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Tesi sul tema "Genetic disorders"
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1
Melin, Malin. "Identification of Candidate Genes in Four Human Disorders." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7344.
Testo completo
2
Fung, Hon Chung. "Genetic characterisation of neurodegenerative disorders." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/4930/.
Testo completoAbstract (sommario):
Our global population is ageing and an ever increasing number of elderly are affected with neurodegenerative diseases, including the subjects of the studies in this work, Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). On strong evidence that several genes may influence the development of sporadic neurodegenerative diseases, the genetic association approach was used in the work of this thesis to identify the multiple variants of small effect that may modulate susceptibility to common, complex neurodegenerative diseases. It has been shown that the common genetic variation of one of these susceptibility genes, MAPT, that of the microtubule associated protein, tau, is an important genetic risk factor for neurodegenerative diseases. There are two major MAPT haplotypes at 17q21.31 designated as H1 and H2. In order to dissect the relationship between MAPT variants and the pathogenesis of neurodegenerative diseases, the architecture and distribution the major haplotypes of MAPT have been assessed. The distribution of H2 haplotype is almost exclusively in the Caucasian population, with other populations having H2 allele frequencies of essentially zero. A series of association studies of common variation of MAPT in PSP, CBD, AD and PD in different populations were performed in this work with the hypothesis that common molecular pathways are involved in these disorders. Multiple common variants of the H1 haplotypes were identified and one common haplotype, H1c, showed preferential association with PSP and AD. A whole-genome association study of PD was also undertaken in this study in order to detect if common genetic variability exerts a large effect in risk for disease in idiopathic PD. Twenty six candidate loci have been found in this whole-genome association study and they provide the basis for our investigation of disease causing genetic variants in idiopathic PD.
3
Schneider, Katja Susanne Annika. "Electrophysiological biomarkers in genetic movement disorders." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/15926/.
Testo completoAbstract (sommario):
Background: Neurodegenerative diseases are diseases of the nervous system with progressive course leading to death. Treatment remains symptomatic. Development of neuroprotective agents has been hampered for various reasons. This includes the inability of making the diagnosis accurately early in the course and the lack of reliable disease progression markers which could be used in future treatment trials. Transcranial magnetic stimulation (TMS) is a non-invasive and pain-free method for assessment of brain function. Methods: Here we evaluated TMS and its potential of serving as a reliable biomarker for neurodegenerative diseases with genetic cause. After clinical delineation of our patient cohorts with Huntington's chorea and young-onset Parkin-related Parkinsonism, we enrolled both patients as well as asymptomatic/presymptomatic gene-carriers. Patients, carriers and age-matched healthy controls were studied using TMS to establish an electrophysiological footprint of these conditions. Results: We found abnormalities in electrophysiological parameters which were present in manifesting patients and/or non-manifesting gene mutation carriers. In HD, both presymptomatic and early manifest patients had increased resting and active motor cortex thresholds. Short afferent inhibition (SAI), a measure of sensory-motor integration, was reduced in manifesting patients only. SAI changes were inversely correlated with clinical parameters like predicted years to onset and UHDRS motor score. Abnormalities in Parkin patients included prolonged central motor conduction time (CMCT), while thresholds and cortical inhibitory activity were normal. Asymptomatic carriers had increased motor thresholds and abnormal inhibitory measures (SICI recruitment) while CMCT was normal. Conclusion: We conclude that TMS may be a potential biomarker for neurodegenerative genetic diseases: 1) to detect changes early in the disease course and to monitor disease progression; 2) to help differentiating between clinically similar diseases on the basis of certain electrophysiological patterns; and 3) to give insight into underlying mechanisms of the disorders studied. Our findings suggest the potential for future research.
4
Migdalska, Anna Marta. "Modelling human genetic disorders in mice." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610341.
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5
Leiser, Kimberly A. "Assessing the association between the increased resolution of the signaturechip WG and the abnormality detection rate." Pullman, Wash. : Washington State University, 2009. http://www.dissertations.wsu.edu/Thesis/Spring2009/k_leiser_042709.pdf.
Testo completoAbstract (sommario):
Thesis (Master of Health Policy and Administration)--Washington State University, May 2009.<br>Title from PDF title page (viewed on June 5, 2009). "Department of Health Policy and Administration." Includes bibliographical references (p. 34-39).
6
Spataro, Nino 1984. "Human genetic disorders: Mendelian and complex diseases." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/482220.
Testo completoAbstract (sommario):
From Darwin’s “On the Origin of Species”, many years elapsed before human diseases were considered in an evolutionary framework. Besides theoretical and empirical advances, we are far from the complete understanding of disease aetiology. Highly penetrant disorders with Mendelian inheritance are mostly explained by the mutation-selection balance model, which is insufficient to describe the selective pressures acting on the full set of alleles related to diseases. We show in the first two papers that Next Generation Sequencing (NGS) technologies provide a unique opportunity to investigate variation and contribute to the understanding of the genetic architecture of disease. Besides exploring the role of rare and copy number variants in Parkinson’s disease (PD), we demonstrate the functional relation between Mendelian and idiopathic PD. In the last paper, we report that variation in genes previously related to Mendelian disorders has a more important role in driving complex disease susceptibility than genes associated only to complex diseases.<br>Des de l'Origen de les Espècies de Darwin van passar molts anys abans que les malalties humanes fossin considerades sota un marc evolutiu. Tanmateix, tot i els darrers avenços teòrics i empírics, estem molt lluny de tenir una comprensió completa de l'etiologia de les malalties humanes. Mentre els trastorns altament penetrants amb herència mendeliana poden explicar-se sota un model d’equilibri mutació-selecció, aquest és insuficient per descriure les pressions selectives que actuen sobre tot el conjunt d'al·lels associats a malalties. Mostrem en els dos primers treballs que les noves tecnologies de seqüenciació proporcionen una oportunitat única per investigar la variació i contribuir a la comprensió de l'arquitectura genètica de la malaltia. A més d'explorar el paper de les variants rares i en el nombre de còpies en la malaltia de Parkinson (PD), demostrem la relació funcional entre les formes mendelianes i idiopàtiques d’aquesta malaltia. En el darrer treball, mostrem sota una perspectiva evolutiva i funcional que, en comparació amb la variació genètica en gens associats només a malalties complexes, la variació en gens prèviament relacionats amb trastorns Mendelians sembla tenir un paper clarament més important en la susceptibilitat a la malaltia complexa.
7
Valente, Enza Maria. "Movement disorders : a clinical and genetic study." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405854.
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8
Dubois, Patrick Charles Alexander. "Genetic risk variants in intestinal inflammatory disorders." Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/704.
Testo completoAbstract (sommario):
This thesis includes work on the genetics of intestinal inflammatory disorders, concentrating on coeliac disease and Crohn’s disease. It explores how common genetic variants influence risk of complex phenotypes including immunological intolerance to gluten (coeliac disease) and intolerance to therapeutic agents (azathioprine and mercaptopurine) used in the treatment of intestinal inflammatory diseases. Finally it presents work aiming to move from genetic associations with complex phenotypes to understanding of how these variants modulate immunological processes. Results of a large genome wide association study that identified more than 13 new genetic risk regions influencing susceptibility to coeliac disease are presented. Results of a genome wide association study of azathioprine and 6-mercaptopurine-induced pancreatitis in inflammatory bowel disease-affected individuals are presented. Finally, a cell cytokine release assay for the prostaglandin EP4 receptor was developed, with a view to investigating how SNPs associated with Crohn’s disease in the 5p13.1 region influence EP4 receptor signalling and contribute to disease pathogenesis. This work highlights some of the challenges in moving from SNP-disease associations identified in GWASs to understanding how genetic variants change biological processes.
9
Liskova, P. "Molecular genetic study of inherited corneal disorders." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18007/.
Testo completoAbstract (sommario):
The inherited corneal diseases form a clinically and genetically heterogeneous group of disorders. They include the various types of progressive corneal dystrophies as well as some corneal structural abnormalities for which there is thought to be a genetic basis. These conditions are distinct from the corneal degenerations that result solely from aging or environmental effects. In this thesis I have concentrated on some selected inherited disorders. To try to improve our understanding of the disease mechanisms I have phenotyped affected families, performed candidate gene screening, and made genotype-phenotype correlations. I have collected the largest cohort of families with keratoconus reported to date and probands were screened for mutations in the VSX1 gene previously reported to be associated with this disorder. No disease-causing mutations were identified confirming that this gene only plays a very minor role in the pathogenesis of keratoconus. In a white British family with cornea plana the c.740A>G mutation within the KERA gene was identified and evidence was sought for a common founder with previously reported Finnish patients with cornea plana. One novel mutation was found and common founder in some of the cases was suggested. Disease-causing changes were found in seven Czech families with anterior and stromal corneal dystrophies known to be associated with the TGFBI gene and, of great interest, was a novel phenotype in a family with a p.H626P change. A set of Czech families with macular corneal dystrophy was screened for mutations in the CHST6 gene. In one British family with early-onset Fuchs endothelial corneal dystrophy we demonstrated a previously reported p.L450W mutation in the COL8A2 gene. Finally, by screening all three known genes implicated in posterior polymorphous corneal dystrophy four novel mutations were identified in the ZEB1 gene which provides additional evidence for the genetic heterogeneity of this disorder.
10
Chen, Huijia. "Skin barrier dysfunction in common genetic disorders." Thesis, University of Dundee, 2011. https://discovery.dundee.ac.uk/en/studentTheses/37ccdf72-e6b2-43e2-b5a0-954be5cb6811.
Testo completoAbstract (sommario):
One of the most important roles of the skin is the formation of an effective barrier to prevent desiccation as well as to keep out foreign pathogens and allergens. This is a tightly regulated process and involves many structural proteins, lipids, enzymes and biochemical components. One of the proteins that has an indispensable role in barrier formation is filaggrin, which is encoded by the filaggrin gene (FLG) that lies within a cluster of epidermal genes known as the epidermal differentiation complex (EDC) on chromosome 1q21. Recent studies in Europe have shown that null mutations in FLG lead to the loss of the filaggrin protein; this is the underlying genetic cause of ichthyosis vulgaris (IV) and is a significant predisposing factor for atopic dermatitis (AD) and other atopic conditions such as asthma, allergic rhinitis and food allergy. In this thesis, the critical role of FLG-null mutations was examined and confirmed as a strong predisposing factor for AD in Singaporean Chinese patients. In addition, AD patients with FLG mutations also showed an increased susceptibility for recurrent skin infections. Interestingly, a diverse and wide spectrum of FLG-null mutations was identified in the Singaporean Chinese population, as opposed to the dominance of a few common FLG mutations in Europe. This result highlighted discrete genetic variations between different ethnic groups. FLG-null mutations were also shown to have significant gene modifying effects on other skin barrier genes such as steroid sulphatase gene (STS) to exacerbate the phenotype of X-linked ichthyosis (XLI). Next, the effect of FLG¬-null mutations on other complex conditions such as acne vulgaris and childhood peanut sensitisation was investigated but no significant association of FLG mutations with these diseases were observed in the Singaporean Chinese population. Lastly, a study was attempted to search for a candidate gene for psoriasis within the EDC, through the use of fine mapping techniques. With the advent of faster and cheaper next generation sequencing (NGS) in the near future, the quest for susceptibility factors in complex traits will increase in effectiveness and speed.
11
Wallis, Colin E. "Genetic disorders on the island of Mauritius." Master's thesis, University of Cape Town, 1988. http://hdl.handle.net/11427/26606.
Testo completoAbstract (sommario):
Inherited disorders are an important cause of physical handicap, deafness, mental retardation and blindness. There is considerable variation in the geographic and ethnic distribution of genetic disease due to biological pressures and historical accidents. In this context the relative prevalence of common inherited disorders and the recognition of rare conditions in isolated communities is of great academic importance. Oceanic islands are of special significance in the study of inherited disease. Virtually nothing has been documented concerning genetic disorders on the Island of Mauritius with a population of one million people. This study was undertaken to document the impact of inherited disorders on handicapping conditions in this community. As genetic disease concentrates in institutions, formal screening of all the schools for the deaf and blind, and the associations for the physically and mentally handicapped on Mauritius was undertaken. This involved a careful history, clinical examination and genealogical study, with radiographic, biochemical and ancillary testing performed where appropriate. Referral clinics were also established for the assessment of individuals and families known, or thought to be afflicted with abnormalities or handicap of a genetic origin. To ensure completeness, a similar survey was performed on Rodrigues, a neighbouring island, as this community is included under the responsibilities of the Mauritian Ministry of Health. Accumulated data concerning 681 patients were analysed. Genetic disorders accounted for disability in 265 individuals representing 38,6% of the causes of handicap. Of these persons 54 were deaf, 30 were blind, 99 were mentally retarded and 80 were physically handicapped. Several new entities, considered unique to the area and a consequence of either consanguinity or the founder effect, were documented. Karyotyping on selected individuals was undertaken in the laboratories of the Department of Human Genetics, University of Cape Town. A molecular genetic study of a large family with X-linked deafness of Nance, conducted by the same laboratory, revealed tight linkage with the probe pDP34; linkage analysis was performed on patients with Duchenne muscular dystrophy. The collation of these original data, the delineation of the new genetic conditions and an analysis of the results form the subject of this thesis and provide a basis for the future development of genetic services on Mauritius.
12
Kumar, Kishore Raj. "Advances in genetic studies for movement disorders." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/12129.
Testo completoAbstract (sommario):
Aims: We investigated the genes causing Parkinson disease (PD), dystonia and hereditary spastic paraplegia (HSP). Methods: We performed Sanger sequencing of the GBA, VPS35, PRRT2 and GNAL genes. We sought to identify the cause of ‘hereditary whispering dysphonia’ (DYT4). We investigated a consanguineous Pakistani family with a complex neurological phenotype using next generation sequencing (NGS). We also used ‘targeted’ NGS to screen for a genetic diagnosis in patients with HSP. Results: The findings were as follows; i) GBA mutations were associated with increased susceptibility to PD in a Serbian sample, ii) a VPS35 mutation was identified in a patient with an ‘idiopathic’ PD phenotype, iii) a PRRT2 mutation was found to cause both paroxysmal kinesigenic dyskinesia and benign infantile seizures, iv) two patients with craniocervical dystonia had mutations in GNAL, v) TUBB4 was identified as the DYT4 gene, vi), an OPA3 mutation was identified in the Pakistani family using a process known as ‘reverse phenotyping’, and vii) we demonstrated that targeted NGS can be a useful diagnostic strategy in HSP. Conclusion: We determined the mutation frequency and clinical phenotype in recently identified movement disorder genes, and showed that NGS has an important role for both gene discovery and clinical diagnosis.
13
Goncalves, Pontes Jacinto Joana <1994>. "New perspectives of genetic disorders in cattle." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2022. http://amsdottorato.unibo.it/10418/1/jacinto_joana_tesi.pdf.
Testo completoAbstract (sommario):
In the last decades a negative trend in inbreeding has accompanied the evident improvement in productivity and performance of bovine domestic population, predisposing to the occurrence of recessively inherited disorders.
The objectives of this thesis were:
a) the study of genetic diseases applying a “forward genetic approach” (FGA);
b) the estimation of the prevalence of deleterious alleles responsible for eight recessive disorders in different breeds;
c) the collection of well-characterized materials in a Biobank for Bovine Genetic Disorders.
The FGA allowed the identification of seven new recessive deleterious variants (Paunch calf syndrome - KDM2B; Congenital cholesterol deficiency - APOB; Ichthyosis congenita - FA2H; Hypotrichosis - KRT71; Hypotrichosis - HEPHL1; Achromatopsia - CNGB3; Hemifacial microsomia – LAMB1) and of seven new de novo dominant deleterious variants (Achondrogenesis type II - two variants in COL2A1; Osteogenesis imperfecta - COL1A1; Skeletal-cardio-enteric dysplasia - MAP2K2; Congenital neuromuscular channelopathy - KGNG1; Epidermolysis bullosa simplex - KRT5; Classical Ehlers-Danlos syndrome - COL5A2) in different breeds, associated with a large spectrum of phenotypes affecting different systems.
The FGA was based on the sequence of a clinical, genealogical, gross- and/or histopathological and genomic study. In particular, a WGS trio-approach (patient, dam and sire) was applied.
The prevalence of deleterious alleles was calculated for the Pseudomyotonia congenita, Paunch calf syndrome, Hemifacial microsomia, Congenital bilateral cataract, Ichthyosis congenita, Ichthyosis fetalis, Achromatopsia and Hypotrichosis. A particular concern resulted the allelic frequency of 12% for the Paunch calf syndrome in Romagnola cattle.
In respect to the Biobank for Bovine Genetic Diseases, biological materials of clinical cases and their available relatives as well as controls used for the allelic frequency estimations were stored at -20 °C. Altogether, around 16.000 samples were added to the biobank.
14
Adewuyi, Emmanuel Olorunleke. "Common comorbid disorders in endometriosis patients." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/212039/1/Emmanuel%20Olorunleke_Adewuyi_Thesis.pdf.
Testo completoAbstract (sommario):
This PhD project advances our understanding of the relationship between endometriosis and its common comorbid disorders with a focus on asthma, depression, and migraine. Appropriate sets of well-regarded statistical genetic approaches were utilised in the analysis of world-leading genetic data. Findings confirm a comorbid association between endometriosis and each of asthma, depression, and migraine, largely due to shared genetics and biological mechanisms. Causality assessment suggests a potential causal relationship between endometriosis and depression. Further analyses implicate causal links between each of endometriosis and depression and at least one abnormal condition of gastric mucosa—gastritis and gastroesophageal reflux disease.
15
Ekvall, Sara. "Genetic and Clinical Investigation of Noonan Spectrum Disorders." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-183325.
Testo completoAbstract (sommario):
Noonan spectrum disorders belong to the RASopathies, a group of clinically related developmental disorders caused by dysregulation of the RAS-MAPK pathway. This thesis describes genetic and clinical investigations of six families with Noonan spectrum disorders. In the first family, the index patient presented with severe Noonan syndrome (NS) and multiple café-au-lait (CAL) spots, while four additional family members displayed multiple CAL spots only. Genetic analysis of four RAS-MAPK genes revealed a de novo PTPN11 mutation and a paternally inherited NF1 mutation, which could explain the atypically severe NS, but not the CAL spots trait in the family. The co-occurrence of two mutations was also present in another patient with a severe/complex NS-like phenotype. Genetic analysis of nine RASopathy-associated genes identified a de novo SHOC2 mutation and a maternally inherited PTPN11 mutation. The latter was also identified in her brother. Both the mother and the brother displayed mild phenotypes of NS. The results from these studies suggest that an additive effect of co-occurring mutations contributes to severe/complex NS phenotypes. The inherent difficulty in diagnosing Noonan spectrum disorders is evident in families with neurofibromatosis-Noonan syndrome (NFNS). An analysis of nine RASopathy-associated genes in a five-generation family with NFNS revealed a novel NF1 mutation in all affected family members. Notably, this family was initially diagnosed with NS and CAL spots. The clinical overlap between NS and NFNS was further demonstrated in three additional NFNS families. An analysis of twelve RASopathy-associated genes revealed three different NF1 mutations, all segregating with the disorder in each family. These mutations have been reported in patients with NF1, but have, to our knowledge, not been associated with NFNS previously. Together, these findings support the notion that NFNS is a variant of NF1. Due to the clinical overlap between NS and NFNS, we propose screening for NF1 mutations in NS patients negative for mutations in NS-associated genes, preferentially when CAL spots are present. In conclusion, this thesis suggests that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway contributes to the clinical variability observed within Noonan spectrum disorders and further demonstrates the importance of accurate genetic diagnosis.
16
Dixon, Peter Hendy. "Molecular genetic studies of hypophosphataemic and hypoparathyroid disorders." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322579.
Testo completo
17
Doran, Graeme Paul. "Functional and genetic analysis of human neurological disorders." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543472.
Testo completo
18
Jarman, Paul Richard. "A molecular genetic study of inherited movement disorders." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325154.
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19
Warner, Thomas Treharne. "A molecular genetic study of inherited movement disorders." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285185.
Testo completo
20
Kurian, Manju Ann. "Molecular genetic investigation of autosomal recessive neurodevelopmental disorders." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1126/.
Testo completoAbstract (sommario):
Development of the human brain occurs in a number of complex pre- and postnatal stages which are governed by both genetic and environmental factors. Aberrant brain development due to inherited defects may result in a wide spectrum of neurological disorders which are commonly encountered in the clinical field of paediatric neurology. In the work for this thesis, I have investigated the molecular basis and defined the clinical features of three autosomal recessive neurological syndromes. I studied a cohort of children with early onset epileptic encephalopathy and, in one family, identified a novel homozygous pathogenic mutation of PLCB1. I have also utilised autozygosity mapping techniques to study consanguineous families with a complex motor disorder, infantile parkinsonism-dystonia, and identified loss-of function mutations in the gene encoding the dopamine transporter (SLC6A3). Subsequent acquisition of a cohort of similarly affected children allowed detailed clinical and molecular characterisation of this novel disorder, dopamine transporter deficiency syndrome. Finally I have delineated the clinical and genetic features of PLA2G6-associated neurodegeneration. The identification of disease-causing genes contributes greatly to understanding the disease mechanisms underlying such early-onset disorders, and also provides novel insights into normal human neurodevelopment.
21
Li, M. Y. "The genetic and pathological correlations of ataxic disorders." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1404013/.
Testo completoAbstract (sommario):
This thesis will examine several pure and complex ataxic conditions with a focus on the genetic and neuropathological characterisation of these disorders. These disorders include Hallervorden Spatz syndrome (HSS), infantile neuroaxonal dystrophy (iNAD) both disorders are part of the neurodegeneration with brain iron accumulation (NBIA) spectrum. Mutations in the pantothenate kinase 2 (PANK2) and phopholipase A2 group 6 (PLA2G6) genes contribute to these disorders, respectively. The latter half of the thesis discusses the movement disorders known as the spinocerebellar ataxias (SCAs) with a focus on SCA11 and SCA15. Mutant mouse models of SCA11 and SCA15 with mutations in the tau tubulin kinase 2 (TTBK2) and inositol 1,4,5-triphosphate type 1 receptor (ITPR1) resepectively, were pathologicaly characterised. Each disorder will be discussed in the introductory chapter and an overall summary conclusion at the end.
22
Maison, Patrick Opoku Manu. "Genetic basis of human disorders of gonadal development." Master's thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/28015.
Testo completoAbstract (sommario):
South Africa is unique in the arena of Intersex, in that for unknown reasons we have a very high percentage of ovotesticular DSD (True Hermaphrodite). Whereas ovotesticular DSD is the least common cause of hermaphroditism in other parts of the world, it is the most common cause of hermaphroditism in South Africa. There have been several studies in the past to determine the cause of ovotesticular DSD in our population but none of these studies found appropriate answers. The current state of understanding implicates signaling and signal transduction molecules and transcription factors suggesting that it is likely not all of the genetic factors involved have already been identified. It was hypothesized that exome sequencing of individuals with DGDs will identify new mutations and genes for these conditions. Therefore, this study aims to identify additional genes that are associated with ovotesticular DSD. By using a whole-genome sequencing approach we expected to be able to identify rare variants with this condition and determine the prevalence of mutations in these genes in the ovotesticular DSD population. After obtaining informed consent, blood specimen was obtained from eleven out of fifteen patients who had histological diagnosis of Ovotesticular DSD at the Red Cross War Memorial Hospital over a 10 year period. Blood specimen was also obtained from the biological parents of these children and sent to the Ostrer laboratory for whole genome sequencing and analysis. At the Ostrer laboratory, high quality DNA was extracted from blood for all of subjects and lymphoblastoid cell lines were created. Following sample preparation using the Illumina library preparation kit, sequencing was accomplished using paired-end sequencing technology on an Illumina HiSeq2000 sequencer. The data from the Illumina sequencers was analyzed first using the Illumina sequencing data analysis pipeline for quality control. Paired end reads were aligned to the Human Reference Genome (NCBI Build 36) using the BWA software. Each alignment was assigned a mapping quality score by BWA, which is the Phredscaled probability that a read is misaligned. The basic functional annotation of SNPs/Indels is performed by ANNOVAR. The clinical features of these patients was consistent with those found by other studies on Ovotesticular DSD in South Africa and it also showed the same pattern of variation to the clinical features of Ovotesticular DSD from other parts of the world. Similar to previous South African studies, this study found no convincing gene mutations as the possible etiology of Ovotesticular DSD in South Africa. Whiles gene mutations such as duplication of SOX 9 have been found in patients with XX Ovotesticular DSD from outside South Africa, this study could not identify any such mutations. This further adds to the suspicion that the unique features of Ovotesticular DSD in South Africa suggests a different etiology from that of other parts of the world. In conclusion, the etiology of Ovotesticular DSD in South Africa still remains elusive. It is however possible that a genetic mutation may be found from a more critical analysis of the genome of the patients and their parents.
23
Modi, Bhavi P. "GENETIC AND EPIGENETIC MECHANISMS OF COMPLEX REPRODUCTIVE DISORDERS." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4574.
Testo completoAbstract (sommario):
Common, complex disorders are polygenic and multifactorial traits representing interactions between environmental, genetic and epigenetic risk factors. More often than not, contributions of these risk factors have been studied individually and this is especially true for complex reproductive traits where application of genomic technologies has been challenging and slow to progress. This thesis explores the potential of genetic and epigenetic components contributing to a better understanding of the biological pathways underlying disease risk in two specific female complex reproductive traits - polycystic ovary syndrome (PCOS) and preterm premature rupture of membranes (PPROM). The PCOS projects focus on characterization of a gene, DENND1A, whose association to PCOS has been established by Genome Wide Association Studies (GWAS) and is known to contribute to PCOS steroidogenic phenotype. In addition, differential microRNAs expression contributing to DENND1A expression regulation in PCOS theca cells was identified. The studies on PPROM utilize a Whole Exome Sequencing approach to identify rare variants in fetal genes contributing to extracellular matrix composition and synthesis contributing to PPROM risk. The results suggest that fetal contribution to PPROM is polygenic and is driven by a significant genetic burden of potentially damaging rare variants in genes contributing to fetal membrane strength and integrity. Tissue and location specific expression patterns of the Chromosome 21 miRNA cluster (miR-99a, miR-125b, let-7c) in fetal membranes from term pregnancies with spontaneous rupture were investigated. The results suggest that these miRNAs play potential roles in fetal membrane rupture and fetal membrane defects associated with T21.
24
Ylönen, S. (Susanna). "Genetic risk factors for movement disorders in Finland." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526223988.
Testo completoAbstract (sommario):
Abstract Parkinson’s disease and Huntington’s disease are progressive neurodegenerative movement disorders that typically manifest in adulthood. In this study, genetic risk factors contributing to these two movement disorders were investigated in Finnish patients. Patients with early-onset or late-onset Parkinson’s disease as well as population controls were examined. The p.L444P mutation in GBA was found to contribute to the risk of Parkinson’s disease. POLG1 compound heterozygous mutations were detected in two patients with Parkinson’s disease and rare length variants in POLG1 were associated with Parkinson’s disease. Variants in SMPD1, LRRK2 or CHCHD10, previously detected in other populations, were not detected, suggesting that they are rare or even absent in the Finnish population. Patients with Huntington’s disease were investigated for HTT gene haplotypes as well as whether these haplotypes alter the stability of the elongated CAG repeat. Haplogroup A was less common in Finns than in other European populations, whereas it was significantly more common in patients with Huntington’s disease than in the general population. Certain HTT haplotypes as well as the parental gender were found to affect the repeat instability. We found that compound heterozygous mutations in POLG1 were causative of Parkinson’s disease, rare length variants in POLG1 were associated with Parkinson’s disease and GBA p.L444P was significantly more frequent in patients than in the controls, which suggests that these mutations are associated with the development of Parkinson’s disease. The low prevalence of Huntington’s disease in Finland correlates with the low frequency of the disease-associated HTT haplogroup A. Paternal inheritance combined with haplotype A1 increased the risk of repeat expansion. Movement disorders in Finland were found to share some of the same genetic risk factors found in other European populations, but some other recognized genetic variants could not be detected<br>Tiivistelmä Parkinsonin tauti ja Huntingtonin tauti ovat hermostoa rappeuttavia eteneviä liikehäiriösairauksia, jotka tyypillisesti ilmenevät aikuisiällä. Tässä tutkimuksessa selvitettiin näiden kahden liikehäiriösairauden geneettisiä riskitekijöitä suomalaisilla potilailla. Tutkimme potilaita, joilla oli varhain alkava Parkinsonin tauti tai myöhään alkava Parkinsonin tauti sekä väestökontrolleja. GBA-geenin p.L444P mutaation havaittiin lisäävän Parkinsonin taudin riskiä. Kaksi Parkinsonin tautia sairastavaa potilasta oli yhdistelmäheterotsygootteja haitallisten POLG1-geenin varianttien suhteen ja harvinaiset POLG1 CAG toistojaksovariantit assosioituivat Parkinsonin tautiin. Tutkittuja variantteja SMPD1-, LRRK2- ja CHCHD10-geeneissä ei löydetty tästä aineistosta lainkaan, mikä viittaa siihen, että ne puuttuvat suomalaisesta väestöstä tai ovat harvinaisia. Huntingtonin tautia sairastavilta potilailta tutkittiin HTT-geenin haploryhmiä ja niiden vaikutusta Huntingtonin tautia aiheuttavan pidentyneen toistojakson epästabiiliuteen. Haploryhmä A oli suomalaisessa väestössä harvinainen verrattuna eurooppalaiseen väestöön ja se oli huomattavasti yleisempi Huntingtonin tautipotilailla kuin väestössä. Toistojakson epästabiiliuteen vaikuttivat tietyt HTT-geenin haplotyypit samoin kuin sen vanhemman sukupuoli, jolta pidentynyt toistojakso periytyy. POLG1 yhdistelmäheterotsygoottien katsottiin aiheuttavat Parkinsonin tautia ja harvinaisten POLG1 CAG toistojaksovarianttien todettiin assosioituvan Parkinsonin tautiin Suomessa. GBA p.L444P mutaatio merkittävästi yleisempi Parkinsonin tautipotilailla kuin kontrolleilla, mikä viittaa siihen, että se on Parkinsonin taudin riskitekijä. Huntingtonin tautiin assosioituvan haploryhmä A:n matala frekvenssi selittää taudin vähäistä esiintyvyyttä Suomessa. Paternaalinen periytyminen ja haplotyyppi A1 lisäsivät HTT-geenin toistojakson pidentymisen riskiä. Liikehäiriösairauksilla todettiin Suomessa osittain samanlaisia riskitekijöitä kuin muualla Euroopassa, mutta kaikkia tutkittuja variantteja emme havainneet
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ANNUNZIATA, SILVIA. "Genetic and phenotypic characterization of Autism Spectrum Disorders." Doctoral thesis, Università degli studi di Pavia, 2022. http://hdl.handle.net/11571/1452943.
Testo completo
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McGregor, Nathaniel Wade. "The identification of novel susceptibility genes involved in anxiety disorders." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/95859.
Testo completoAbstract (sommario):
Thesis (PhD)--Stellenbosch University, 2014.<br>ENGLISH ABSTRACT: The etiology of anxiety disorders remains incompletely understood. Clear evidence for a genetic component has been proposed; however, there is also an increasing focus on environmental factors and the interaction between these and the genetic components that may mediate (anxiety) disorder pathogenesis.
No single gene or genetic component has been explicitly identified as being involved in the development of anxiety disorders. This is most likely due to a number of reasons, which include, for example, the heterogeneity of anxiety disorders, the contribution of environmental factors and methodological limitations (e.g. small sample size) of research studies. Until now, genetic association studies usually focused on one particular psychiatric disorder at a time. However, with the difficulty in identifying susceptibility genes and/or loci in heterogeneous disorders like obsessive-compulsive disorder and other conditions in the anxiety spectrum, it is perhaps timely to consider multivariate genetics and epidemiological studies in a number of disorders sharing a core characteristic – such as anxiety. In addition to genetic underpinnings, a number of environmental variables have also been identified as risk factors for pathological anxiety, including adverse life events like childhood physical and sexual abuse.
The hypothesis for this project is that a pre-existing genetic vulnerability (or genetic risk) interacts with the impact of adverse life events to result in the development of one or more anxiety disorder(s). Considering phenotypic overlap amongst the anxiety disorders, it is likely that diverse networks of genes and/ or interacting pathways are responsible for the phenotypic manifestations observed. Sprague Dawley rats exhibiting behaviours indicative of anxiety in the context of environmental stressors (maternal separation and restraint stress) were used as model for the identification of novel susceptibility genes for anxiety disorders in humans. The striatum has previously been implicated as a candidate in the brain architecture of anxiety pathogenicity, and is also a site exhibiting a high degree of synaptic plasticity. The synaptic plasticity pathway was investigated using the dorsal striatum of the rat brain and several genes were identified to be aberrantly expressed in “anxious” rats relative to controls (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 and Arc). In humans, it was found that the severity of early adversity was significantly and positively associated with the presence of an anxiety disorder in adulthood. When the human homologues of the susceptibility candidate genes that were identified using the animal model were screened in a human cohort of patients with obsessive-compulsive disorder (OCD), panic disorder (PD) or social anxiety disorder (SAD) (relative to controls), five single nucleotide polymorphisms (SNPs) were found to be significantly associated with these conditions. Four of these SNPs were also found to significantly interact with the severity of childhood trauma. Haplotype analysis of variants within the identified susceptibility candidates revealed novel haplotype associations, four of which are located in the MMP9 gene. Notably, this the first study to link these particular mutations in the MMP9 gene with anxiety disorders and this finding is consistent with previous work suggesting that MMP9 is involved in conditions like cardiovascular disease and cancer which have been associated with increased prevalence of anxiety disorders.
In conclusion, this project yielded important findings pertaining to the etiology of anxiety disorders. The use of a combined anxiety disorders cohort (OCD, PD and SAD) may suggest that the associations found here may hold true for anxiety disorders in general and not only for a particular clinically delineated condition. Childhood trauma was confirmed as an increased susceptibility risk for anxiety disorders. Also, this research contributed several novel susceptibility genes (MMP9, EGR2, EGR4, NTF4, and ARC), five significant SNP associations, four significant SNP-environment interactions and five haplotype associations (within MMP9 and BDNF) as candidates for anxiety pathogenicity. The identified polymorphisms and haplotypes were demonstrated to be associated with susceptibility to anxiety disorders in a gene-environment correlation and gene-environment interaction.<br>AFRIKAANSE OPSOMMING: Die oorsake van angssteurings word steeds nie volledig verstaan nie. Daar is duidelike bewyse vir 'n genetiese komponent, maar daar is ook toenemende fokus op omgewingsfaktore en die interaksie tussen hierdie omgewingsfaktore en genetiese komponente by angssteurings.
Geen enkele geen of genetiese komponent is al geïdentifiseer as diè wat betrokke is by die ontwikkeling van angssteurings nie. Dit is waarskynlik weens 'n aantal redes, wat byvoorbeeld, die heterogeneïteit van angssteurings, die bydrae van omgewingsfaktore en metodologiese beperkings (bv. klein steekproef) van die navorsingstudies, insluit. Verder het genetiese assosiasiestudies tot nou toe gewoonlik net op een spesifieke psigiatriese versteuring op 'n slag gefokus. Maar, gegewe die uitdaging om vatbaarheidsgene en / of loci in heterogene steurings soos obsessief – kompulsiewe steuring (OKV) en ander toestande op die angsspektrum te identifiseer, is dit tyd om genetiese en kliniese studies in ‘n aantal steurings - met ‘n oorvleuende kern-element soos angs -, gesamentlik te oorweeg. Bykomend tot die genetiese boustene, is ‘n aantal omgewingsveranderlikes soos traumatiese lewenservarings tydens die kinderjare as risikofaktore vir patologiese angs geidentifiseer.
Die hipotese vir hierdie projek is dat daar 'n interaksie tussen genetiese kwesbaarheid (of genetiese risiko) en traumatiese lewensevarings is en dat dit tot die ontwikkeling van 'n / veelvoudige angssteuring(s) kan lei. Inaggenome die fenotipiese oorvleueling tussen die angssteurings, is dit waarskynlik dat diverse netwerke van gene en / of interaktiewe geen-paaie vir die manifestasie van hierdie toestande verantwoordelik is. Sprague Dawley-rotte met gedragswyses aanduidend van angs, in die konteks van omgewingstressore (d.i. skeiding van die ma-rot en bedwang-stres [restraint stress]), is as model gebruik vir die identifisering van nuwe vatbaarheidsgene vir angssteurings in mense. Die striatum is voorheen as ‘n kandidaat in die brein-argitektuur van patologiese angs voorgehou, en is ook ‘n plek met ‘n hoë mate van sinaptiese plastisiteit. Die sinaptiese plastisiteit is ondersoek deur te fokus op die dorsale striatum van die rotbrein en daar is verskeie gene gevind wat anders is in “angstige” rotte in vergelyking met kontroles (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 en Arc). In mense is daar gevind dat die ernstigheidsgraad van vroeë trauma beduidend en positief met die teenwoordigheid van ‘n angssteuring tydens volwassenheid verband hou. Toe die menslike ekwivalente van die vatbaarheidsgene wat met die dieremodel geïdentifiseer is in ‘n mens-kohort met obsessief-kompulsiewe steuring (OKS), panieksteuring (PS) en sosiale angssteuring (SAS) ondersoek is, is gevind dat daar 5 enkele nukleotied polimorfismes (ENPs) is wat met die toestande verband hou. Daar is ook gevind dat vier van hierdie ENPs beduidend verband hou met die ernstigheidsgraad van trauma tydens die kinderjare. Haplotipe analise van variante binne die geïdentifiseerde vatbaarheidsgene het op nuwe haplotipe assosiasies – waarvan 4 op die MMP9-geen geleë is – gedui. Hierdie is dus die eerste studie wat gevind het dat dié spesifieke mutasies van die MMP9-geen met angssteurings verband hou. Hierdie bevinding strook met vorige werk wat daarop dui dat die MMP9-geen by toestande soos kardiovaskulêre siekte en kanker wat ook met verhoogde voorkoms van angssteurings verband hou, betrokke is.
Ter afsluiting kan ons sê dat hierdie projek belangrike bevindinge oor die oorsake van angssteurings gemaak het. Die gebruik van ‘n gekombineerde angssteurings-kohort (OKS. PS en SAS) kan moontlik suggereer dat die assosiasies wat ons hier gevind het, waar is vir alle angssteurings en nie net vir ‘n spesifieke afgebakende toestand nie. Traumatiese ervarings tydens die kinderjare is ook bevestig as ‘n risiko vir die ontwikkeling van angssteurings. Hierdie navorsing het ook verskeie nuwe vatbaarheidsgene (MMP9, EGR2, EGR4, NTF4, en ARC), 5 beduidende ENP assosiasies, 4 beduidende ENP-omgewings-interaksies en 5 haplotipe assosiasies (by MMP9 en BDNF) geïdentifiseer as moontlike kandidate wat ‘n rol speel by die ontstaan van patologiese angs. Daar is ook gevind dat die geïdentifiseerde polimorfismes en haplotipes met vatbaarheid vir angssteurings in ‘n geen-omgewing- korrelasie en geen-omgewing- interaksie verband hou. Stellenbosch University http://scholar.sun.ac.za
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Codina, i. Solà Marta 1988. "Genetic variation and complex rearrangements in Autism Spectrum Disorders: implications for genetic counseling." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/388031.
Testo completoAbstract (sommario):
The etiology of Autism Spectrum Disorders (ASD) remains unknown for most of the cases, in spite of its strong genetic component. A greater knowledge of its genetic basis would result in many benefits, including specific genetic counseling for families and, eventually, the development of personalized therapeutic strategies. In this thesis, we have applied several recent sequencing technologies and adapted pipelines to its study. We have investigated the role of rare variants and its transcriptional consequences and explored the contribution of complex rearrangements to its missing heritability. In addition, we have studied second-hit susceptibility genetic factors in a group of individuals with Williams-Beuren syndrome, a genomic disorder associated with a mirror phenotype. Finally, we have explored parental knowledge and the effect of genetic counseling in affected families. Our results reveal that both highly penetrant mutations and inherited variants of milder effect contribute to its susceptibility, following monogenic and oligogenic or multifactorial models, respectively. Each of them may contribute to part of the variability and may explain a subset of cases.<br>Malgrat el fort component genètic dels Trastorns de l’Espectre Autista (TEA), l’etiologia de la majoria de casos es desconeix. Un major coneixement de les seves bases genètiques seria molt beneficiós, ja que permetria un assessorament genètic específic a les famílies i, a la llarga, el desenvolupament d’estratègies terapèutiques personalitzades. En aquesta tesis, s’han aplicat diverses tècniques recents de seqüenciació i estratègies d’anàlisi adaptades. S’ha investigat el paper de variants rares i les seves conseqüències transcripcionals, així com de reordenaments complexos. A més, hem estudiat la presència de variants de susceptibilitat en un grup de persones amb síndrome de Williams, un trastorn genòmic associat a un fenotip oposat. Finalment, hem explorat el coneixement i les opinions en un grup de famílies afectades i, també, l’efecte de l’assessorament genètic. Els resultats obtinguts indiquen que, en el TEA, hi contribueixen tant mutacions altament penetrants, com variants heretades que augmenten lleugerament el risc i poden seguir tant models monogènics com oligogènics. Cada un d’aquests models contribuiria a explicar part de la variabilitat i dels casos
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Liu, Xuan, and 劉絢. "BARF1 sequence analysis and functional significance in EBV-Related disorders." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B36190445.
Testo completo
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Melley, Caitlin. "Surgical fetal intervention assessing the current practices of genetic counselors /." Waltham, Mass. : Brandeis University, 2009. http://dcoll.brandeis.edu/handle/10192/23321.
Testo completo
30
Dahlqvist, Johanna. "Genetic and Molecular Studies of Two Hereditary Skin Disorders." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-149185.
Testo completoAbstract (sommario):
Monogenic disorders, i.e., disorders caused by mutations in a single gene, are rare and clinically heterogeneous conditions. Identification of the genetic cause of monogenic traits can bring new insights into molecular pathways and disease mechanisms. The aims of the present study were to identify the mutant genes in two autosomal recessive skin disorders and to characterize the functions of the mutated genes. In order to identify candidate genes for the two disorders whole-genome SNP analysis, homozygosity mapping and gene sequencing were used. Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by extensive scaling and redness of the skin. A subgroup of ARCI patients (n=27) was selected based on specific ultrastructural aberrations in their skin, revealed by electron microscopy. Mutations were identified in the Ichthyin gene in 93% of the selected patients, indicating a strong association between mutant Ichthyin and the specific morphological abnormalities. Ichthyin mRNA levels were shown to increase during keratinocyte differentiation in cells from healthy and affected individuals. Electron microscopy revealed a localization of ichthyin protein to keratins and desmosomes in epidermis. Staining of epidermal lipids identified aberrant lipid aggregates in skin sections of patients with Ichthyin mutations, indicating a role for Ichthyin in epidermal lipid metabolism. In twelve KLICK syndrome patients with ichthyosis, palmoplantar keratoderma and keratotic striae on joints, a single-nucleotide deletion was identified in the 5’ region of the proteasome maturation protein (POMP) gene. The deletion caused an increase in the proportion of POMP transcripts with long 5’ UTR’s in patient keratinocytes. Immunohistochemical analysis of differentiated skin cell layers revealed aberrant expression of POMP, proteasome subunits and the skin protein filaggrin in patients. CHOP expression, associated with endoplasmic reticulum stress, was increased in the same layers. siRNA silencing of POMP in cell cultures reduced proteasome subunit levels and induced expression of CHOP. The results indicate that the mutation in KLICK patients causes POMP and proteasome insufficiency with subsequent cellular stress. This study conclusively contributes to the understanding of epidermal physiology and the pathogenesis of two inherited skin diseases.
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Bergman, Olle. "On the influence of dopamine-related genetic variation on dopamine-related disorders /." Göteborg : Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, 2009. http://hdl.handle.net/2077/21077.
Testo completo
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Stattin, Eva-Lena. "Clinical and genetic studies of three inherited skeletal disorders." Doctoral thesis, Umeå universitet, Medicinsk och klinisk genetik, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-22402.
Testo completoAbstract (sommario):
Mutations in genes of importance for cartilage development may lead to skeletal malformations, chondroskeletal dysfunction and increased susceptibility to degenerative joint disease. Characterization of these mutations and identification of molecular pathways for the corresponding gene products have contributed to our understanding of mechanisms regulating skeletal patterning, endochondral ossification and joint formation. A five generation family segregating autosomal dominant osteochondritis dissecans (OCD) was identified. Affected family members presented with OCD in knees, hips and elbows, short stature, and early osteoarthritis. A genome wide scan and a multipoint linkage analysis identified aggrecan (ACAN) as a prime candidate gene. DNA sequence analysis of the ACAN-gene revealed heterozygosity for a missense mutation (c.6907G>A) in affected subjects, resulting in a p.V2303M substitution in the aggrecan G3 domain C-type lectin. This domain is important for the interaction with other proteins in the cartilage extracellular matrix. To determine the effect of the V2303M substitution on secretion and interaction, we performed binding studies with recombinant mutated and wild type G3 proteins. We found decreased affinity or complete loss of interaction between V2303M aggrecan and fibulin1, fibulin2 and tenascin-R. Analysis of articular cartilage from an affected family member confirmed that V2303M aggrecan is produced and present. In search for gene mutations associated with multiple epiphyseal dysplasia (MED) we considered the ACAN-gene a likely candidate. The ACAN-gene was analysed in 39 individuals with MED and screened negative for mutations in six previously known MED genes. Sequence analysis revealed a heterozygous missense mutation (c.1448G>T) in one adult male and compound heterozygous missense mutations (c.1366T>C and c.836G>A) in a five year old boy with healthy parents, each of them carrier for one of the mutations. A large family segregating autosomal dominant brachymesophalangia and OCD in finger joints was characterised. The clinical presentation in six affected family members was consistent with the diagnosis Brachydactyly type A1, in this family characterized by shortening of the middle phalanges, short ulnar styloid process, flattening of the metacarpal heads and mild osteoarthritis. The condition may be caused by mutations in the Indian hedgehog gene (IHH) or a yet unidentified gene on chromosome 5p13. Sequence analysis of the IHH-gene in affected individuals revealed a novel C to T transition (c.472C>T) leading to a p.158Arg>Cys substitution. Residue 158 in IHH is highly conserved throughout evolution and molecular structure modelling of IHH suggests that the R158C substitution leads to a conformational change at the site of interaction with the IHH-receptor. This supports that the substitution causes Brachydactyly type A1 in this family. In summary, we report on the clinical, radiological and molecular genetic characteristics of the three skeletal disorders OCD, MED and BDA1. Our results provide a novel molecular mechanism in the pathophysiology of familial osteochondritis dissecans confirming the importance of aggrecan C-type lectin for cartilage function. We also show that ACAN-gene mutations may be associated with MED extending the spectrum of skeletal dysplasias associated with the aggrecan gene. Finally, we report on a novel missense mutation in a conserved region of the IHH-gene associated with BDA1.
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Al-Abri, Mohammed Ali. "Genetic variability of health disorders in Ontario Holstein cows." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112310.
Testo completoAbstract (sommario):
Extensive emphasis on selection for milk yield with minimal attention to the animals' functional performance has increased the yield of North American dairy cattle. The high intensity of selection for production traits such as milk yield, protein yield and fat yield has also brought about a rapid increase in genetic relationships among animals. In dairy cattle, correlated response to selection for milk yield includes fertility and susceptibility to diseases. Although the high producing cows have greater net profit, they also have higher mammary and discarded milk costs associated with high production. Long-term genetic selection against clinically diagnosed diseases might be useful to diminish their incidence. The Scandinavian countries have incorporated the health traits into their selection indices. Canadian breeding programs realize the need to consider traits other than the yield in selection decisions. The objective of this study was to determine the genetic variability of various clinically diagnosed health traits. Data from 171 herds of the Ontario milk-recording program were used. These herds are collaborating with the University of Guelph (Dr. David Kelton) to record health traits. A major impediment to estimating heritabilities for the majority of the disorders was that the progeny group size per sire was not large enough to enable detecting a significant difference among sires. Hence, heritability estimates were not obtained for all the health disorders included in the study. The progeny group size per sire has to be increased such that there are at least 5 cases per progeny group to enable detecting a difference among sires. Heritability estimates for retained placenta and displaced abomasum in the first lactation were 0.067 and 0.212 respectively. The heritability estimate of cystic ovaries in the second lactation was 0.092. In the third lactation, the heritability estimate of mastitis was 0.10 whereas retained placenta had a heritability of 0.25.
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Eicher, John Dickinson. "Examining the Genetic Underpinnings of Commonly Comorbid Language Disorders." Thesis, Yale University, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3580677.
Testo completoAbstract (sommario):
<p> Impairments in various aspects of language, including the manipulation and comprehension of verbal and written language, are common in pediatric populations. Some disorders of language are secondary to other clinical presentations, while others, such as dyslexia (or reading disability [RD]), language impairment (LI), speech sound disorder (SSD), and autism spectrum disorders (ASD), have primary deficits in language skills. Each of these is a distinct disorder with unique clinical presentations and deficits. For instance, children with RD have deficits in reading and the use of written language, while those with LI have deficits in the manipulation and comprehension of verbal language. Additionally, children with SSD have difficulties in the production of speech sounds, while children with ASD may have delays or regressions in language and an inability to use complex, proper syntax and pragmatics. However, there is substantial comorbidity of these disorders, as children affected with one of these disorders are more likely to have or develop another disorder than their typically developing peers. These 'disorders—RD, LI, SSD, and ASD—are complex traits, with significant environmental and genetic components contributing to each. Similar to their phenotypic relationships, there is limited evidence that these disorders may share genetic contributors. In fact, these shared genetic components may explain the common phenotypic comorbidities of these disorders. Therefore, the overall goal of this project is to determine whether and to what extent RD, LI, SSD, and ASD share genetic associations with the hypothesis that these disorders have common genetic contributors. To accomplish this goal, I assess whether genetic associations were shared among these disorders or specific to individual disorders. First, I expand the association of the RD environmental risk factor, prenatal exposure to nicotine, to include LI and show the association of dopamine-related genes <i> ANKK1</i> and <i>DRD2</i> to LI. Second, two RD risk genes, <i> DCDC2</i> and <i>KIAA0319</i>, located within the DYX2 locus on chromosome 6p22, show associations with both LI and SSD. Third, I identify <i> ZNF385D</i> as a novel risk gene for subjects affected with comorbid RD and LI. I also assess the neuroimaging implications of DYX2 genes and <i> ZNF385D</i>, specifically in regards to cortical thickness, fiber tract volume, and fractional anisotropy. Finally, two LI risk genes, <i>ATP2C2 </i> and <i>CMIP</i> located within the SLI1 locus on chromosome 16, are associated with language skills of subjects with ASD. Taken together, these results characterize the relationship of previously identified risk genes to other related language disorders and identify novel risk genes that specifically contribute to language comorbidity. Shared genetic associations among these language disorders appear to be commonplace as opposed to the exception. However, the question remains of how these genetic variants interact with each other and other genes/exposures to ultimately lead to one or more of these language deficits seen clinically.</p>
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Clarke, Samantha Elizabeth. "Quality of life of people with rare genetic disorders." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6192/.
Testo completoAbstract (sommario):
Volume One focuses on the quality of life (Qol) of those with intellectual disabilities, commencing with a systematic review of established Qol measures to identify how these measures have been utilised and the factors that have been explored. In the resulting papers, environmental factors were considered more frequently than individual characteristics. Further research is needed for the continued development of Qol measures in order to provide services with a pragmatic way of documenting change and encourage continued focus on the individual. The empirical paper focuses on the health related quality of life (HrQol) of individuals with rare genetic disorders (Angelman, Cornelia de Lange and Cri du Chat syndromes). The variable of health, HrQol and level of challenging behaviour (CB) was explored. Individuals were found to have a high prevalence of health problems, which in turn was associated with lower HrQol. Understanding the progression of health problems and the impact in those with intellectual disabilities can aid early recognition and treatment. Volume Two contains five clinical practice reports including a service evaluation, case study and single case experiment. The reports cover a range of disorders and theoretic approaches and provide details of assessment, formulation, treatment, evaluation and reflections.
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Sailer, A. M. E. "Genetic analysis of multiple system atrophy and related disorders." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1427436/.
Testo completoAbstract (sommario):
Multiple system atrophy is a sporadic neurodegenerative disorder presenting clinically with parkinsonism, ataxia and autonomic dysfunction in variable combinations. It is clinically and pathologically heterogenous but unified by the key pathological finding of alpha-synuclein containing glial cytoplasmic inclusions. Little is known about the pathogenesis of this relatively newly defined sporadic disease. In this PhD I will present an analysis of different genetic risk factors as in many diseases, in particular neurodegenerative disorders, the study of genetics has revealed important knowledge about the biological mechanisms. As a basis for genetic studies the largest cohort of MSA samples with about 1000 MSA samples was collected as part of this PhD. These samples were then used to investigate common genetic risk factors by performing a genome wide association study (GWAS) and several candidate genes - namely MAPT, Pink1, Parkin and EIF4G1 - known to be involved in similar disorders were screened for mutations. I also collected DNA from one of the few described families with proposed autosomal dominant inheritance and performed exome sequencing, thus screening this family genome-wide for coding mutations. I then went on to study clinically or pathologically related disorders. In the genetically very heterogeneous group of hereditary ataxias new genomic technologies were shown to rapidly diagnose two families with SCA14 and SCA20, the latter being the second family of SCA20 described to date. Finally, genetic variants in the SNCA gene known to be involved in PD and MSA were investigated in a cohort of Dementia with Lewy Bodies cases.
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Petropoulou, Evmorfia. "Investigating the underlying genetic mechanisms of inherited cardiac disorders." Thesis, St George's, University of London, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.753990.
Testo completoAbstract (sommario):
Sudden cardiac death (SCD) is the most common cause of death worldwide, responsible for more than 50% of all deaths. SCD is associated with inherited cardiac conditions (ICCs) such as channelopathies and cardiomyopathies, that are heterogeneous disorders affecting the function and the structure of the myocardium. ICCs are predominantly Mendelian conditions whieh often present with reduced penetrance and variable expressivity. However, the underlying genetic cause is often not explained by screening for the current known genes, supporting the utility of whole exome and whole genome sequencing in these cases. Molecular diagnosis will enhance the clinical diagnosis and will provide a better and more targeted management for diseases. QRS interval prolongation is one of the features observed on the electrocardiogram (ECG) in Brugada Syndrome (BrS) cases. Initially a candidate gene study based on genome-wide association studies (GWASs) findings for QRS duration on the ECG was performed in a cohort of 156 unrelated SCN5A-mutation negative Brugada Syndrome (BrS) cases. Novel putative pathogenic mutations in the QRS duration-associated loci were found in only 4.5% of the BrS cases carried, suggesting that rare coding variants in the seven genes screened are not a major cause of BrS. However, a common putative benign variant (c.3218T>C - V1073A - rs6795970) in SCN10A was found to be significantly associated with BrS [P=1.39e-18; OR (95% CI) 3.02 (2.35-3.87)]. Then, the potential association with BrS with genes implicated in ICCs other than BrS, such as cardiomyopathies, was investigated using a multi-gene (174 genes) panel in a cohort of 79 unrelated -mutation negative BrS cases. Seven BrS cases (8.9%) had mutations in non SCN5A BrS-associated genes; 43% of these cases had a second mutation in cardiomyopathy (CM)-related genes. Thirteen BrS cases (16.5%) were found to have only one putative pathogenic mutation in CM- or other ICC-related genes. I then went on to investigate the utility of whole exome sequencing (WES) to identify the underlying genetic cause in a series of rare familial cardiac arrhythmias and cardiomyopathies in six Middle Eastern families - five consanguineous and one non- consanguineous. The proband of the first consanguineous family presented with DCM; WES identified a homozygous rare variant in PNPLA2 as potentially causal. Indeed, further investigation revealed the proband suffering from neutral lipid storage disease with myopathy (NLSD-M). The proband of the second consanguineous family died 90 days post birth and was diagnosed with hypertrophic CM (HCM). WES identified a homozygous rare variant in GAA (the gene mutated in Pompe disease) which was suggested to be the most possible cause. The proband of the next consanguineous family as well as all his siblings were diagnosed with HCM. WES of the proband only did not identify any good candidates; combining data from additional WES of his sister identified a homozygous rare variant in KLHL24. The proband of the non- consanguineous family was diagnosed with HCM. WES identified two heterozygous missense rare variants in two potential candidate genes, XIRP2 and SCUBE3, however none of the variants co-segregated with the disease. Two siblings of a consanguineous family were diagnosed with dilated CM (DCM) and were both sent for WES, which revealed digenic heterozygosity; two novel missense variants were identified one in TNNT2 and one in MYH7. Finally, I tried to investigate the genetic mechanism of a consanguineous family whose affected members displayed symptoms of cardiac arrhythmia and cardiomyopathy with variable expressivity among the affected members of the family. WES of two affected family members identified a rare heterozygous missense variant in CNOT1 (a gene previously associated with increased QT interval duration in a GWAS and a meta-analysis study); the variant was absent from a healthy family member that was also sent for WES. Following on from its identification, I used a gene knockdown approach in zebrafish to obtain more support for its potentially causative nature. The CN0T1 knockdown groups seemed to display atrial fibrillation. ECG measurements showed statistically significant difference between the CN0T1 knockdown groups and the control group of the heart rate of the fish (UIC vs SPL: P=0.037; UIC vs ATG: P=0.005). Statistically significant differences were also observed for the QRS and QT interval between the ATG morphants and the control group (P=0.008 and P=0.038, respectively). In conclusion, the above data together provide an insight into the role of rare and common variants in rare diseases, the advantages and disadvantages of the various approaches when trying to investigate the genetic background of rare familial diseases, the importance of co-segregation analysis for genotype-phenotype correlation and the necessity of functional analysis in diseases where the frequency of reduced penetrance is high.
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Sucheston, Lara E. "STATISTICAL METHODS FOR THE GENETIC ANALYSIS OF DEVELOPMENTAL DISORDERS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1175883318.
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Nahas, Shareef Amin. "Mechanisms of cellular radiosensitivity and human molecular genetic disorders." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1581479791&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Ichikawa, Shoji. "The molecular genetic analysis of three human neurological disorders." free online free to MU campus, others may purchase, 2002. http://wwwlib.umi.com/cr/mo/preview?3074409.
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GEMELLI, CHIARA. "Genetic approach to neuromuscular disorders in the NGS era." Doctoral thesis, Università degli studi di Genova, 2022. http://hdl.handle.net/11567/1089374.
Testo completoAbstract (sommario):
Introduction/aims. Currently, there are no straightforward guidelines for the clinical and diagnostic management of neuromuscular disorders. Therefore, I have aimed to describe the diagnostic workflow which is used in my neuromuscular clinic for evaluating patients with this condition. The neuromuscular clinic is situated in IRCCS Policlinico San Martino in Genova and is a neuromuscular university centre in Northwest Italy.
Methods. I describe our diagnostic approach to two frequent neuromuscular disorders: hyperCKemia and CMT neuropathy.
The first work is an Italian multicentre study evaluating our diagnostic workflow for isolated hyperCKemia, which is based on electrodiagnostic data, biochemical screening and first-line genetic investigations, followed by successive targeted sequencing panels. Using this approach, we established a definitive diagnosis in one third of the patients. The detection rate was higher in patients with severe hyperCKemia and abnormal electromyographic findings.
The second work includes patients affected by CMT with regular follow-ups in our CMT clinic. I describe the genetic distribution of CMT subtypes in our cohort and report a peculiar phenotype. Moreover, I define our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation.
Discussion/conclusion. Taking as a model our experience, I generalise the genetic approach to neuromuscular disorders: the diagnosis strategy should be flexible and tuned to the clinical features of the patient in order to select the best molecular approach for each patient.
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Zhang, Lu, and 张璐. "Identification and prioritization of single nucleotide variation for Mendelian disorders from whole exome sequencing data." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48521905.
Testo completoAbstract (sommario):
With the completion of human genome sequencing project and the rapid development of sequencing technologies, our capacity in tackling with genetic and genomic changes that underlie human diseases has never been greater. The recent successes in identifying disease causal single nucleotide variations (SNVs) for Mendelian disorders using whole exome sequencing may bring us one step further to understand the pathogenesis of Mendelian diseases. However, many hurdles need to be overcome before the promises can become widespread reality.
In this study, we investigated various strategies and designed a toolkit named PriSNV for SNV identification and prioritization, respectively. The SNV identification pipeline including read alignment, PCR duplication removal, indel realignment, base quality score recalibration, SNV and genotype calling was examined by simulation and real sequencing data. By incorporating sequencing errors and small indels, most of the read alignment software can achieve satisfied results. Nonetheless, the reads with medium size and large indels are prone to be wrongly mapped to the reference genome due to the limitation of gap opening strategies of available read alignment software. In addition, although mapping quality can only reflect certain information of the mapping error rate, it is still important to be adopted to filter out obvious read alignment errors. The PCR duplication removal, indel realignment and base quality score recalibration have proven to be necessary and can substantially reduce the false positive SNV calls. Based on the same quality criterion, Varscan performs as the most sensitive software for SNV calling, unfortunately at mean time the false positive calls are enriched in its result.
In order to prioritize the small subset of functionally important variants from tens of thousands of variants in whole human exome, we developed a toolkit called PriSNV, a systematic prioritization pipeline that makes use of information on variant quality, gene candidacy based on the number of novel nonsynonymous mutations in a gene, gene functional annotation, known involvement in the disease or relevant pathways, and location in linkage regions. Prediction of functional impact of the coding variants is also used to aid the search for causal mutations in Mendelian disorders. For the patient affected by Chron's disease, the candidate genes can be substantially reduced from 9615 to 3 by the gene selection strategies implemented in PriSNV.
In general, our results for SNV identification can help the biologists to realize the limitation of available software and shed light on the development of new strategies for accurately identifying SNV calls in the future. PriSNV, the software we developed for SNV prioritization, can provide significant help to biologists in prioritizing SNV calls in a systematic way and reducing search space for further analysis and experimental verification.<br>published_or_final_version<br>Paediatrics and Adolescent Medicine<br>Master<br>Master of Philosophy
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Ying, Dingge, and 应鼎阁. "Identification of shared extended haplotypes in both population-based studies of complex disease and family-based studies of Mendelian disorders." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/205837.
Testo completoAbstract (sommario):
Recent founder mutations may play important roles in complex diseases and Mendelian disorders. Detecting shared haplotypes of identity by descent (IBD) could facilitate discovery of these mutations. Several programs address this such as threshold-based methods on genetic distance and probabilistic model-based methods, but they are usually limited to only detecting pair-wise shared haplotypes and not providing a comparison between cases and controls.
In this study, a novel algorithm and a applied software package (HaploShare)is developed to detect extended haplotypes that are shared by multiple individuals, which also allows comparisons between cases and controls. A catalog of haplotypes is firstly generated from healthy controls from the same population and used for phasing genotypes in cases. By accounting for all possible haplotype pairs that could explain the genotypes for each individual in a given haplotype block and possible transitions between blocks, the effect of phase uncertainty on detection power is minimized. In cases, haplotypes shared by pairs are identified and used to detect sharing of these haplotypes by different pairs. A likelihood ratio of a shared haplotype due to IBD or chance is estimated for each extended haplotype. Controls are used similarly through many rounds of simulations to obtain an empirical null distribution of the largest likelihood ratios of shared haplotypes, to give statistical estimates of shared haplotypes detected in cases that may be associated with an underlying disease.
Series of tests were performed to investigate the performance of HaploShare. Simulations of shared haplotypes demonstrated that HaploShare has better power not only on the detection of pair-wise shared haplotypes but multiple shared haplotypes in most of the simulation scenarios, comparing with other four commonly used programs. False positive rate (FPR) and the false discovery rate (FDR) were also evaluated by statistical calculation. According to the result, both of the two values were extremely low (FPR = 6.28x10-6 , FDR = 0.006), indicating that very few randomly shared haplotypes can be wrongly reported as IBD by HaploShare.
HaploShare was also tested on real cases on population data and family linkage analysis. 14 out of 173 Hirschsprung's disease cases were reported by HaploShare of carrying a common haplotype of 250 kb in length, which was consistent with previous findings by direct genotyping and candidate approach. Another testing case is an affected family with 8 cases and 9 unaffected individuals. Disease linked region can be correctly identified by traditional methods if all the data and the entire pedigree were provided. HaploShare showed the ability to locate the shared region even when very limited cases are available, which is clearly beyond the detection power of traditional methods.
The results from empirical simulations and real case applications indicate that HaploShare could effectively make use of population genotype information to improve the power of detection of shared haplotypes. The method may extend the findings in human genetics of both complex and single gene diseases.<br>published_or_final_version<br>Psychiatry<br>Doctoral<br>Doctor of Philosophy
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Carss, Keren Jacqueline. "Identifying and modelling genes that are associated with rare developmental disorders." Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708682.
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Yip, Poon-chi Benedict. "Uses of short tandem repeats in the diagnosis of genetic diseases /." Hong Kong : University of Hong Kong, 1997. http://sunzi.lib.hku.hk/hkuto/record.jsp?B18865458.
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Melville, Scott Andrew Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Disease gene mapping in border collie dogs." Awarded by:University of New South Wales. School of Biotechnology and Biomolecular Sciences, 2006. http://handle.unsw.edu.au/1959.4/25511.
Testo completoAbstract (sommario):
Pedigree dog breeds are genetically isolated and inbred populations with characteristics specific to each breed. Some breeds carry genetic diseases which affect the health of the animals, but may also serve as a valuable model to identify genes involved in human disease. In the Border Collie breed in Australia, the identification of two disease genes would enable breeders to DNA test their animals and prevent future cases. Over 530 samples were collected to identify the genes responsible for these diseases through linkage mapping and candidate gene approaches. Collie Eye Anomaly (CEA) defines a group of symptoms that cause the incorrect development of different regions within the eye, and may also result in the detachment of the retina. The presence of the disease in different breeds of collies suggests that the disease originated before the differentiation of the collie breeds. The CEA gene was mapped to a region of CFA37, but the disease gene was identified by another research group. Neuronal Ceroid Lipofuscinosis (NCL) is a fatal neurodegenerative disorder that affects Border Collie dogs from approximately 16 months of age. The disease is inherited in an autosomal recessive manner and affected animals display a range of physiological and behavioural symptoms that include loss of muscular control, nervousness and sometimes aggression. Due to the debilitating nature of the disease, dogs rarely survive beyond 28 months of age. Microsatellite markers were used to exclude the Border Collie NCL gene from the region of the English Setter NCL gene (homolog of human NCL gene CLN8). Further work mapped the disease gene to CFA22, in a region containing the homolog for CLN5, one of the identified human disease genes for NCL. Subsequent sequencing of canine CLN5 revealed a nonsense mutation (c.619C>T, Q206X) that co-segregated with NCL in Border Collie pedigrees. This truncation mutation resulted in a protein product of similar size to some mutations identified in human CLN5 and therefore the Border Collie may make a good model for future NCL studies. With DNA testing now available, breeders of Border Collies can now ensure that no animal will die of NCL.
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Glass, Jennifer Elaine. "CURRENT PRACTICES OF PEDIATRICIANS REGARDING SCREENING FOR METABOLIC DISORDERS AMONG INTERNATIONALLY ADOPTED CHILDREN." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1244084138.
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Gauthier, Julie. "Genetic investigation of pervasive developmental disorders in the Quebec population." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=100369.
Testo completoAbstract (sommario):
Pervasive developmental disorders are a group of neurodevelopmental-neuropsychiatric disorders that are characterized by variable and severe pervasive impairments in several areas of child development, notably social interaction, communication and imagination. They all share clinical features but differ in the severity and age of onset of the impairments. Except for Rett Syndrome (RTT), the etiology of these disorders is unknown, but there is strong evidence that genetic factors contribute to their pathogenesis. While no major genes have been linked to theses disorders linkages, association and chromosomal studies suggest that many loci may be involved.<br>One aim of the present study was to search for genetics variants associated with autism and other related disorders. This study represents the first family-based association study looking at the entire X chromosome using a French-Canadian autistic population, a genetically homogenous group. We found association between autism and markers at two loci. Our results support the existence of a putative gene located on the X chromosome and moreover the founder effect, in the French-Canadian population, may provide greater power to fine map disease genes especially in complex traits.<br>The second aim of the present thesis was to confirm the involvement of the MECP2 gene in our RTT group of patients. While we confirm the presence of mutations in this gene in our cohort of RTT patients we also demonstrated that clinical stringency greatly influences the mutation detection rate for this disorder.
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Zhang, Ying. "Exploring functional genetic variants in genes involved in mental disorders." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1186433668.
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Kostareva, Anna. "Genetic and pathophysiological study of desmin derangements in cardiac disorders /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-294-1/.
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