A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome

SRNS Study Group

Research output: Contribution to journalArticle

218 Citations (Scopus)

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.

Original languageEnglish
Pages (from-to)1279-1289
Number of pages11
JournalJournal of the American Society of Nephrology
Volume26
Issue number6
DOIs
Publication statusPublished - Jun 1 2015

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Nephrotic Syndrome
Steroids
Genes
coenzyme Q10
Age of Onset
Mutation
Microfluidics
Molecular Pathology
Multiplex Polymerase Chain Reaction
Age Distribution
Genetic Association Studies
Gene Frequency
Causality
Chronic Kidney Failure
Molecular Biology
Exons
Therapeutics
Age Groups

ASJC Scopus subject areas

  • Nephrology

Cite this

A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. / SRNS Study Group.

In: Journal of the American Society of Nephrology, Vol. 26, No. 6, 01.06.2015, p. 1279-1289.

Research output: Contribution to journalArticle

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title = "A single-gene cause in 29.5{\%} of cases of steroid-resistant nephrotic syndrome",
abstract = "Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5{\%} (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4{\%}), between 4 and 12 months old (49.7{\%}), between 1 and 6 years old (25.3{\%}), between 7 and 12 years old (17.8{\%}), and between 13 and 18 years old (10.8{\%}). For PLCE1, specific mutations correlated with age of onset. Notably, 1{\%} of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.",
author = "{SRNS Study Group} and Sadowski, {Carolin E.} and Svjetlana Lovric and Shazia Ashraf and Pabst, {Werner L.} and Gee, {Heon Yung} and Stefan Kohl and Susanne Engelmann and Virginia Vega-Warner and Humphrey Fang and Jan Halbritter and Somers, {Michael J.} and Weizhen Tan and Shirlee Shril and In{\`e}s Fessi and Lifton, {Richard P.} and Detlef Bockenhauer and Sherif El-Desoky and Kari, {Jameela A.} and Martin Zenker and Kemper, {Markus J.} and Dominik Mueller and Fathy, {Hanan M.} and Soliman, {Neveen A.} and Friedhelm Hildebrandt and Repetto, {H. A.} and P. MacTaggart and L. Johnstone and S. Alexander and E. Hodson and C. Mache and Jungraithmayr, {T. C.} and C. Aufricht and K. Arbeiter and M. Lilova and C. Sweeny and G. Filler and C. Licht and Chan, {S. Y.} and S. Skalova and T. Seeman and M. Nuutinen and C. Antignac and S. Briese and U. Querfeld and I. Franke and H. Bachmann and M. Kirschstein and Weber, {L. T.} and B. Hoppe and G. Reusz",
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AU - SRNS Study Group

AU - Sadowski, Carolin E.

AU - Lovric, Svjetlana

AU - Ashraf, Shazia

AU - Pabst, Werner L.

AU - Gee, Heon Yung

AU - Kohl, Stefan

AU - Engelmann, Susanne

AU - Vega-Warner, Virginia

AU - Fang, Humphrey

AU - Halbritter, Jan

AU - Somers, Michael J.

AU - Tan, Weizhen

AU - Shril, Shirlee

AU - Fessi, Inès

AU - Lifton, Richard P.

AU - Bockenhauer, Detlef

AU - El-Desoky, Sherif

AU - Kari, Jameela A.

AU - Zenker, Martin

AU - Kemper, Markus J.

AU - Mueller, Dominik

AU - Fathy, Hanan M.

AU - Soliman, Neveen A.

AU - Hildebrandt, Friedhelm

AU - Repetto, H. A.

AU - MacTaggart, P.

AU - Johnstone, L.

AU - Alexander, S.

AU - Hodson, E.

AU - Mache, C.

AU - Jungraithmayr, T. C.

AU - Aufricht, C.

AU - Arbeiter, K.

AU - Lilova, M.

AU - Sweeny, C.

AU - Filler, G.

AU - Licht, C.

AU - Chan, S. Y.

AU - Skalova, S.

AU - Seeman, T.

AU - Nuutinen, M.

AU - Antignac, C.

AU - Briese, S.

AU - Querfeld, U.

AU - Franke, I.

AU - Bachmann, H.

AU - Kirschstein, M.

AU - Weber, L. T.

AU - Hoppe, B.

AU - Reusz, G.

PY - 2015/6/1

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N2 - Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.

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