Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children

David Schapiro, Ankana Daga, Jennifer A. Lawson, Amar J. Majmundar, Svjetlana Lovric, Weizhen Tan, Jillian K. Warejko, Inés Fessi, Jia Rao, Merlin Airik, Heon Yung Gee, Ronen Schneider, Eugen Widmeier, Tobias Hermle, Shazia Ashraf, Tilman Jobst-Schwan, Amelie T. Van Der Ven, Makiko Nakayama, Shirlee Shril, Daniela A. BraunFriedhelm Hildebrandt

Research output: Contribution to journalArticle

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Abstract

Background. Alport syndrome (AS) and atypical hemolytic- uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. Methods. We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. Results. We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%). Conclusions. We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.

Original languageEnglish
Pages (from-to)474-485
Number of pages12
JournalNephrology Dialysis Transplantation
Volume34
Issue number3
DOIs
Publication statusPublished - 2019 Mar 1

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Nephrosis
Hereditary Nephritis
Nephritis
Hematuria
Proteinuria
Exome
Nephrotic Syndrome
Genes
Chronic Renal Insufficiency
Steroids
Pediatrics
Mutation
Exons
Thrombotic Thrombocytopenic Purpura
Mutation Rate
Atypical Hemolytic Uremic Syndrome
Kidney

All Science Journal Classification (ASJC) codes

  • Nephrology
  • Transplantation

Cite this

Schapiro, D., Daga, A., Lawson, J. A., Majmundar, A. J., Lovric, S., Tan, W., ... Hildebrandt, F. (2019). Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children. Nephrology Dialysis Transplantation, 34(3), 474-485. https://doi.org/10.1093/ndt/gfy050
Schapiro, David ; Daga, Ankana ; Lawson, Jennifer A. ; Majmundar, Amar J. ; Lovric, Svjetlana ; Tan, Weizhen ; Warejko, Jillian K. ; Fessi, Inés ; Rao, Jia ; Airik, Merlin ; Gee, Heon Yung ; Schneider, Ronen ; Widmeier, Eugen ; Hermle, Tobias ; Ashraf, Shazia ; Jobst-Schwan, Tilman ; Van Der Ven, Amelie T. ; Nakayama, Makiko ; Shril, Shirlee ; Braun, Daniela A. ; Hildebrandt, Friedhelm. / Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children. In: Nephrology Dialysis Transplantation. 2019 ; Vol. 34, No. 3. pp. 474-485.
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title = "Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children",
abstract = "Background. Alport syndrome (AS) and atypical hemolytic- uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10{\%} of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. Methods. We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. Results. We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1{\%} of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7{\%}), 3 aHUS-causing genes (1.4{\%}) and 12 NS-causing genes (8.0{\%}). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7{\%} versus 10.1{\%}). Conclusions. We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.",
author = "David Schapiro and Ankana Daga and Lawson, {Jennifer A.} and Majmundar, {Amar J.} and Svjetlana Lovric and Weizhen Tan and Warejko, {Jillian K.} and In{\'e}s Fessi and Jia Rao and Merlin Airik and Gee, {Heon Yung} and Ronen Schneider and Eugen Widmeier and Tobias Hermle and Shazia Ashraf and Tilman Jobst-Schwan and {Van Der Ven}, {Amelie T.} and Makiko Nakayama and Shirlee Shril and Braun, {Daniela A.} and Friedhelm Hildebrandt",
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Schapiro, D, Daga, A, Lawson, JA, Majmundar, AJ, Lovric, S, Tan, W, Warejko, JK, Fessi, I, Rao, J, Airik, M, Gee, HY, Schneider, R, Widmeier, E, Hermle, T, Ashraf, S, Jobst-Schwan, T, Van Der Ven, AT, Nakayama, M, Shril, S, Braun, DA & Hildebrandt, F 2019, 'Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children', Nephrology Dialysis Transplantation, vol. 34, no. 3, pp. 474-485. https://doi.org/10.1093/ndt/gfy050

Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children. / Schapiro, David; Daga, Ankana; Lawson, Jennifer A.; Majmundar, Amar J.; Lovric, Svjetlana; Tan, Weizhen; Warejko, Jillian K.; Fessi, Inés; Rao, Jia; Airik, Merlin; Gee, Heon Yung; Schneider, Ronen; Widmeier, Eugen; Hermle, Tobias; Ashraf, Shazia; Jobst-Schwan, Tilman; Van Der Ven, Amelie T.; Nakayama, Makiko; Shril, Shirlee; Braun, Daniela A.; Hildebrandt, Friedhelm.

In: Nephrology Dialysis Transplantation, Vol. 34, No. 3, 01.03.2019, p. 474-485.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children

AU - Schapiro, David

AU - Daga, Ankana

AU - Lawson, Jennifer A.

AU - Majmundar, Amar J.

AU - Lovric, Svjetlana

AU - Tan, Weizhen

AU - Warejko, Jillian K.

AU - Fessi, Inés

AU - Rao, Jia

AU - Airik, Merlin

AU - Gee, Heon Yung

AU - Schneider, Ronen

AU - Widmeier, Eugen

AU - Hermle, Tobias

AU - Ashraf, Shazia

AU - Jobst-Schwan, Tilman

AU - Van Der Ven, Amelie T.

AU - Nakayama, Makiko

AU - Shril, Shirlee

AU - Braun, Daniela A.

AU - Hildebrandt, Friedhelm

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Background. Alport syndrome (AS) and atypical hemolytic- uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. Methods. We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. Results. We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%). Conclusions. We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.

AB - Background. Alport syndrome (AS) and atypical hemolytic- uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. Methods. We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. Results. We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%). Conclusions. We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.

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