The University of Southampton
University of Southampton Institutional Repository

A study of the genetics of chronic kidney disease

A study of the genetics of chronic kidney disease
A study of the genetics of chronic kidney disease
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 Half of the collagen 4 mutations occurred in COL4A5, which was a previously unpublished finding.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.
Gast, Christine
4126ea74-b62d-4356-84ed-572fdfb1c5e3
Gast, Christine
4126ea74-b62d-4356-84ed-572fdfb1c5e3
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Venkat-Raman, Gopalakrishnan
d7b865e1-4bb3-445b-9cdc-6b9885d452bd

(2015) A study of the genetics of chronic kidney disease. University of Southampton, Faculty of Medicine, Doctoral Thesis, 217pp.

Record type: Thesis (Doctoral)

Abstract

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.

PDF
PhD Thesis Christine Gast v3.pdf - Other
Download (2MB)

More information

Published date: October 2015
Organisations: University of Southampton, Human Development & Health

Identifiers

Local EPrints ID: 397107
URI: http://eprints.soton.ac.uk/id/eprint/397107
PURE UUID: 5a2f1e2c-2af5-4f22-8c52-25bc40c96b30
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

Catalogue record

Date deposited: 12 Jul 2016 14:11
Last modified: 31 Jan 2019 01:37

Export record

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×