PUBLICATION

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Authors
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., 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.
ID
ZDB-PUB-170126-3
Date
2017
Source
The New England Journal of Medicine   376(8): 742-754 (Journal)
Registered Authors
Drummond, Iain, Katsanis, Nicholas
Keywords
none
MeSH Terms
  • Adaptor Proteins, Signal Transducing/genetics*
  • Adolescent
  • Animals
  • Child
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 22
  • DiGeorge Syndrome/genetics*
  • Exome
  • Female
  • Haploinsufficiency*
  • Heterozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Kidney/abnormalities*
  • Male
  • Mice
  • Models, Animal
  • Nuclear Proteins/genetics*
  • Sequence Analysis, DNA
  • Urinary Tract/abnormalities*
  • Young Adult
  • Zebrafish
PubMed
28121514 Full text @ N. Engl. J. Med.
Citation
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., 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. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. The New England Journal of Medicine. 376(8):742-754.
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.).
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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