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. Braun; Friedhelm Hildebrandt

doi:10.1093/ndt/gfy050

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

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

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 language	English
Pages (from-to)	474-485
Number of pages	12
Journal	Nephrology Dialysis Transplantation
Volume	34
Issue number	3
DOIs	https://doi.org/10.1093/ndt/gfy050
Publication status	Published - 2019 Mar 1

Bibliographical note

Funding Information:
This research was supported by grants from the National Institutes of Health (DK076683 to F.H.), Harvard Stem Cell Institute and National Institutes of Health (T32DK007726-31A1 to A.J.M.), Deutsche Forschungsgemeinschaft (JO 1324/ 1-1 to T.J.S.) and German Research Foundation (VE 916/1-1 to A.T.v.d.V.). Deutsche Forschungsgemeinschaft (HE 7456/ 1-1 to T.H.) and German National Academy of Sciences Leopoldina (LPDS 2015-07 to E.W.) and American Society of Nephrology (Benjamin J. Lipps Research Fellowship Award FP01014311 to W.T.).

Funding Information:
F.H. is a cofounder of Goldfinch Bio and receives royalties from Claritas Genomics. E.W. reports grants from the National Institutes of Health and the German National Academy of Sciences Leopoldina during the conduct of the study. Neither this manuscript nor substantial parts of it are under consideration for publication elsewhere. Twenty-two families analyzed in this study were independently and previously published, either as index families in papers describing novel SRNS-causing genes or in our previous high-throughput exon sequencing paper on monogenic forms of SRNS [16]; however, none of the families included in this study had previously been analyzed comprehensively for ASor aHUS-causing mutations.

Publisher Copyright:
© 2018 The Author(s).

All Science Journal Classification (ASJC) codes

Nephrology
Transplantation

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10.1093/ndt/gfy050

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Schapiro, D., Daga, A., Lawson, J. A., Majmundar, A. J., Lovric, S., Tan, W., Warejko, J. K., Fessi, I., Rao, J., Airik, M., Gee, H. Y., Schneider, R., Widmeier, E., Hermle, T., Ashraf, S., Jobst-Schwan, T., Van Der Ven, A. T., Nakayama, M., Shril, S., ... 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

@article{ef1016782dae419e87e519832bf210d0,

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",

note = "Funding Information: This research was supported by grants from the National Institutes of Health (DK076683 to F.H.), Harvard Stem Cell Institute and National Institutes of Health (T32DK007726-31A1 to A.J.M.), Deutsche Forschungsgemeinschaft (JO 1324/ 1-1 to T.J.S.) and German Research Foundation (VE 916/1-1 to A.T.v.d.V.). Deutsche Forschungsgemeinschaft (HE 7456/ 1-1 to T.H.) and German National Academy of Sciences Leopoldina (LPDS 2015-07 to E.W.) and American Society of Nephrology (Benjamin J. Lipps Research Fellowship Award FP01014311 to W.T.). Funding Information: F.H. is a cofounder of Goldfinch Bio and receives royalties from Claritas Genomics. E.W. reports grants from the National Institutes of Health and the German National Academy of Sciences Leopoldina during the conduct of the study. Neither this manuscript nor substantial parts of it are under consideration for publication elsewhere. Twenty-two families analyzed in this study were independently and previously published, either as index families in papers describing novel SRNS-causing genes or in our previous high-throughput exon sequencing paper on monogenic forms of SRNS [16]; however, none of the families included in this study had previously been analyzed comprehensively for ASor aHUS-causing mutations. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2019",

month = mar,

day = "1",

doi = "10.1093/ndt/gfy050",

language = "English",

volume = "34",

pages = "474--485",

journal = "Nephrology Dialysis Transplantation",

issn = "0931-0509",

publisher = "Oxford University Press",

number = "3",

}

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

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

N1 - Funding Information: This research was supported by grants from the National Institutes of Health (DK076683 to F.H.), Harvard Stem Cell Institute and National Institutes of Health (T32DK007726-31A1 to A.J.M.), Deutsche Forschungsgemeinschaft (JO 1324/ 1-1 to T.J.S.) and German Research Foundation (VE 916/1-1 to A.T.v.d.V.). Deutsche Forschungsgemeinschaft (HE 7456/ 1-1 to T.H.) and German National Academy of Sciences Leopoldina (LPDS 2015-07 to E.W.) and American Society of Nephrology (Benjamin J. Lipps Research Fellowship Award FP01014311 to W.T.). Funding Information: F.H. is a cofounder of Goldfinch Bio and receives royalties from Claritas Genomics. E.W. reports grants from the National Institutes of Health and the German National Academy of Sciences Leopoldina during the conduct of the study. Neither this manuscript nor substantial parts of it are under consideration for publication elsewhere. Twenty-two families analyzed in this study were independently and previously published, either as index families in papers describing novel SRNS-causing genes or in our previous high-throughput exon sequencing paper on monogenic forms of SRNS [16]; however, none of the families included in this study had previously been analyzed comprehensively for ASor aHUS-causing mutations. Publisher Copyright: © 2018 The Author(s).

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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DO - 10.1093/ndt/gfy050

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JO - Nephrology Dialysis Transplantation

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ER -

Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children

Abstract

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