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Genomic and clinical profiling of a national Nephrotic Syndrome cohort advocates a precision medicine approach to disease management

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Genomic and clinical profiling of a national Nephrotic Syndrome cohort advocates a precision medicine approach to disease management. / Bierzynska, Agnieszka; McCarthy, Hugh; Soderquest, Katrina; Sen, Ethan; Colby, Elizabeth; Ding, Wen; Nabhan, Marwa; Kerecuk, Larissa; Welsh, Gavin; Saleem, Moin.

In: Kidney International, Vol. 91, No. 4, 04.2017, p. 937–947.

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Bierzynska, Agnieszka ; McCarthy, Hugh ; Soderquest, Katrina ; Sen, Ethan ; Colby, Elizabeth ; Ding, Wen ; Nabhan, Marwa ; Kerecuk, Larissa ; Welsh, Gavin ; Saleem, Moin. / Genomic and clinical profiling of a national Nephrotic Syndrome cohort advocates a precision medicine approach to disease management. In: Kidney International. 2017 ; Vol. 91, No. 4. pp. 937–947.

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@article{c730c0d65527435a8c27a99fd990a0e8,
title = "Genomic and clinical profiling of a national Nephrotic Syndrome cohort advocates a precision medicine approach to disease management",
abstract = "Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing aetiologies with monogenic disease accounting for 2.9-30{\%} in selected series. We aimed, using whole exome sequencing, to stratify a national population of SRNS children into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysisPaedatric SRNS patients were collected via a national UK Renal Registry (RaDaR). Whole exome sequencing (WES) was performed on 187 patients, of which 12{\%} had a positive family history. Analysis focused on the 53 genes currently known to be associated with NS. Genetic findings were correlated with individual case disease characteristics.Disease causing variants were detected in 26.2{\%} of patients. Most occurred in the three most commonly SRNS associated genes: NPHS1, NPHS2 and WT1 but also in 14 other genes. Genotype did not always correlate with expected phenotype, e.g. mutations in OCRL, COL4A3 and DGKE, associated with specific syndromes, were detected in isolated renal disease. Analysis by primary/presumed vs. secondary steroid resistance revealed 30.8{\%} monogenic disease in primary compared to 0{\%} in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8{\%} risk of recurrence In this unbiased paediatric population, WES allowed screening of all current candidate genes. Together with deep phenotyping we propose that this is an effective tool for early identification of SRNS aetiology, yielding an evidence-based algorithm for clinical management.",
keywords = "Cytoskeleton, Focal Segmental Glomerulosclerosis, nephrotic syndrome, paediatric nephrology, podocyte, proteinuria",
author = "Agnieszka Bierzynska and Hugh McCarthy and Katrina Soderquest and Ethan Sen and Elizabeth Colby and Wen Ding and Marwa Nabhan and Larissa Kerecuk and Gavin Welsh and Moin Saleem",
year = "2017",
month = "4",
doi = "10.1016/j.kint.2016.10.013",
language = "English",
volume = "91",
pages = "937–947",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Elsevier Inc.",
number = "4",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - Genomic and clinical profiling of a national Nephrotic Syndrome cohort advocates a precision medicine approach to disease management

AU - Bierzynska, Agnieszka

AU - McCarthy, Hugh

AU - Soderquest, Katrina

AU - Sen, Ethan

AU - Colby, Elizabeth

AU - Ding, Wen

AU - Nabhan, Marwa

AU - Kerecuk, Larissa

AU - Welsh, Gavin

AU - Saleem, Moin

PY - 2017/4

Y1 - 2017/4

N2 - Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing aetiologies with monogenic disease accounting for 2.9-30% in selected series. We aimed, using whole exome sequencing, to stratify a national population of SRNS children into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysisPaedatric SRNS patients were collected via a national UK Renal Registry (RaDaR). Whole exome sequencing (WES) was performed on 187 patients, of which 12% had a positive family history. Analysis focused on the 53 genes currently known to be associated with NS. Genetic findings were correlated with individual case disease characteristics.Disease causing variants were detected in 26.2% of patients. Most occurred in the three most commonly SRNS associated genes: NPHS1, NPHS2 and WT1 but also in 14 other genes. Genotype did not always correlate with expected phenotype, e.g. mutations in OCRL, COL4A3 and DGKE, associated with specific syndromes, were detected in isolated renal disease. Analysis by primary/presumed vs. secondary steroid resistance revealed 30.8% monogenic disease in primary compared to 0% in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence In this unbiased paediatric population, WES allowed screening of all current candidate genes. Together with deep phenotyping we propose that this is an effective tool for early identification of SRNS aetiology, yielding an evidence-based algorithm for clinical management.

AB - Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing aetiologies with monogenic disease accounting for 2.9-30% in selected series. We aimed, using whole exome sequencing, to stratify a national population of SRNS children into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysisPaedatric SRNS patients were collected via a national UK Renal Registry (RaDaR). Whole exome sequencing (WES) was performed on 187 patients, of which 12% had a positive family history. Analysis focused on the 53 genes currently known to be associated with NS. Genetic findings were correlated with individual case disease characteristics.Disease causing variants were detected in 26.2% of patients. Most occurred in the three most commonly SRNS associated genes: NPHS1, NPHS2 and WT1 but also in 14 other genes. Genotype did not always correlate with expected phenotype, e.g. mutations in OCRL, COL4A3 and DGKE, associated with specific syndromes, were detected in isolated renal disease. Analysis by primary/presumed vs. secondary steroid resistance revealed 30.8% monogenic disease in primary compared to 0% in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence In this unbiased paediatric population, WES allowed screening of all current candidate genes. Together with deep phenotyping we propose that this is an effective tool for early identification of SRNS aetiology, yielding an evidence-based algorithm for clinical management.

KW - Cytoskeleton

KW - Focal Segmental Glomerulosclerosis

KW - nephrotic syndrome

KW - paediatric nephrology

KW - podocyte

KW - proteinuria

U2 - 10.1016/j.kint.2016.10.013

DO - 10.1016/j.kint.2016.10.013

M3 - Article

VL - 91

SP - 937

EP - 947

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 4

ER -