(BRC) Investigating rare kidney disease: improving diagnosis using genetic testing and developing a new algorithm for use in clinical practice


   Faculty of Biology, Medicine and Health

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  Prof Smeeta Sinha, Prof B Newman, Dr S Banka, Prof Philip Kalra  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Diagnosis of rare kidney diseases can prove difficult with conventional diagnostic workup. As such, a proportion of patients with rare kidney disease do not receive an underlying diagnosis, this is termed Kidney Disease of Unknown Aetiology (KDUA). KDUA represents about 10-15% of the total CKD population. This is a large, underserved group in which patients have diseases that are not being identified. We also know that, for a variety of reasons, a greater proportion of these patients are from ethnic minorities and socially deprived backgrounds when compared to CKD where the underlying cause is known.

It has been shown that the diagnostic yield for patients with KDUA following genetic and targeted testing is between 7 and 40%, with exome sequencing performing better than targeted gene panels [1]. At our centre we have a large prospective observational study known as the Salford Kidney Study (SKS) with over 3,500 patients enrolled since 2002, of which 3% are from ethnic minorities. All patients have full clinical data recorded and may or not have had a kidney biopsy. Within SKS, there are over 400 patients (11%) with KDUA. Extrapolated to our whole outpatient population this figure increases to around 1100-1650 patients. This suggests that, undoubtedly, there are many patients within our service with a diagnosis where genetic and other specialised testing would be able to provide one.

This project will analyse DNA, using whole genome sequencing and whole exome sequencing (WES), from pateints with KDUA within the Salford Kidney Study. Analysis of this data will allow us to determine the number of patients with an underlying genetic cause. This is likely to include a variety of monogenic causes encompassing the whole range of kidney conditions (for example ADPKD and glomerulopathy related to COL4A genetic variants). Whilst some of these diagnoses will already be apparent prior to genetic testing, it has been shown that when WES has been tested on a large cohort of kidney patients, the majority of diagnoses were found only in a single patient [1]. The variety and rarity of conditions make the probability of prior diagnosis much lower.

Through collaborating with geneticists and bio-informaticians, analysis of this data will allow us to determine the number of patients with an underlying genetic cause for their KDUA, as well as the number within our overall cohort. We will perform detailed analysis to determine if the clinical phenotype correlates with the genotype.

Groopman E, Goldstein D, Gharavi A. Diagnostic Utility of Exome Sequencing for Kidney Disease. Reply. N Engl J Med. 2019;380(21):2080-2081

Northern Care Alliance Renal Research https://www.ncaresearch.org.uk/research/renal/

https://www.ncaresearch.org.uk/cms/wp-content/uploads/2022/02/Renal-brochure-2022.pdf

Prof Willilam Newman https://www.research.manchester.ac.uk/portal/william.newman.html

Biological Sciences (4)

Funding Notes

This studentship covers tuition fees and stipend and is open to both the UK and international applicants. We are able to offer a limited number of studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.