The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Miguel Verbitsky; Rik Westland; Alejandra Perez; Krzysztof Kiryluk; Qingxue Liu; Priya Krithivasan; Adele Mitrotti; David A. Fasel; Ekaterina Batourina; Matthew G. Sampson; Monica Bodria; Max Werth; Charlly Kao; Jeremiah Martino; Valentina P. Capone; Asaf Vivante; Shirlee Shril; Byum Hee Kil; Maddalena Marasà; Jun Y. Zhang; Young Ji Na; Tze Y. Lim; Dina Ahram; Patricia L. Weng; Erin L. Heinzen; Alba Carrea; Giorgio Piaggio; Loreto Gesualdo; Valeria Manca; Giuseppe Masnata; Maddalena Gigante; Daniele Cusi; Claudia Izzi; Francesco Scolari; Joanna A.E. van Wijk; Marijan Saraga; Domenico Santoro; Giovanni Conti; Pasquale Zamboli; Hope White; Dorota Drozdz; Katarzyna Zachwieja; Monika Miklaszewska; Marcin Tkaczyk; Daria Tomczyk; Anna Krakowska; Przemyslaw Sikora; Tomasz Jarmoliński; Maria K. Borszewska-Kornacka; Robert Pawluch; Maria Szczepanska; Piotr Adamczyk; Malgorzata Mizerska-Wasiak; Grazyna Krzemien; Agnieszka Szmigielska; Marcin Zaniew; Mark G. Dobson; John M. Darlow; Prem Puri; David E. Barton; Susan L. Furth; Bradley A. Warady; Zoran Gucev; Vladimir J. Lozanovski; Velibor Tasic; Isabella Pisani; Landino Allegri; Lida M. Rodas; Josep M. Campistol; Cécile Jeanpierre; Shumyle Alam; Pasquale Casale; Craig S. Wong; Fangming Lin; Débora M. Miranda; Eduardo A. Oliveira; Ana Cristina Simões-e-Silva; Jonathan M. Barasch; Brynn Levy; Nan Wu; Friedhelm Hildebrandt; Gian Marco Ghiggeri; Anna Latos-Bielenska; Anna Materna-Kiryluk; Feng Zhang; Hakon Hakonarson; Virginia E. Papaioannou; Cathy L. Mendelsohn; Ali G. Gharavi; Simone Sanna-Cherchi

doi:10.1038/s41588-018-0281-y

The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Miguel Verbitsky, Rik Westland, Alejandra Perez, Krzysztof Kiryluk, Qingxue Liu, Priya Krithivasan, Adele Mitrotti, David A. Fasel, Ekaterina Batourina, Matthew G. Sampson, Monica Bodria, Max Werth, Charlly Kao, Jeremiah Martino, Valentina P. Capone, Asaf Vivante, Shirlee Shril, Byum Hee Kil, Maddalena Marasà, Jun Y. ZhangYoung Ji Na, Tze Y. Lim, Dina Ahram, Patricia L. Weng, Erin L. Heinzen, Alba Carrea, Giorgio Piaggio, Loreto Gesualdo, Valeria Manca, Giuseppe Masnata, Maddalena Gigante, Daniele Cusi, Claudia Izzi, Francesco Scolari, Joanna A.E. van Wijk, Marijan Saraga, Domenico Santoro, Giovanni Conti, Pasquale Zamboli, Hope White, Dorota Drozdz, Katarzyna Zachwieja, Monika Miklaszewska, Marcin Tkaczyk, Daria Tomczyk, Anna Krakowska, Przemyslaw Sikora, Tomasz Jarmoliński, Maria K. Borszewska-Kornacka, Robert Pawluch, Maria Szczepanska, Piotr Adamczyk, Malgorzata Mizerska-Wasiak, Grazyna Krzemien, Agnieszka Szmigielska, Marcin Zaniew, Mark G. Dobson, John M. Darlow, Prem Puri, David E. Barton, Susan L. Furth, Bradley A. Warady, Zoran Gucev, Vladimir J. Lozanovski, Velibor Tasic, Isabella Pisani, Landino Allegri, Lida M. Rodas, Josep M. Campistol, Cécile Jeanpierre, Shumyle Alam, Pasquale Casale, Craig S. Wong, Fangming Lin, Débora M. Miranda, Eduardo A. Oliveira, Ana Cristina Simões-e-Silva, Jonathan M. Barasch, Brynn Levy, Nan Wu, Friedhelm Hildebrandt, Gian Marco Ghiggeri, Anna Latos-Bielenska, Anna Materna-Kiryluk, Feng Zhang, Hakon Hakonarson, Virginia E. Papaioannou, Cathy L. Mendelsohn, Ali G. Gharavi^*, Simone Sanna-Cherchi

^*Corresponding author for this work

Pediatrics

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

146 Scopus citations

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Original language	English
Pages (from-to)	117-127
Number of pages	11
Journal	Nature Genetics
Volume	51
Issue number	1
DOIs	https://doi.org/10.1038/s41588-018-0281-y
State	Published - 1 Jan 2019

Funding

Funders	Funder number
Fondazione Malattie Renali nel Bambino
GENESIS
Irish Health Research Board	AAE07007KSA, HRA-POR-2014–693
NZOZ Center for Medical Genetics
Polish Kidney Genetics Network
National Institutes of Health	13GRNT14680075
National Institutes of Health
National Heart, Lung, and Blood Institute
National Institute of Diabetes and Digestive and Kidney Diseases	U01DK082194, R01DK105124
National Institute of Diabetes and Digestive and Kidney Diseases
American Heart Association	RF-2010–2307403
American Heart Association
Eunice Kennedy Shriver National Institute of Child Health and Human Development	RO1DK082394, U01DK66143, U01DK66174, R37HD033082, U01DK66116
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Children's Research Centre
Nierstichting
Conselho Nacional de Desenvolvimento Científico e Tecnológico	460334/2014-0
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Fundação de Amparo à Pesquisa do Estado de Minas Gerais	PPM-005555-15, 15OKK95
Fundação de Amparo à Pesquisa do Estado de Minas Gerais
GIS-Institut des Maladies Rares
Ministerstwo Zdrowia
Ministrstvo za zdravje

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Verbitsky, M., Westland, R., Perez, A., Kiryluk, K., Liu, Q., Krithivasan, P., Mitrotti, A., Fasel, D. A., Batourina, E., Sampson, M. G., Bodria, M., Werth, M., Kao, C., Martino, J., Capone, V. P., Vivante, A., Shril, S., Kil, B. H., Marasà, M., ... Sanna-Cherchi, S. (2019). The copy number variation landscape of congenital anomalies of the kidney and urinary tract. Nature Genetics, 51(1), 117-127. https://doi.org/10.1038/s41588-018-0281-y

@article{083607afa6954419b21343ec128f9d8d,

title = "The copy number variation landscape of congenital anomalies of the kidney and urinary tract",

abstract = "Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.",

author = "Miguel Verbitsky and Rik Westland and Alejandra Perez and Krzysztof Kiryluk and Qingxue Liu and Priya Krithivasan and Adele Mitrotti and Fasel, {David A.} and Ekaterina Batourina and Sampson, {Matthew G.} and Monica Bodria and Max Werth and Charlly Kao and Jeremiah Martino and Capone, {Valentina P.} and Asaf Vivante and Shirlee Shril and Kil, {Byum Hee} and Maddalena Maras{\`a} and Zhang, {Jun Y.} and Na, {Young Ji} and Lim, {Tze Y.} and Dina Ahram and Weng, {Patricia L.} and Heinzen, {Erin L.} and Alba Carrea and Giorgio Piaggio and Loreto Gesualdo and Valeria Manca and Giuseppe Masnata and Maddalena Gigante and Daniele Cusi and Claudia Izzi and Francesco Scolari and {van Wijk}, {Joanna A.E.} and Marijan Saraga and Domenico Santoro and Giovanni Conti and Pasquale Zamboli and Hope White and Dorota Drozdz and Katarzyna Zachwieja and Monika Miklaszewska and Marcin Tkaczyk and Daria Tomczyk and Anna Krakowska and Przemyslaw Sikora and Tomasz Jarmoli{\'n}ski and Borszewska-Kornacka, {Maria K.} and Robert Pawluch and Maria Szczepanska and Piotr Adamczyk and Malgorzata Mizerska-Wasiak and Grazyna Krzemien and Agnieszka Szmigielska and Marcin Zaniew and Dobson, {Mark G.} and Darlow, {John M.} and Prem Puri and Barton, {David E.} and Furth, {Susan L.} and Warady, {Bradley A.} and Zoran Gucev and Lozanovski, {Vladimir J.} and Velibor Tasic and Isabella Pisani and Landino Allegri and Rodas, {Lida M.} and Campistol, {Josep M.} and C{\'e}cile Jeanpierre and Shumyle Alam and Pasquale Casale and Wong, {Craig S.} and Fangming Lin and Miranda, {D{\'e}bora M.} and Oliveira, {Eduardo A.} and Sim{\~o}es-e-Silva, {Ana Cristina} and Barasch, {Jonathan M.} and Brynn Levy and Nan Wu and Friedhelm Hildebrandt and Ghiggeri, {Gian Marco} and Anna Latos-Bielenska and Anna Materna-Kiryluk and Feng Zhang and Hakon Hakonarson and Papaioannou, {Virginia E.} and Mendelsohn, {Cathy L.} and Gharavi, {Ali G.} and Simone Sanna-Cherchi",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = jan,

day = "1",

doi = "10.1038/s41588-018-0281-y",

language = "אנגלית",

volume = "51",

pages = "117--127",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

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Verbitsky, M, Westland, R, Perez, A, Kiryluk, K, Liu, Q, Krithivasan, P, Mitrotti, A, Fasel, DA, Batourina, E, Sampson, MG, Bodria, M, Werth, M, Kao, C, Martino, J, Capone, VP, Vivante, A, Shril, S, Kil, BH, Marasà, M, Zhang, JY, Na, YJ, Lim, TY, Ahram, D, Weng, PL, Heinzen, EL, Carrea, A, Piaggio, G, Gesualdo, L, Manca, V, Masnata, G, Gigante, M, Cusi, D, Izzi, C, Scolari, F, van Wijk, JAE, Saraga, M, Santoro, D, Conti, G, Zamboli, P, White, H, Drozdz, D, Zachwieja, K, Miklaszewska, M, Tkaczyk, M, Tomczyk, D, Krakowska, A, Sikora, P, Jarmoliński, T, Borszewska-Kornacka, MK, Pawluch, R, Szczepanska, M, Adamczyk, P, Mizerska-Wasiak, M, Krzemien, G, Szmigielska, A, Zaniew, M, Dobson, MG, Darlow, JM, Puri, P, Barton, DE, Furth, SL, Warady, BA, Gucev, Z, Lozanovski, VJ, Tasic, V, Pisani, I, Allegri, L, Rodas, LM, Campistol, JM, Jeanpierre, C, Alam, S, Casale, P, Wong, CS, Lin, F, Miranda, DM, Oliveira, EA, Simões-e-Silva, AC, Barasch, JM, Levy, B, Wu, N, Hildebrandt, F, Ghiggeri, GM, Latos-Bielenska, A, Materna-Kiryluk, A, Zhang, F, Hakonarson, H, Papaioannou, VE, Mendelsohn, CL, Gharavi, AG & Sanna-Cherchi, S 2019, 'The copy number variation landscape of congenital anomalies of the kidney and urinary tract', Nature Genetics, vol. 51, no. 1, pp. 117-127. https://doi.org/10.1038/s41588-018-0281-y

TY - JOUR

T1 - The copy number variation landscape of congenital anomalies of the kidney and urinary tract

AU - Verbitsky, Miguel

AU - Westland, Rik

AU - Perez, Alejandra

AU - Kiryluk, Krzysztof

AU - Liu, Qingxue

AU - Krithivasan, Priya

AU - Mitrotti, Adele

AU - Fasel, David A.

AU - Batourina, Ekaterina

AU - Sampson, Matthew G.

AU - Bodria, Monica

AU - Werth, Max

AU - Kao, Charlly

AU - Martino, Jeremiah

AU - Capone, Valentina P.

AU - Vivante, Asaf

AU - Shril, Shirlee

AU - Kil, Byum Hee

AU - Marasà, Maddalena

AU - Zhang, Jun Y.

AU - Na, Young Ji

AU - Lim, Tze Y.

AU - Ahram, Dina

AU - Weng, Patricia L.

AU - Heinzen, Erin L.

AU - Carrea, Alba

AU - Piaggio, Giorgio

AU - Gesualdo, Loreto

AU - Manca, Valeria

AU - Masnata, Giuseppe

AU - Gigante, Maddalena

AU - Cusi, Daniele

AU - Izzi, Claudia

AU - Scolari, Francesco

AU - van Wijk, Joanna A.E.

AU - Saraga, Marijan

AU - Santoro, Domenico

AU - Conti, Giovanni

AU - Zamboli, Pasquale

AU - White, Hope

AU - Drozdz, Dorota

AU - Zachwieja, Katarzyna

AU - Miklaszewska, Monika

AU - Tkaczyk, Marcin

AU - Tomczyk, Daria

AU - Krakowska, Anna

AU - Sikora, Przemyslaw

AU - Jarmoliński, Tomasz

AU - Borszewska-Kornacka, Maria K.

AU - Pawluch, Robert

AU - Szczepanska, Maria

AU - Adamczyk, Piotr

AU - Mizerska-Wasiak, Malgorzata

AU - Krzemien, Grazyna

AU - Szmigielska, Agnieszka

AU - Zaniew, Marcin

AU - Dobson, Mark G.

AU - Darlow, John M.

AU - Puri, Prem

AU - Barton, David E.

AU - Furth, Susan L.

AU - Warady, Bradley A.

AU - Gucev, Zoran

AU - Lozanovski, Vladimir J.

AU - Tasic, Velibor

AU - Pisani, Isabella

AU - Allegri, Landino

AU - Rodas, Lida M.

AU - Campistol, Josep M.

AU - Jeanpierre, Cécile

AU - Alam, Shumyle

AU - Casale, Pasquale

AU - Wong, Craig S.

AU - Lin, Fangming

AU - Miranda, Débora M.

AU - Oliveira, Eduardo A.

AU - Simões-e-Silva, Ana Cristina

AU - Barasch, Jonathan M.

AU - Levy, Brynn

AU - Wu, Nan

AU - Hildebrandt, Friedhelm

AU - Ghiggeri, Gian Marco

AU - Latos-Bielenska, Anna

AU - Materna-Kiryluk, Anna

AU - Zhang, Feng

AU - Hakonarson, Hakon

AU - Papaioannou, Virginia E.

AU - Mendelsohn, Cathy L.

AU - Gharavi, Ali G.

AU - Sanna-Cherchi, Simone

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

AB - Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

UR - http://www.scopus.com/inward/record.url?scp=85058908326&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0281-y

DO - 10.1038/s41588-018-0281-y

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C2 - 30578417

AN - SCOPUS:85058908326

SN - 1061-4036

VL - 51

SP - 117

EP - 127

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

The copy number variation landscape of congenital anomalies of the kidney and urinary tract

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