Whole exome sequencing of patients with steroid-resistant nephrotic syndrome

Jillian K. Warejko; Weizhen Tan; Ankana Daga; David Schapiro; Jennifer A. Lawson; Shirlee Shril; Svjetlana Lovric; Shazia Ashraf; Jia Rao; Tobias Hermle; Tilman Jobst-Schwan; Eugen Widmeier; Amar J. Majmundar; Ronen Schneider; Heon Yung Gee; J. Magdalena Schmidt; Asaf Vivante; Amelie T. van Der Ven; Hadas Ityel; Jing Chen; Carolin E. Sadowski; Stefan Kohl; Werner L. Pabst; Makiko Nakayama; Michael J.G. Somers; Nancy M. Rodig; Ghaleb Daouk; Michelle Baum; Deborah R. Stein; Michael A. Ferguson; Avram Z. Traum; Neveen A. Soliman; Jameela A. Kari; Sherif El Desoky; Hanan Fathy; Martin Zenker; Sevcan A. Bakkaloglu; Dominik Müller; Aytul Noyan; Fatih Ozaltin; Melissa A. Cadnapaphornchai; Seema Hashmi; Jeffrey Hopcian; Jeffrey B. Kopp; Nadine Benador; Detlef Bockenhauer; Radovan Bogdanovic; Nataša Stajić; Gil Chernin; Robert Ettenger; Henry Fehrenbach; Markus Kemper; Reyner Loza Munarriz; Ludmila Podracka; Rainer Büscher; Erkin Serdaroglu; Velibor Tasic; Shrikant Mane; Richard P. Lifton; Daniela A. Braun; Friedhelm Hildebrandt

doi:10.2215/CJN.04120417

Whole exome sequencing of patients with steroid-resistant nephrotic syndrome

Jillian K. Warejko, Weizhen Tan, Ankana Daga, David Schapiro, Jennifer A. Lawson, Shirlee Shril, Svjetlana Lovric, Shazia Ashraf, Jia Rao, Tobias Hermle, Tilman Jobst-Schwan, Eugen Widmeier, Amar J. Majmundar, Ronen Schneider, Heon Yung Gee, J. Magdalena Schmidt, Asaf Vivante, Amelie T. van Der Ven, Hadas Ityel, Jing ChenCarolin E. Sadowski, Stefan Kohl, Werner L. Pabst, Makiko Nakayama, Michael J.G. Somers, Nancy M. Rodig, Ghaleb Daouk, Michelle Baum, Deborah R. Stein, Michael A. Ferguson, Avram Z. Traum, Neveen A. Soliman, Jameela A. Kari, Sherif El Desoky, Hanan Fathy, Martin Zenker, Sevcan A. Bakkaloglu, Dominik Müller, Aytul Noyan, Fatih Ozaltin, Melissa A. Cadnapaphornchai, Seema Hashmi, Jeffrey Hopcian, Jeffrey B. Kopp, Nadine Benador, Detlef Bockenhauer, Radovan Bogdanovic, Nataša Stajić, Gil Chernin, Robert Ettenger, Henry Fehrenbach, Markus Kemper, Reyner Loza Munarriz, Ludmila Podracka, Rainer Büscher, Erkin Serdaroglu, Velibor Tasic, Shrikant Mane, Richard P. Lifton, Daniela A. Braun, Friedhelm Hildebrandt^*

^*Corresponding author for this work

Pediatrics

Boston Children's Hospital

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

188 Scopus citations

Abstract

Background and objectives Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. Design, setting, participants, & measurements Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. Results In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. Conclusions Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

Original language	English
Pages (from-to)	53-62
Number of pages	10
Journal	Clinical Journal of the American Society of Nephrology
Volume	13
Issue number	1
DOIs	https://doi.org/10.2215/CJN.04120417
State	Published - 6 Jan 2018

Funding

Funders	Funder number
Ii-numa-Tsuchiya Foundation for Overseas Research
Deutsche Akademie der Naturforscher Leopoldina - Nationale Akademie der Wissenschaften
National Institutes of Health
European Commission
California Department of Fish and Game
NIH Office of the Director	S10OD018521
Hacettepe Üniversitesi	06A101008
Manton Center for Orphan Disease Research, Boston Children's Hospital	VE 916/1-1
National Institute of Arthritis and Musculoskeletal and Skin Diseases	T32AR053461
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK076683, T32DK007726, ZIADK043308, P30DK079310, FP01014311
National Center for Advancing Translational Sciences	UL1TR001863
Seventh Framework Programme	305608, 2012-305608
American Society of Nephrology	DK007726-31A1, FP01014311
National Human Genome Research Institute	U54HG006504
Deutsche Forschungsgemeinschaft	HE 7456/1-1, Jo 1324/1-1
National Academy of Sciences	LPDS-2015-07
National Research Foundation of Korea	2015R1D1A1A01056685

Keywords

Child
Exome
Genetic renal disease
Humans
Kidney failure, chronic
Kidney transplantation
Molecular genetics
Mutation
Nephrosis, congenital
Nephrotic syndrome
Pediatric
Phenotype
Renal insufficiency, chronic

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10.2215/CJN.04120417

Cite this

Warejko, J. K., Tan, W., Daga, A., Schapiro, D., Lawson, J. A., Shril, S., Lovric, S., Ashraf, S., Rao, J., Hermle, T., Jobst-Schwan, T., Widmeier, E., Majmundar, A. J., Schneider, R., Gee, H. Y., Schmidt, J. M., Vivante, A., van Der Ven, A. T., Ityel, H., ... Hildebrandt, F. (2018). Whole exome sequencing of patients with steroid-resistant nephrotic syndrome. Clinical Journal of the American Society of Nephrology, 13(1), 53-62. https://doi.org/10.2215/CJN.04120417

@article{8a68a08c6ef44baeabb04e6acccdc282,

title = "Whole exome sequencing of patients with steroid-resistant nephrotic syndrome",

abstract = "Background and objectives Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. Design, setting, participants, & measurements Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. Results In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. Conclusions Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.",

keywords = "Child, Exome, Genetic renal disease, Humans, Kidney failure, chronic, Kidney transplantation, Molecular genetics, Mutation, Nephrosis, congenital, Nephrotic syndrome, Pediatric, Phenotype, Renal insufficiency, chronic",

author = "Warejko, {Jillian K.} and Weizhen Tan and Ankana Daga and David Schapiro and Lawson, {Jennifer A.} and Shirlee Shril and Svjetlana Lovric and Shazia Ashraf and Jia Rao and Tobias Hermle and Tilman Jobst-Schwan and Eugen Widmeier and Majmundar, {Amar J.} and Ronen Schneider and Gee, {Heon Yung} and Schmidt, {J. Magdalena} and Asaf Vivante and {van Der Ven}, {Amelie T.} and Hadas Ityel and Jing Chen and Sadowski, {Carolin E.} and Stefan Kohl and Pabst, {Werner L.} and Makiko Nakayama and Somers, {Michael J.G.} and Rodig, {Nancy M.} and Ghaleb Daouk and Michelle Baum and Stein, {Deborah R.} and Ferguson, {Michael A.} and Traum, {Avram Z.} and Soliman, {Neveen A.} and Kari, {Jameela A.} and {El Desoky}, Sherif and Hanan Fathy and Martin Zenker and Bakkaloglu, {Sevcan A.} and Dominik M{\"u}ller and Aytul Noyan and Fatih Ozaltin and Cadnapaphornchai, {Melissa A.} and Seema Hashmi and Jeffrey Hopcian and Kopp, {Jeffrey B.} and Nadine Benador and Detlef Bockenhauer and Radovan Bogdanovic and Nata{\v s}a Staji{\'c} and Gil Chernin and Robert Ettenger and Henry Fehrenbach and Markus Kemper and Munarriz, {Reyner Loza} and Ludmila Podracka and Rainer B{\"u}scher and Erkin Serdaroglu and Velibor Tasic and Shrikant Mane and Lifton, {Richard P.} and Braun, {Daniela A.} and Friedhelm Hildebrandt",

note = "Publisher Copyright: {\textcopyright} 2018 by the American Society of Nephrology.",

year = "2018",

month = jan,

day = "6",

doi = "10.2215/CJN.04120417",

language = "אנגלית",

volume = "13",

pages = "53--62",

journal = "Clinical Journal of the American Society of Nephrology",

issn = "1555-9041",

publisher = "Lippincott Williams and Wilkins",

number = "1",

}

Warejko, JK, Tan, W, Daga, A, Schapiro, D, Lawson, JA, Shril, S, Lovric, S, Ashraf, S, Rao, J, Hermle, T, Jobst-Schwan, T, Widmeier, E, Majmundar, AJ, Schneider, R, Gee, HY, Schmidt, JM, Vivante, A, van Der Ven, AT, Ityel, H, Chen, J, Sadowski, CE, Kohl, S, Pabst, WL, Nakayama, M, Somers, MJG, Rodig, NM, Daouk, G, Baum, M, Stein, DR, Ferguson, MA, Traum, AZ, Soliman, NA, Kari, JA, El Desoky, S, Fathy, H, Zenker, M, Bakkaloglu, SA, Müller, D, Noyan, A, Ozaltin, F, Cadnapaphornchai, MA, Hashmi, S, Hopcian, J, Kopp, JB, Benador, N, Bockenhauer, D, Bogdanovic, R, Stajić, N, Chernin, G, Ettenger, R, Fehrenbach, H, Kemper, M, Munarriz, RL, Podracka, L, Büscher, R, Serdaroglu, E, Tasic, V, Mane, S, Lifton, RP, Braun, DA & Hildebrandt, F 2018, 'Whole exome sequencing of patients with steroid-resistant nephrotic syndrome', Clinical Journal of the American Society of Nephrology, vol. 13, no. 1, pp. 53-62. https://doi.org/10.2215/CJN.04120417

TY - JOUR

T1 - Whole exome sequencing of patients with steroid-resistant nephrotic syndrome

AU - Warejko, Jillian K.

AU - Tan, Weizhen

AU - Daga, Ankana

AU - Schapiro, David

AU - Lawson, Jennifer A.

AU - Shril, Shirlee

AU - Lovric, Svjetlana

AU - Ashraf, Shazia

AU - Rao, Jia

AU - Hermle, Tobias

AU - Jobst-Schwan, Tilman

AU - Widmeier, Eugen

AU - Majmundar, Amar J.

AU - Schneider, Ronen

AU - Gee, Heon Yung

AU - Schmidt, J. Magdalena

AU - Vivante, Asaf

AU - van Der Ven, Amelie T.

AU - Ityel, Hadas

AU - Chen, Jing

AU - Sadowski, Carolin E.

AU - Kohl, Stefan

AU - Pabst, Werner L.

AU - Nakayama, Makiko

AU - Somers, Michael J.G.

AU - Rodig, Nancy M.

AU - Daouk, Ghaleb

AU - Baum, Michelle

AU - Stein, Deborah R.

AU - Ferguson, Michael A.

AU - Traum, Avram Z.

AU - Soliman, Neveen A.

AU - Kari, Jameela A.

AU - El Desoky, Sherif

AU - Fathy, Hanan

AU - Zenker, Martin

AU - Bakkaloglu, Sevcan A.

AU - Müller, Dominik

AU - Noyan, Aytul

AU - Ozaltin, Fatih

AU - Cadnapaphornchai, Melissa A.

AU - Hashmi, Seema

AU - Hopcian, Jeffrey

AU - Kopp, Jeffrey B.

AU - Benador, Nadine

AU - Bockenhauer, Detlef

AU - Bogdanovic, Radovan

AU - Stajić, Nataša

AU - Chernin, Gil

AU - Ettenger, Robert

AU - Fehrenbach, Henry

AU - Kemper, Markus

AU - Munarriz, Reyner Loza

AU - Podracka, Ludmila

AU - Büscher, Rainer

AU - Serdaroglu, Erkin

AU - Tasic, Velibor

AU - Mane, Shrikant

AU - Lifton, Richard P.

AU - Braun, Daniela A.

AU - Hildebrandt, Friedhelm

PY - 2018/1/6

Y1 - 2018/1/6

N2 - Background and objectives Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. Design, setting, participants, & measurements Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. Results In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. Conclusions Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

AB - Background and objectives Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. Design, setting, participants, & measurements Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. Results In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. Conclusions Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

KW - Child

KW - Exome

KW - Genetic renal disease

KW - Humans

KW - Kidney failure, chronic

KW - Kidney transplantation

KW - Molecular genetics

KW - Mutation

KW - Nephrosis, congenital

KW - Nephrotic syndrome

KW - Pediatric

KW - Phenotype

KW - Renal insufficiency, chronic

UR - http://www.scopus.com/inward/record.url?scp=85040225565&partnerID=8YFLogxK

U2 - 10.2215/CJN.04120417

DO - 10.2215/CJN.04120417

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 29127259

AN - SCOPUS:85040225565

SN - 1555-9041

VL - 13

SP - 53

EP - 62

JO - Clinical Journal of the American Society of Nephrology

JF - Clinical Journal of the American Society of Nephrology

IS - 1

ER -

Whole exome sequencing of patients with steroid-resistant nephrotic syndrome

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