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Title: A study of the genetics of chronic kidney disease
Author: Gast, Christine
ISNI:       0000 0004 5922 333X
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2015
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This study examines the prevalence and distribution of genetic kidney diseases in a cohort of chronic kidney disease (CKD) patients. The literature and national registries hold a paucity of information on genetic kidney disease prevalence in adult patients with CKD. Through a questionnaire study of all patients of the Wessex Renal and Transplant Service in CKD stages 3-5 on family history, a systematic database search and patient interviews, this study established a prevalence of genetic kidney diseases other than polycystic kidney disease(PKD) of 7.6% amongst end-stage renal disease patients and 3.8% amongst CKD patients, which is higher than previously reported. The study reveals uromodulin associated kidney disease (UAKD) to be the most prevalent genetic kidney disease after PKD, which has not been reported previously. The prevalence for UAKD in Wessex was established at 8.5 per million by UMOD gene sequencing. This is much higher than the only published prevalence of 1.7 per million in Austria. Established diagnostic biochemical tests for UAKD were evaluated and found to have relatively poor sensitivity and specificity –70 and 45% respectively in the case of the fractional excretion of urate, and 70 and 63% for urinary uromodulin, measured by enzyme linked immunosorbent assay (ELISA). On review of clinical phenotypes, hyperuricaemia and gout as the typical clinical features were not statistically associated with UAKD, highlighting the need for gene testing to establish the diagnosis. 81 patients with the clinico-pathological diagnosis focal segmental glomerulosclerosis (FSGS) were recruited to examine underlying gene mutations by a custom-designed targeted next generation sequencing (NGS) panel. Underlying gene mutations were established in 13-20% of patients, which is higher than in previous adult series. Of relevance, the most frequent mutations occurred in the collagen 4 gene, which was unexpected and changed the clinical diagnosis of these patients to Alport disease. Half of the collagen 4 mutations occurred in COL4A5, which was a previously unpublished finding. Whole exome sequencing (WES) was employed in the search for a genetic diagnosis in a previously undiagnosed family. A systematic analysis of both renal and pan-genomic variants failed to identify a disease-causing variant and illustrated the challenges of WES, leading to a discussion of future genetic investigations by NGS.
Supervisor: Ennis, Sarah ; Venkat-Raman, Gopalakrishnan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available