Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.
Document Type
Article
Publication Date
2-23-2017
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
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.).
Publisher
Massachusetts Medical Society.
Publication Title
The New England journal of medicine
ISSN
1533-4406
Volume
376
Issue
8
First Page
742
Last Page
754
Recommended Citation
Lopez-Rivera, Esther; 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 Bodria; Matthew 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; and Simone Sanna-Cherchi.
"Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.."
The New England journal of medicine
