고 종양 이질성이 높고 진행 양상이 복잡하여 통일된 연구를 진행하기 어렵다. 다양한 양상의 간암에 대한 편향 없는 분석을 위해서는 모든 유전자를 함께 관찰하는 genomewide한 연구가 필요하다. 간암의 기존 서열 변이 연구에서 잘 알려진 암 유발 유전자의 변이가 발견되었다. 이질성의 양상을 조사하고 아형에 따라 비교 및 분석하기 위해 12 명의 간암 환자에게서 절제한 암 및 정상 간 조직을 사용했으며, 엑솜 염기서열 분석을 통한 변이 양상과 microarray를 통한 유전자 발현 양상을 확인하는 통합 분석을 실시했다. 유전자 발현 패턴 분석에서 두 개의 아형을 얻었으며, 이는 임상적으로 진단된 단계에 따라 구분되었다. 침윤성이 낮은 아형 (Class 1)에서는 물질 대사와 관련된 유전자군의, 높은 아형 (Class 2)에서는 후성유전학적 조절과 관련된 유전자군의 발현 수준이 높게 나타났다. 유전자 변이 분석에서는 총 144개의 유전자에서 엑손 영역에 위치하며 알려진 단일염기 다형성 목록에 없고 단백질 서열에 변화를 일으키는 암 특이적 변이가 발견되었다. 변이가 중복 발견된 유전자로는 immunoglobulin family에 속하는 HMCN1과 sodium ion channel을 구성하는 UNC80이 있었고, Sanger 염기서열 분석을 통해 검증되었다. Gene ontology를 이용한 서열 변이체의 기능 분석을 통해, 모든 환자에게서 세포 흡착 관련 유전자의 변이가 관찰되었고, 아형에 따라 Class 1에서 세포 분화, Class 2에서…

Advisors/Committee Members: 대학원 의생명과학과, 201124158, 조, 현우.

Subjects/Keywords: 간암; 엑솜 염기서열 분석; Microarray; Gene ontology; Hepatocellular carcinoma; Exome sequencing

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

조, �. (2013). Analysis of Exome Sequencing in Hepatocellular Carcinoma. (Thesis). Ajou University. Retrieved from http://repository.ajou.ac.kr/handle/201003/8583 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000013484

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

조, 현우. “Analysis of Exome Sequencing in Hepatocellular Carcinoma.” 2013. Thesis, Ajou University. Accessed April 14, 2021. http://repository.ajou.ac.kr/handle/201003/8583 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000013484.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

조, 현우. “Analysis of Exome Sequencing in Hepatocellular Carcinoma.” 2013. Web. 14 Apr 2021.

Vancouver:

조 �. Analysis of Exome Sequencing in Hepatocellular Carcinoma. [Internet] [Thesis]. Ajou University; 2013. [cited 2021 Apr 14]. Available from: http://repository.ajou.ac.kr/handle/201003/8583 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000013484.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

조 �. Analysis of Exome Sequencing in Hepatocellular Carcinoma. [Thesis]. Ajou University; 2013. Available from: http://repository.ajou.ac.kr/handle/201003/8583 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000013484

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

29. M. Robusto. INHERITED HEARING LOSS: FROM GENE VARIANTS TO MECHANISMS OF DISEASE.

Degree: 2014, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/229902

► Nonsyndromic Sensorineural Hearing Loss (NSHL) is the most common sensory disorder worldwide, affecting at least 1 in 500 newborns and more than half individuals older… (more)

▼ Nonsyndromic Sensorineural Hearing Loss (NSHL) is the most common sensory disorder worldwide, affecting at least 1 in 500 newborns and more than half individuals older than 80 years. It is estimated that about 60-70% of cases are due to genetic factors [Raviv et al., 2010]. More than 70 genes have been associated with NSHL so far, but many others are still to be discovered. In this thesis, we investigated the genetic and molecular bases of NSHL by a double approach, consisting in: a) investigating the pathogenic mechanisms of mutations within the MIR96 gene, and b) searching for new genes/mutations by Whole-Exome Sequencing (WES) in selected NSHL families. As far as MIR96 is concerned, we identified and characterized a novel mutation (the third described) within the MIR96 gene, miR-96 (+57T>C), in an Italian family with autosomal dominant NSHL. MiR-96 is part of the conserved miR-183 microRNA (miRNA) family, which plays essential functions in the vertebrate inner ear. Point mutations within the seed region of miR-96 (miR-96-5p) cause autosomal dominant NSHL (AD-NSHL). The novel identified mutation replaces a highly conserved nucleotide and is predicted to reduce the stability of the pre-miRNA hairpin. Ex vivo assays in mammalian cells confirmed that both miR-96 and miR-96*(miR-96-3p) mature species were significantly reduced in the mutant, whereas the precursor level was unaffected. Moreover, miR-96 and miR-96* expression could be restored to normal levels by reconstituting the secondary structure of the pre-miR-96 hairpin, thus demonstrating that the mutation hinders the precursor processing. Finally, even though the mature miR-96 sequence is not altered, we demonstrated that the identified mutation significantly impacts on miR-96 regulation of selected targets. Taken together, these data provide further evidence of the involvement of miR-96 in human deafness and demonstrate that a quantitative defect of this miRNA may contribute to NSHL. As far as WES is concerned, the application of NGS to the identification of novel genes/mutations in 6 genetically undiagnosed Italian families (NSHL1-4 and 6, 7), with recessive NSHL and at least two affected individuals, has enabled the molecular diagnosis in two families (NSHL4 and NSHL6), and highlighted a putative novel deafness-associated gene in another family (NSHL3). In particular, a novel missense mutation within the PRPS1 gene was found in family NSHL4 and functionally characterized, together with other two mutations identified by candidate-gene screening in a larger X-linked NSHL cohort. In the NSHL3 family, WES pointed out a novel missense variant in DIAPH2, a gene not directly linked to NSHL but belonging to a family of proteins already involved in hearing loss. Studies aimed at the functional characterization of this mutation and at the clarification of the possible involvement of the gene in the pathogenesis of the disease are now being performed. For the other three families (NSHL1, 2 and NSHL7), the search for pathogenic variations is still ongoing. Advisors/Committee Members: tutor: G. Soldà, SOLDA', GIULIA MARIA EMILIA ANTONIETTA.

Subjects/Keywords: NSHL; miR-96; whole exome sequencing; Settore BIO/13 - Biologia Applicata

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❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Robusto, M. (2014). INHERITED HEARING LOSS: FROM GENE VARIANTS TO MECHANISMS OF DISEASE. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/229902

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Robusto, M.. “INHERITED HEARING LOSS: FROM GENE VARIANTS TO MECHANISMS OF DISEASE.” 2014. Thesis, Università degli Studi di Milano. Accessed April 14, 2021. http://hdl.handle.net/2434/229902.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Robusto, M.. “INHERITED HEARING LOSS: FROM GENE VARIANTS TO MECHANISMS OF DISEASE.” 2014. Web. 14 Apr 2021.

Vancouver:

Robusto M. INHERITED HEARING LOSS: FROM GENE VARIANTS TO MECHANISMS OF DISEASE. [Internet] [Thesis]. Università degli Studi di Milano; 2014. [cited 2021 Apr 14]. Available from: http://hdl.handle.net/2434/229902.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Robusto M. INHERITED HEARING LOSS: FROM GENE VARIANTS TO MECHANISMS OF DISEASE. [Thesis]. Università degli Studi di Milano; 2014. Available from: http://hdl.handle.net/2434/229902

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of California – San Francisco

30. Rojo, Carlos. Elucidating the Genetics of Vaccine-Induced Febrile Seizure Through a GWAS and Exome Sequencing.

Degree: Biomedical Sciences, 2014, University of California – San Francisco

URL: http://www.escholarship.org/uc/item/56s84992

► Despite the tremendous success of vaccination efforts across the globe, outbreaks of vaccine-preventable childhood diseases in communities around the United States are increasing. These localized… (more)

▼ Despite the tremendous success of vaccination efforts across the globe, outbreaks of vaccine-preventable childhood diseases in communities around the United States are increasing. These localized outbreaks, due in part to decreased vaccination coverage, are likely the result of a public skepticism about the safety of childhood vaccinations. To help restore trust in the vaccination effort, it is important to understand a vaccine's full range of side effects. For example, an increased risk of febrile seizure has been associated with a variety of common childhood vaccines including measles-containing vaccines such as the measles, mumps, and rubella vaccines. Currently, however, the biological cause of vaccination induced febrile seizure (VIFS) remains unclear and little is known as to why only a subset of the vaccine's recipients is affected. Towards these goals, we conducted a genome-wide association study and exome sequencing analysis to survey the genetic architecture of VIFS following measles vaccination. 274 California residents, 133 of whom experienced febrile seizure post-measles vaccination and 141 matched controls, were genotyped and exome sequenced. Using the software PLINK v.1.07, 5,757,137 markers were tested for association with VIFS, which highlighted potential genes of interest in VIFS that either regulate neuronal activity or cytokine production (rs202194476 in PTPRD, p = 1.6x10-6 ; rs11186481 near SH2D4B, p = 7.7x10-6; and rs56682383 in DPYD, p = 2.4X10-5). After using the Burrows Wheeler Aligner (BWA), Picard, and the Genome Analysis Toolkit (GATK) to process the exome sequencing data, optimized sequence kernel association testing (SKAT-O) was used to implement gene-based association testing. This analysis highlighted potential genes of interests with roles in immune system regulation and apoptosis (BATF, p = 6.1x10-6; DDI2, p = 6.5x10-5; NDUFS3, p = 8.9x10-5; DEFB126, p = 2.1x10-5). As the first GWAS and exome sequencing analysis of VIFS, this study provides the first large-scale look at the underlying genetic architecture of VIFS. As such, it builds the foundation for our understanding of a serious but unexplained side effect of the common measles vaccine, which could not only help restore any lost trust in the safety of vaccination but also potentially work towards a strategy to stratify a patient's risk for developing VIFS.

Subjects/Keywords: Genetics; exome sequencing; febrile seizure; GWAS; measles; vaccine

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❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rojo, C. (2014). Elucidating the Genetics of Vaccine-Induced Febrile Seizure Through a GWAS and Exome Sequencing. (Thesis). University of California – San Francisco. Retrieved from http://www.escholarship.org/uc/item/56s84992

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Rojo, Carlos. “Elucidating the Genetics of Vaccine-Induced Febrile Seizure Through a GWAS and Exome Sequencing.” 2014. Thesis, University of California – San Francisco. Accessed April 14, 2021. http://www.escholarship.org/uc/item/56s84992.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Rojo, Carlos. “Elucidating the Genetics of Vaccine-Induced Febrile Seizure Through a GWAS and Exome Sequencing.” 2014. Web. 14 Apr 2021.

Vancouver:

Rojo C. Elucidating the Genetics of Vaccine-Induced Febrile Seizure Through a GWAS and Exome Sequencing. [Internet] [Thesis]. University of California – San Francisco; 2014. [cited 2021 Apr 14]. Available from: http://www.escholarship.org/uc/item/56s84992.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Rojo C. Elucidating the Genetics of Vaccine-Induced Febrile Seizure Through a GWAS and Exome Sequencing. [Thesis]. University of California – San Francisco; 2014. Available from: http://www.escholarship.org/uc/item/56s84992

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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Open Access Theses and Dissertations