Genetic drivers of kidney defects in the digeorge syndrome

E. Lopez-Rivera, Y. P. Liu, M. Verbitsky, B. R. Anderson, V. P. Capone, E. A. Otto, Z. Yan, A. Mitrotti, J. Martino, N. J. Steers, D. A. Fasel, K. Vukojevic, R. Deng, S. E. Racedo, Q. Liu, M. Werth, R. Westland, A. Vivante, G. S. Makar, M. Bodria & 62 others M. G. Sampson, C. E. Gillies, V. Vega-Warner, M. Maiorana, D. S. Petrey, B. Honig, V. J. Lozanovski, R. Salomon, L. Heidet, W. Carpentier, D. Gaillard, A. Carrea, L. Gesualdo, D. Cusi, C. Izzi, F. Scolari, J. A.E. Van Wijk, A. Arapovic, M. Saraga-Babic, M. Saraga, N. Kunac, A. Samii, D. M. McDonald-McGinn, T. B. Crowley, E. H. Zackai, D. Drozdz, M. Miklaszewska, M. Tkaczyk, P. Sikora, M. Szczepanska, M. Mizerska-Wasiak, G. Krzemien, A. Szmigielska, M. Zaniew, J. M. Darlow, P. Puri, D. Barton, E. Casolari, S. L. Furth, B. A. Warady, Z. Gucev, H. Hakonarson, H. Flogelova, V. Tasic, A. Latos-Bielenska, A. Materna-Kiryluk, L. Allegri, C. S. Wong, I. A. Drummond, V. D'Agati, A. Imamoto, J. M. Barasch, F. Hildebrandt, K. Kiryluk, R. P. Lifton, B. E. Morrow, C. Jeanpierre, V. E. Papaioannou, G. M. Ghiggeri, A. G. Gharavi, N. Katsanis, S. Sanna-Cherchi

Research output: Contribution to journalArticle

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 = 4.5×1014). 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.

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

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DiGeorge Syndrome
Kidney
Zebrafish
Embryo Loss
Exome
Haploinsufficiency
Chromosome Deletion
Population Control
Nonsense Codon
Nervous System
Genes
Odds Ratio
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

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, E.; Liu, Y. P.; Verbitsky, M.; Anderson, B. R.; Capone, V. P.; Otto, E. A.; Yan, Z.; Mitrotti, A.; Martino, J.; Steers, N. J.; Fasel, D. A.; Vukojevic, K.; Deng, R.; Racedo, S. E.; Liu, Q.; Werth, M.; Westland, R.; Vivante, A.; Makar, G. S.; Bodria, M.; Sampson, M. G.; Gillies, C. E.; Vega-Warner, V.; Maiorana, M.; Petrey, D. S.; Honig, B.; Lozanovski, V. J.; Salomon, R.; Heidet, L.; Carpentier, W.; Gaillard, D.; Carrea, A.; Gesualdo, L.; Cusi, D.; Izzi, C.; Scolari, F.; Van Wijk, J. A.E.; Arapovic, A.; Saraga-Babic, M.; Saraga, M.; Kunac, N.; Samii, A.; McDonald-McGinn, D. M.; Crowley, T. B.; Zackai, E. H.; Drozdz, D.; Miklaszewska, M.; Tkaczyk, M.; Sikora, P.; Szczepanska, M.; Mizerska-Wasiak, M.; Krzemien, G.; Szmigielska, A.; Zaniew, M.; Darlow, J. M.; Puri, P.; Barton, D.; Casolari, E.; Furth, S. L.; Warady, B. A.; Gucev, Z.; Hakonarson, H.; Flogelova, H.; Tasic, V.; Latos-Bielenska, A.; Materna-Kiryluk, A.; Allegri, L.; Wong, C. S.; Drummond, I. A.; D'Agati, V.; Imamoto, A.; Barasch, J. M.; Hildebrandt, F.; Kiryluk, K.; Lifton, R. P.; Morrow, B. E.; Jeanpierre, C.; Papaioannou, V. E.; Ghiggeri, G. M.; Gharavi, A. G.; Katsanis, N.; Sanna-Cherchi, S.

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, E. ; Liu, Y. P. ; Verbitsky, M. ; Anderson, B. R. ; Capone, V. P. ; Otto, E. A. ; Yan, Z. ; Mitrotti, A. ; Martino, J. ; Steers, N. J. ; Fasel, D. A. ; Vukojevic, K. ; Deng, R. ; Racedo, S. E. ; Liu, Q. ; Werth, M. ; Westland, R. ; Vivante, A. ; Makar, G. S. ; Bodria, M. ; Sampson, M. G. ; Gillies, C. E. ; Vega-Warner, V. ; Maiorana, M. ; Petrey, D. S. ; Honig, B. ; Lozanovski, V. J. ; Salomon, R. ; Heidet, L. ; Carpentier, W. ; Gaillard, D. ; Carrea, A. ; Gesualdo, L. ; Cusi, D. ; Izzi, C. ; Scolari, F. ; Van Wijk, J. A.E. ; Arapovic, A. ; Saraga-Babic, M. ; Saraga, M. ; Kunac, N. ; Samii, A. ; McDonald-McGinn, D. M. ; Crowley, T. B. ; Zackai, E. H. ; Drozdz, D. ; Miklaszewska, M. ; Tkaczyk, M. ; Sikora, P. ; Szczepanska, M. ; Mizerska-Wasiak, M. ; Krzemien, G. ; Szmigielska, A. ; Zaniew, M. ; Darlow, J. M. ; Puri, P. ; Barton, D. ; Casolari, E. ; Furth, S. L. ; Warady, B. A. ; Gucev, Z. ; Hakonarson, H. ; Flogelova, H. ; Tasic, V. ; Latos-Bielenska, A. ; Materna-Kiryluk, A. ; Allegri, L. ; Wong, C. S. ; Drummond, I. A. ; D'Agati, V. ; Imamoto, A. ; Barasch, J. M. ; Hildebrandt, F. ; Kiryluk, K. ; Lifton, R. P. ; Morrow, B. E. ; Jeanpierre, C. ; Papaioannou, V. E. ; Ghiggeri, G. M. ; Gharavi, A. G. ; Katsanis, N. ; Sanna-Cherchi, S. / 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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title = "Genetic drivers of kidney defects in the digeorge syndrome",
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 = 4.5×1014). 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.",
author = "E. Lopez-Rivera and Liu, {Y. P.} and M. Verbitsky and Anderson, {B. R.} and Capone, {V. P.} and Otto, {E. A.} and Z. Yan and A. Mitrotti and J. Martino and Steers, {N. J.} and Fasel, {D. A.} and K. Vukojevic and R. Deng and Racedo, {S. E.} and Q. Liu and M. Werth and R. Westland and A. Vivante and Makar, {G. S.} and M. Bodria and Sampson, {M. G.} and Gillies, {C. E.} and V. Vega-Warner and M. Maiorana and Petrey, {D. S.} and B. Honig and Lozanovski, {V. J.} and R. Salomon and L. Heidet and W. Carpentier and D. Gaillard and A. Carrea and L. Gesualdo and D. Cusi and C. Izzi and F. Scolari and {Van Wijk}, {J. A.E.} and A. Arapovic and M. Saraga-Babic and M. Saraga and N. Kunac and A. Samii and McDonald-McGinn, {D. M.} and Crowley, {T. B.} and Zackai, {E. H.} and D. Drozdz and M. Miklaszewska and M. Tkaczyk and P. Sikora and M. Szczepanska and M. Mizerska-Wasiak and G. Krzemien and A. Szmigielska and M. Zaniew and Darlow, {J. M.} and P. Puri and D. Barton and E. Casolari and Furth, {S. L.} and Warady, {B. A.} and Z. Gucev and H. Hakonarson and H. Flogelova and V. Tasic and A. Latos-Bielenska and A. Materna-Kiryluk and L. Allegri and Wong, {C. S.} and Drummond, {I. A.} and V. D'Agati and A. Imamoto and Barasch, {J. M.} and F. Hildebrandt and K. Kiryluk and Lifton, {R. P.} and Morrow, {B. E.} and C. Jeanpierre and Papaioannou, {V. E.} and Ghiggeri, {G. M.} and Gharavi, {A. G.} and N. Katsanis and S. Sanna-Cherchi",
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month = "2",
day = "23",
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language = "English (US)",
volume = "376",
pages = "742--754",
journal = "New England Journal of Medicine",
issn = "0028-4793",
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TY - JOUR

T1 - Genetic drivers of kidney defects in the digeorge syndrome

AU - Lopez-Rivera, E.

AU - Liu, Y. P.

AU - Verbitsky, M.

AU - Anderson, B. R.

AU - Capone, V. P.

AU - Otto, E. A.

AU - Yan, Z.

AU - Mitrotti, A.

AU - Martino, J.

AU - Steers, N. J.

AU - Fasel, D. A.

AU - Vukojevic, K.

AU - Deng, R.

AU - Racedo, S. E.

AU - Liu, Q.

AU - Werth, M.

AU - Westland, R.

AU - Vivante, A.

AU - Makar, G. S.

AU - Bodria, M.

AU - Sampson, M. G.

AU - Gillies, C. E.

AU - Vega-Warner, V.

AU - Maiorana, M.

AU - Petrey, D. S.

AU - Honig, B.

AU - Lozanovski, V. J.

AU - Salomon, R.

AU - Heidet, L.

AU - Carpentier, W.

AU - Gaillard, D.

AU - Carrea, A.

AU - Gesualdo, L.

AU - Cusi, D.

AU - Izzi, C.

AU - Scolari, F.

AU - Van Wijk, J. A.E.

AU - Arapovic, A.

AU - Saraga-Babic, M.

AU - Saraga, M.

AU - Kunac, N.

AU - Samii, A.

AU - McDonald-McGinn, D. M.

AU - Crowley, T. B.

AU - Zackai, E. H.

AU - Drozdz, D.

AU - Miklaszewska, M.

AU - Tkaczyk, M.

AU - Sikora, P.

AU - Szczepanska, M.

AU - Mizerska-Wasiak, M.

AU - Krzemien, G.

AU - Szmigielska, A.

AU - Zaniew, M.

AU - Darlow, J. M.

AU - Puri, P.

AU - Barton, D.

AU - Casolari, E.

AU - Furth, S. L.

AU - Warady, B. A.

AU - Gucev, Z.

AU - Hakonarson, H.

AU - Flogelova, H.

AU - Tasic, V.

AU - Latos-Bielenska, A.

AU - Materna-Kiryluk, A.

AU - Allegri, L.

AU - Wong, C. S.

AU - Drummond, I. A.

AU - D'Agati, V.

AU - Imamoto, A.

AU - Barasch, J. M.

AU - Hildebrandt, F.

AU - Kiryluk, K.

AU - Lifton, R. P.

AU - Morrow, B. E.

AU - Jeanpierre, C.

AU - Papaioannou, V. E.

AU - Ghiggeri, G. M.

AU - Gharavi, A. G.

AU - Katsanis, N.

AU - Sanna-Cherchi, S.

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 = 4.5×1014). 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.

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 = 4.5×1014). 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.

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U2 - 10.1056/NEJMoa1609009

DO - 10.1056/NEJMoa1609009

M3 - Article

VL - 376

SP - 742

EP - 754

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 8

ER -