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 & 70 others 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, C. cile Jeanpierre, Shumyle Alam, Pasquale Casale, Craig S. Wong, Fangming Lin, D. bora 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

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)117-127
JournalNature Genetics
Volume51
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Cite this

Verbitsky, M., Westland, R., Perez, A., Kiryluk, K., Liu, Q., Krithivasan, P., ... 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
Verbitsky, Miguel ; Westland, Rik ; Perez, Alejandra ; Kiryluk, Krzysztof ; Liu, Qingxue ; Krithivasan, Priya ; Mitrotti, Adele ; Fasel, David A. ; Batourina, Ekaterina ; Sampson, Matthew G. ; Bodria, Monica ; Werth, Max ; Kao, Charlly ; Martino, Jeremiah ; Capone, Valentina P. ; Vivante, Asaf ; Shril, Shirlee ; Kil, Byum Hee ; Marasà, Maddalena ; Zhang, Jun Y. ; Na, Young-Ji ; Lim, Tze Y. ; Ahram, Dina ; Weng, Patricia L. ; Heinzen, Erin L. ; Carrea, Alba ; Piaggio, Giorgio ; Gesualdo, Loreto ; Manca, Valeria ; Masnata, Giuseppe ; Gigante, Maddalena ; Cusi, Daniele ; Izzi, Claudia ; Scolari, Francesco ; van Wijk, Joanna A. E. ; Saraga, Marijan ; Santoro, Domenico ; Conti, Giovanni ; Zamboli, Pasquale ; White, Hope ; Drozdz, Dorota ; Zachwieja, Katarzyna ; Miklaszewska, Monika ; Tkaczyk, Marcin ; Tomczyk, Daria ; Krakowska, Anna ; Sikora, Przemyslaw ; Jarmoliński, Tomasz ; Borszewska-Kornacka, Maria K. ; Pawluch, Robert ; Szczepanska, Maria ; Adamczyk, Piotr ; Mizerska-Wasiak, Malgorzata ; Krzemien, Grazyna ; Szmigielska, Agnieszka ; Zaniew, Marcin ; Dobson, Mark G. ; Darlow, John M. ; Puri, Prem ; Barton, David E. ; Furth, Susan L. ; Warady, Bradley A. ; Gucev, Zoran ; Lozanovski, Vladimir J. ; Tasic, Velibor ; Pisani, Isabella ; Allegri, Landino ; Rodas, Lida M. ; Campistol, Josep M. ; Jeanpierre, C. cile ; Alam, Shumyle ; Casale, Pasquale ; Wong, Craig S. ; Lin, Fangming ; Miranda, D. bora M. ; Oliveira, Eduardo A. ; Simões-e-Silva, Ana Cristina ; Barasch, Jonathan M. ; Levy, Brynn ; Wu, Nan ; Hildebrandt, Friedhelm ; Ghiggeri, Gian Marco ; Latos-Bielenska, Anna ; Materna-Kiryluk, Anna ; Zhang, Feng ; Hakonarson, Hakon ; Papaioannou, Virginia E. ; Mendelsohn, Cathy L. ; Gharavi, Ali G. ; Sanna-Cherchi, Simone. / The copy number variation landscape of congenital anomalies of the kidney and urinary tract. In: Nature Genetics. 2019 ; Vol. 51, No. 1. pp. 117-127.
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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.",
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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, Y-J, 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, CC, Alam, S, Casale, P, Wong, CS, Lin, F, Miranda, DBM, 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

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

In: Nature Genetics, Vol. 51, No. 1, 01.01.2019, p. 117-127.

Research output: Contribution to journalArticleAcademicpeer-review

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, C. cile

AU - Alam, Shumyle

AU - Casale, Pasquale

AU - Wong, Craig S.

AU - Lin, Fangming

AU - Miranda, D. bora 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 - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85058908326&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30578417

U2 - 10.1038/s41588-018-0281-y

DO - 10.1038/s41588-018-0281-y

M3 - Article

VL - 51

SP - 117

EP - 127

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -