Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.

TitleGenetic Drivers of Kidney Defects in the DiGeorge Syndrome.
Publication TypeJournal Article
Year of Publication2017
AuthorsLopez-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, GMarco, Gharavi, AG, Katsanis, N, Sanna-Cherchi, S
JournalN Engl J Med
Date Published2017 02 23
KeywordsAdaptor 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

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.).

Alternate JournalN. Engl. J. Med.
PubMed ID28121514
Grant ListR01 DK103184 / DK / NIDDK NIH HHS / United States
R21 DK098531 / DK / NIDDK NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
P50 DK096415 / DK / NIDDK NIH HHS / United States
P30 DK096493 / DK / NIDDK NIH HHS / United States
R01 DK080099 / DK / NIDDK NIH HHS / United States
U54 DK104309 / DK / NIDDK NIH HHS / United States
P01 HD070454 / HD / NICHD NIH HHS / United States
R01 GM030518 / GM / NIGMS NIH HHS / United States
R37 HD033082 / HD / NICHD NIH HHS / United States
R01 DK105124 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
U01 DK066143 / DK / NIDDK NIH HHS / United States
U01 DK066174 / DK / NIDDK NIH HHS / United States
U01 DK082194 / DK / NIDDK NIH HHS / United States
U01 DK066116 / DK / NIDDK NIH HHS / United States
R01 DK082394 / DK / NIDDK NIH HHS / United States