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Original ArticlesGenetics
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Simultaneous Sequencing of 24 Genes Associated with Steroid-Resistant Nephrotic Syndrome

Hugh J. McCarthy, Agnieszka Bierzynska, Matt Wherlock, Milos Ognjanovic, Larissa Kerecuk, Shivaram Hegde, Sally Feather, Rodney D. Gilbert, Leah Krischock, Caroline Jones, Manish D. Sinha, Nicholas J.A. Webb, Martin Christian, Margaret M. Williams, Stephen Marks, Ania Koziell, Gavin I. Welsh, Moin A. Saleem and on behalf of RADAR the UK SRNS Study Group
CJASN April 2013, 8 (4) 637-648; DOI: https://doi.org/10.2215/CJN.07200712
Hugh J. McCarthy
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Agnieszka Bierzynska
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Matt Wherlock
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Milos Ognjanovic
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Larissa Kerecuk
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Shivaram Hegde
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Sally Feather
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Rodney D. Gilbert
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Leah Krischock
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Caroline Jones
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Manish D. Sinha
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Nicholas J.A. Webb
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Martin Christian
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Margaret M. Williams
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Stephen Marks
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Ania Koziell
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Gavin I. Welsh
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Moin A. Saleem
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Summary

Background and objectives Up to 95% of children presenting with steroid-resistant nephrotic syndrome in early life will have a pathogenic single-gene mutation in 1 of 24 genes currently associated with this disease. Others may be affected by polymorphic variants. There is currently no accepted diagnostic algorithm for clinical genetic testing. The hypothesis was that the increasing reliability of next generation sequencing allows comprehensive one-step genetic investigation of this group and similar patient groups.

Design, setting, participants, & measurements This study used next generation sequencing to screen 446 genes, including the 24 genes known to be associated with hereditary steroid-resistant nephrotic syndrome. The first 36 pediatric patients collected through a national United Kingdom Renal Registry were chosen with comprehensive phenotypic detail. Significant variants detected by next generation sequencing were confirmed by conventional Sanger sequencing.

Results Analysis revealed known and novel disease-associated variations in expected genes such as NPHS1, NPHS2, and PLCe1 in 19% of patients. Phenotypically unexpected mutations were also detected in COQ2 and COL4A4 in two patients with isolated nephropathy and associated sensorineural deafness, respectively. The presence of an additional heterozygous polymorphism in WT1 in a patient with NPHS1 mutation was associated with earlier-onset disease, supporting modification of phenotype through genetic epistasis.

Conclusions This study shows that next generation sequencing analysis of pediatric steroid-resistant nephrotic syndrome patients is accurate and revealing. This analysis should be considered part of the routine genetic workup of diseases such as childhood steroid-resistant nephrotic syndrome, where the chance of genetic mutation is high but requires sequencing of multiple genes.

  • Received July 17, 2012.
  • Accepted November 24, 2012.
  • Copyright © 2013 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 8 (4)
Clinical Journal of the American Society of Nephrology
Vol. 8, Issue 4
April 05, 2013
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Simultaneous Sequencing of 24 Genes Associated with Steroid-Resistant Nephrotic Syndrome
Hugh J. McCarthy, Agnieszka Bierzynska, Matt Wherlock, Milos Ognjanovic, Larissa Kerecuk, Shivaram Hegde, Sally Feather, Rodney D. Gilbert, Leah Krischock, Caroline Jones, Manish D. Sinha, Nicholas J.A. Webb, Martin Christian, Margaret M. Williams, Stephen Marks, Ania Koziell, Gavin I. Welsh, Moin A. Saleem, on behalf of RADAR the UK SRNS Study Group
CJASN Apr 2013, 8 (4) 637-648; DOI: 10.2215/CJN.07200712

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Simultaneous Sequencing of 24 Genes Associated with Steroid-Resistant Nephrotic Syndrome
Hugh J. McCarthy, Agnieszka Bierzynska, Matt Wherlock, Milos Ognjanovic, Larissa Kerecuk, Shivaram Hegde, Sally Feather, Rodney D. Gilbert, Leah Krischock, Caroline Jones, Manish D. Sinha, Nicholas J.A. Webb, Martin Christian, Margaret M. Williams, Stephen Marks, Ania Koziell, Gavin I. Welsh, Moin A. Saleem, on behalf of RADAR the UK SRNS Study Group
CJASN Apr 2013, 8 (4) 637-648; DOI: 10.2215/CJN.07200712
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  • A Systematic Analysis of Major Susceptible Genes in Childhood-onset Steroid-resistant Nephrotic Syndrome
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  • Clinical syndromes associated with Coenzyme Q10 deficiency
  • Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach
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  • Modeling Monogenic Human Nephrotic Syndrome in the Drosophila Garland Cell Nephrocyte
  • MAGI2 Mutations Cause Congenital Nephrotic Syndrome
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  • Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort
  • Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid-Resistant Nephrotic Syndrome
  • A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome
  • Heterogeneous Genetic Alterations in Sporadic Nephrotic Syndrome Associate with Resistance to Immunosuppression
  • Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing
  • Rapid Detection of Monogenic Causes of Childhood-Onset Steroid-Resistant Nephrotic Syndrome
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