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Title: Investigating the genotype-phenotype correlations in paediatric steroid resistant nephrotic syndrome patients
Author: Bierzynska, Agnieszka
ISNI:       0000 0004 6057 7434
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2016
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Steroid Resistant Nephrotic Syndrome (SRNS) is characterised by either primary or late onset resistance to immunosuppression. Prognosis is poor and often results in rapid progression to end stage renal failure (ESRF). Generally, the incidence of disease-causing mutations in paediatric SRNS is 20-30%. 50 genes are currently associated with SRNS and since the advent of next generation sequencing, new genes are being linked each year. This study aimed to discover the true extent and spectrum of genetic variation in a comprehensive national NS population, selected by clinically relevant inclusion criteria. Patients were collected via a comprehensive national UK Renal Registry (RaDaR), which filtered recruits according to actual or presumed steroid resistance, and exclusion of secondary causes. Exome sequencing together with a stringent filtering algorithm was used to screen 187 paediatric SRNS and/or FSGS patients for the 50 genes associated with NS and to look for novel SRNS gene candidates. 25.7% of the sequenced patients had either, a previously described mutation or variant likely to be disease-causing. Detailed analysis revealed both known and novel disease-associated variations in the most common Nephrotic causing genes: NPH51, NPH52 and WTl and other more rarely associated genes such as LMX1B, MY01E, ADCK4 and the recently identified CRB2 and NUP107. Unexpected phenotypes were found in patients with mutations in genes usually associated with a different renal presentation, such as OCRL and DGKE. Genetic SRNS had no recurrence risk post-transplantation, whereas non-genetic SRNS had a 50% risk. Novel SRNS gene candidates e.g. MAGI2, along with potential risk factors were also found. This study demonstrates: 1. A broader genetic heterogeneity causing SRNS than previously realised and 2. A novel clinical and genetic stratification algorithm yielding a high rate of monogenic disease discovery and prognostic utility. Exome sequencing of this paediatric cohort also enabled novel SRNS genes discovery
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available