Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Esther Lopez-Rivera, Yangfan P Liu, Miguel Verbitsky, Blair R Anderson, Valentina P Capone, Edgar A Otto, Zhonghai Yan, Adele Mitrotti, Jeremiah Martino, Nicholas J Steers, David A Fasel, Katarina Vukojevic, Rong Deng, Silvia E Racedo, Qingxue Liu, Max Werth, Rik Westland, Asaf Vivante, Gabriel S Makar, Monica BodriaMatthew G Sampson, Christopher E Gillies, Virginia Vega-Warner, Mariarosa Maiorana, Donald S Petrey, Barry Honig, Vladimir J Lozanovski, Rémi Salomon, Laurence Heidet, Wassila Carpentier, Dominique Gaillard, Alba Carrea, Loreto Gesualdo, Daniele Cusi, Claudia Izzi, Francesco Scolari, Joanna A E van Wijk, Adela Arapovic, Mirna Saraga-Babic, Marijan Saraga, Nenad Kunac, Ali Samii, Donna M McDonald-McGinn, Terrence B Crowley, Elaine H Zackai, Dorota Drozdz, Monika Miklaszewska, Marcin Tkaczyk, Przemyslaw Sikora, Maria Szczepanska, Malgorzata Mizerska-Wasiak, Grazyna Krzemien, Agnieszka Szmigielska, Marcin Zaniew, John M Darlow, Prem Puri, David Barton, Emilio Casolari, Susan L Furth, Bradley A Warady, Zoran Gucev, Hakon Hakonarson, Hana Flogelova, Velibor Tasic, Anna Latos-Bielenska, Anna Materna-Kiryluk, Landino Allegri, Craig S Wong, Iain A Drummond, Vivette D'Agati, Akira Imamoto, Jonathan M Barasch, Friedhelm Hildebrandt, Krzysztof Kiryluk, Richard P Lifton, Bernice E Morrow, Cecile Jeanpierre, Virginia E Papaioannou, Gian Marco Ghiggeri, Ali G Gharavi, Nicholas Katsanis, Simone Sanna-Cherchi

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.

METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.

RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.

CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

Original languageEnglish
Pages (from-to)742-754
Number of pages13
JournalNew England Journal of Medicine
Volume376
Issue number8
DOIs
Publication statusPublished - Feb 23 2017

Fingerprint

DiGeorge Syndrome
Kidney
Zebrafish
Embryo Loss
Exome
Haploinsufficiency
Chromosome Deletion
Population Control
Nonsense Codon
National Institutes of Health (U.S.)
Nervous System
Genes
Odds Ratio
Phenotype

Keywords

  • Adaptor Proteins, Signal Transducing
  • Adolescent
  • Animals
  • Child
  • Chromosome Deletion
  • Chromosomes, Human, Pair 22
  • DiGeorge Syndrome
  • Exome
  • Female
  • Haploinsufficiency
  • Heterozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Kidney
  • Male
  • Mice
  • Models, Animal
  • Nuclear Proteins
  • Sequence Analysis, DNA
  • Urinary Tract
  • Young Adult
  • Zebrafish
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

Cite this

Lopez-Rivera, E., Liu, Y. P., Verbitsky, M., Anderson, B. R., Capone, V. P., Otto, E. A., ... Sanna-Cherchi, S. (2017). Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. New England Journal of Medicine, 376(8), 742-754. https://doi.org/10.1056/NEJMoa1609009

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. / Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel; Anderson, Blair R; Capone, Valentina P; Otto, Edgar A; Yan, Zhonghai; Mitrotti, Adele; Martino, Jeremiah; Steers, Nicholas J; Fasel, David A; Vukojevic, Katarina; Deng, Rong; Racedo, Silvia E; Liu, Qingxue; Werth, Max; Westland, Rik; Vivante, Asaf; Makar, Gabriel S; Bodria, Monica; Sampson, Matthew G; Gillies, Christopher E; Vega-Warner, Virginia; Maiorana, Mariarosa; Petrey, Donald S; Honig, Barry; Lozanovski, Vladimir J; Salomon, Rémi; Heidet, Laurence; Carpentier, Wassila; Gaillard, Dominique; Carrea, Alba; Gesualdo, Loreto; Cusi, Daniele; Izzi, Claudia; Scolari, Francesco; van Wijk, Joanna A E; Arapovic, Adela; Saraga-Babic, Mirna; Saraga, Marijan; Kunac, Nenad; Samii, Ali; McDonald-McGinn, Donna M; Crowley, Terrence B; Zackai, Elaine H; Drozdz, Dorota; Miklaszewska, Monika; Tkaczyk, Marcin; Sikora, Przemyslaw; Szczepanska, Maria; Mizerska-Wasiak, Malgorzata; Krzemien, Grazyna; Szmigielska, Agnieszka; Zaniew, Marcin; Darlow, John M; Puri, Prem; Barton, David; Casolari, Emilio; Furth, Susan L; Warady, Bradley A; Gucev, Zoran; Hakonarson, Hakon; Flogelova, Hana; Tasic, Velibor; Latos-Bielenska, Anna; Materna-Kiryluk, Anna; Allegri, Landino; Wong, Craig S; Drummond, Iain A; D'Agati, Vivette; Imamoto, Akira; Barasch, Jonathan M; Hildebrandt, Friedhelm; Kiryluk, Krzysztof; Lifton, Richard P; Morrow, Bernice E; Jeanpierre, Cecile; Papaioannou, Virginia E; Ghiggeri, Gian Marco; Gharavi, Ali G; Katsanis, Nicholas; Sanna-Cherchi, Simone.

In: New England Journal of Medicine, Vol. 376, No. 8, 23.02.2017, p. 742-754.

Research output: Contribution to journalArticle

Lopez-Rivera, E, Liu, YP, Verbitsky, M, Anderson, BR, Capone, VP, Otto, EA, Yan, Z, Mitrotti, A, Martino, J, Steers, NJ, Fasel, DA, Vukojevic, K, Deng, R, Racedo, SE, Liu, Q, Werth, M, Westland, R, Vivante, A, Makar, GS, Bodria, M, Sampson, MG, Gillies, CE, Vega-Warner, V, Maiorana, M, Petrey, DS, Honig, B, Lozanovski, VJ, Salomon, R, Heidet, L, Carpentier, W, Gaillard, D, Carrea, A, Gesualdo, L, Cusi, D, Izzi, C, Scolari, F, van Wijk, JAE, Arapovic, A, Saraga-Babic, M, Saraga, M, Kunac, N, Samii, A, McDonald-McGinn, DM, Crowley, TB, Zackai, EH, Drozdz, D, Miklaszewska, M, Tkaczyk, M, Sikora, P, Szczepanska, M, Mizerska-Wasiak, M, Krzemien, G, Szmigielska, A, Zaniew, M, Darlow, JM, Puri, P, Barton, D, Casolari, E, Furth, SL, Warady, BA, Gucev, Z, Hakonarson, H, Flogelova, H, Tasic, V, Latos-Bielenska, A, Materna-Kiryluk, A, Allegri, L, Wong, CS, Drummond, IA, D'Agati, V, Imamoto, A, Barasch, JM, Hildebrandt, F, Kiryluk, K, Lifton, RP, Morrow, BE, Jeanpierre, C, Papaioannou, VE, Ghiggeri, GM, Gharavi, AG, Katsanis, N & Sanna-Cherchi, S 2017, 'Genetic Drivers of Kidney Defects in the DiGeorge Syndrome', New England Journal of Medicine, vol. 376, no. 8, pp. 742-754. https://doi.org/10.1056/NEJMoa1609009
Lopez-Rivera E, Liu YP, Verbitsky M, Anderson BR, Capone VP, Otto EA et al. Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. New England Journal of Medicine. 2017 Feb 23;376(8):742-754. https://doi.org/10.1056/NEJMoa1609009
Lopez-Rivera, Esther ; Liu, Yangfan P ; Verbitsky, Miguel ; Anderson, Blair R ; Capone, Valentina P ; Otto, Edgar A ; Yan, Zhonghai ; Mitrotti, Adele ; Martino, Jeremiah ; Steers, Nicholas J ; Fasel, David A ; Vukojevic, Katarina ; Deng, Rong ; Racedo, Silvia E ; Liu, Qingxue ; Werth, Max ; Westland, Rik ; Vivante, Asaf ; Makar, Gabriel S ; Bodria, Monica ; Sampson, Matthew G ; Gillies, Christopher E ; Vega-Warner, Virginia ; Maiorana, Mariarosa ; Petrey, Donald S ; Honig, Barry ; Lozanovski, Vladimir J ; Salomon, Rémi ; Heidet, Laurence ; Carpentier, Wassila ; Gaillard, Dominique ; Carrea, Alba ; Gesualdo, Loreto ; Cusi, Daniele ; Izzi, Claudia ; Scolari, Francesco ; van Wijk, Joanna A E ; Arapovic, Adela ; Saraga-Babic, Mirna ; Saraga, Marijan ; Kunac, Nenad ; Samii, Ali ; McDonald-McGinn, Donna M ; Crowley, Terrence B ; Zackai, Elaine H ; Drozdz, Dorota ; Miklaszewska, Monika ; Tkaczyk, Marcin ; Sikora, Przemyslaw ; Szczepanska, Maria ; Mizerska-Wasiak, Malgorzata ; Krzemien, Grazyna ; Szmigielska, Agnieszka ; Zaniew, Marcin ; Darlow, John M ; Puri, Prem ; Barton, David ; Casolari, Emilio ; Furth, Susan L ; Warady, Bradley A ; Gucev, Zoran ; Hakonarson, Hakon ; Flogelova, Hana ; Tasic, Velibor ; Latos-Bielenska, Anna ; Materna-Kiryluk, Anna ; Allegri, Landino ; Wong, Craig S ; Drummond, Iain A ; D'Agati, Vivette ; Imamoto, Akira ; Barasch, Jonathan M ; Hildebrandt, Friedhelm ; Kiryluk, Krzysztof ; Lifton, Richard P ; Morrow, Bernice E ; Jeanpierre, Cecile ; Papaioannou, Virginia E ; Ghiggeri, Gian Marco ; Gharavi, Ali G ; Katsanis, Nicholas ; Sanna-Cherchi, Simone. / Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 8. pp. 742-754.
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abstract = "BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1{\%} of the patients with congenital kidney anomalies and in 0.01{\%} of population controls (odds ratio, 81.5; P=4.5×10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).",
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TY - JOUR

T1 - Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

AU - Lopez-Rivera, Esther

AU - Liu, Yangfan P

AU - Verbitsky, Miguel

AU - Anderson, Blair R

AU - Capone, Valentina P

AU - Otto, Edgar A

AU - Yan, Zhonghai

AU - Mitrotti, Adele

AU - Martino, Jeremiah

AU - Steers, Nicholas J

AU - Fasel, David A

AU - Vukojevic, Katarina

AU - Deng, Rong

AU - Racedo, Silvia E

AU - Liu, Qingxue

AU - Werth, Max

AU - Westland, Rik

AU - Vivante, Asaf

AU - Makar, Gabriel S

AU - Bodria, Monica

AU - Sampson, Matthew G

AU - Gillies, Christopher E

AU - Vega-Warner, Virginia

AU - Maiorana, Mariarosa

AU - Petrey, Donald S

AU - Honig, Barry

AU - Lozanovski, Vladimir J

AU - Salomon, Rémi

AU - Heidet, Laurence

AU - Carpentier, Wassila

AU - Gaillard, Dominique

AU - Carrea, Alba

AU - Gesualdo, Loreto

AU - Cusi, Daniele

AU - Izzi, Claudia

AU - Scolari, Francesco

AU - van Wijk, Joanna A E

AU - Arapovic, Adela

AU - Saraga-Babic, Mirna

AU - Saraga, Marijan

AU - Kunac, Nenad

AU - Samii, Ali

AU - McDonald-McGinn, Donna M

AU - Crowley, Terrence B

AU - Zackai, Elaine H

AU - Drozdz, Dorota

AU - Miklaszewska, Monika

AU - Tkaczyk, Marcin

AU - Sikora, Przemyslaw

AU - Szczepanska, Maria

AU - Mizerska-Wasiak, Malgorzata

AU - Krzemien, Grazyna

AU - Szmigielska, Agnieszka

AU - Zaniew, Marcin

AU - Darlow, John M

AU - Puri, Prem

AU - Barton, David

AU - Casolari, Emilio

AU - Furth, Susan L

AU - Warady, Bradley A

AU - Gucev, Zoran

AU - Hakonarson, Hakon

AU - Flogelova, Hana

AU - Tasic, Velibor

AU - Latos-Bielenska, Anna

AU - Materna-Kiryluk, Anna

AU - Allegri, Landino

AU - Wong, Craig S

AU - Drummond, Iain A

AU - D'Agati, Vivette

AU - Imamoto, Akira

AU - Barasch, Jonathan M

AU - Hildebrandt, Friedhelm

AU - Kiryluk, Krzysztof

AU - Lifton, Richard P

AU - Morrow, Bernice E

AU - Jeanpierre, Cecile

AU - Papaioannou, Virginia E

AU - Ghiggeri, Gian Marco

AU - Gharavi, Ali G

AU - Katsanis, Nicholas

AU - Sanna-Cherchi, Simone

PY - 2017/2/23

Y1 - 2017/2/23

N2 - BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

AB - BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

KW - Adaptor Proteins, Signal Transducing

KW - Adolescent

KW - Animals

KW - Child

KW - Chromosome Deletion

KW - Chromosomes, Human, Pair 22

KW - DiGeorge Syndrome

KW - Exome

KW - Female

KW - Haploinsufficiency

KW - Heterozygote

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Kidney

KW - Male

KW - Mice

KW - Models, Animal

KW - Nuclear Proteins

KW - Sequence Analysis, DNA

KW - Urinary Tract

KW - Young Adult

KW - Zebrafish

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, N.I.H., Extramural

U2 - 10.1056/NEJMoa1609009

DO - 10.1056/NEJMoa1609009

M3 - Article

C2 - 28121514

VL - 376

SP - 742

EP - 754

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 8

ER -