Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Esther Lopez-Rivera , Yangfan Liu , Miguel Verbitsky , Blair Anderson , Valentina Capone , Edgar Otto , Zhonghai Yan , Adele Mitrotti , Jeremiah Martino , Nicholas Steers , David Fasel , Katarina Vukojevic , Rong Deng , Silvia Racedo , Qingxue Liu , Max Werth , Rik Westland , Asaf Vivante , Gabriel Makar , Monica Bodria , Matthew Sampson , Christopher Gillies , Virginia Vega-Warner , Mariarosa Maiorana , Donald Petrey , Barry Honig , Vladimir Lozanovski , Rémi Salomon , Laurence Heidet , Wassila Carpentier (1, 2) , 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 Mcdonald-Mcginn , Terrence Crowley , Elaine Zackai , Dorota Drozdz , Monika Miklaszewska , Marcin Tkaczyk , Przemyslaw Sikora , Maria Szczepanska , Malgorzata Mizerska-Wasiak , Grazyna Krzemien , Agnieszka Szmigielska , Marcin Zaniew , John Darlow , Prem Puri , David Barton , Emilio Casolari , Susan L. Furth , Bradley Warady , Zoran Gucev , Hakon Hakonarson , Hana Flogelova , Velibor Tasic , Anna Latos-Bielenska , Anna Materna-Kiryluk , Landino Allegri , Craig Wong , Iain Drummond , Vivette d'Agati , Akira Imamoto , Jonathan Barasch , Friedhelm Hildebrandt , Krzysztof Kiryluk , Richard Lifton , Bernice Morrow , Cécile Jeanpierre , Virginia Papaioannou , Gian Marco Ghiggeri , Ali Gharavi , Nicholas Katsanis , Simone Sanna-Cherchi

1 P3S - Plateforme Post-génomique de la Pitié-Salpêtrière
2 UPMC - Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie

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.).

Domaines: Sciences du Vivant [q-bio]

Esther Lopez-Rivera, Yangfan Liu, Miguel Verbitsky, Blair Anderson, Valentina Capone, et al.. Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. New England Journal of Medicine, 2017, 376 (8), pp.742-754. ⟨10.1056/NEJMoa1609009⟩. ⟨hal-02565169⟩