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; 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

doi:10.1056/NEJMoa1609009

Journal Articles New England Journal of Medicine Year : 2017

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

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Esther Lopez-Rivera

Function : Author

Yangfan Liu

Function : Author

Miguel Verbitsky

Function : Author

Blair Anderson

Function : Author

Valentina Capone

Function : Author

Edgar Otto

Function : Author

Zhonghai Yan

Function : Author

Adele Mitrotti

Function : Author

Jeremiah Martino

Function : Author

Nicholas Steers

Function : Author

David Fasel

Function : Author

Katarina Vukojevic

Function : Author

Rong Deng

Function : Author

Silvia Racedo

Function : Author

Qingxue Liu

Function : Author

Max Werth

Function : Author

Rik Westland

Function : Author

Asaf Vivante

Function : Author

Gabriel Makar

Function : Author

Monica Bodria

Function : Author
PersonId : 1064951

Matthew Sampson

Function : Author
PersonId : 1051376

Christopher Gillies

Function : Author

Virginia Vega-Warner

Function : Author

Mariarosa Maiorana

Function : Author

Donald Petrey

Function : Author

Barry Honig

Function : Author

Vladimir Lozanovski

Function : Author

Rémi Salomon

Function : Author

Laurence Heidet

Function : Author

Wassila Carpentier

Function : Author
PersonId : 910018

Plateforme Post-génomique de la Pitié-Salpêtrière

Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie

Dominique Gaillard

Function : Author

Alba Carrea

Function : Author

Loreto Gesualdo

Function : Author

Daniele Cusi

Function : Author

Claudia Izzi

Function : Author
PersonId : 902586

Francesco Scolari

Function : Author

Joanna A.E. van Wijk

Function : Author

Adela Arapovic

Function : Author

Mirna Saraga-Babic

Function : Author

Marijan Saraga

Function : Author

Nenad Kunac

Function : Author

Ali Samii

Function : Author

Donna Mcdonald-Mcginn

Function : Author

Terrence Crowley

Function : Author

Elaine Zackai

Function : Author
PersonId : 905999

Dorota Drozdz

Function : Author

Monika Miklaszewska

Function : Author

Marcin Tkaczyk

Function : Author

Przemyslaw Sikora

Function : Author

Maria Szczepanska

Function : Author

Malgorzata Mizerska-Wasiak

Function : Author

Grazyna Krzemien

Function : Author

Agnieszka Szmigielska

Function : Author

Marcin Zaniew

Function : Author

John Darlow

Function : Author

Prem Puri

Function : Author

David Barton

Function : Author

Emilio Casolari

Function : Author

Susan L. Furth

Function : Author
PersonId : 988213

Bradley Warady

Function : Author

Zoran Gucev

Function : Author

Hakon Hakonarson

Function : Author
PersonId : 957590

Hana Flogelova

Function : Author

Velibor Tasic

Function : Author

Anna Latos-Bielenska

Function : Author

Anna Materna-Kiryluk

Function : Author

Landino Allegri

Function : Author

Craig Wong

Function : Author

Iain Drummond

Function : Author

Vivette d'Agati

Function : Author

Akira Imamoto

Function : Author

Jonathan Barasch

Function : Author

Friedhelm Hildebrandt

Function : Author

Krzysztof Kiryluk

Function : Author

Richard Lifton

Function : Author

Bernice Morrow

Function : Author

Cécile Jeanpierre

Function : Author
PersonId : 935176

Virginia Papaioannou

Function : Author

Gian Marco Ghiggeri

Function : Author
PersonId : 800453
ORCID : 0000-0003-3659-9062

Ali Gharavi

Function : Author

Nicholas Katsanis

Function : Author

Simone Sanna-Cherchi

Function : Author

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.).

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Submitted on : Wednesday, May 6, 2020-11:25:25 AM

Last modification on : Tuesday, June 20, 2023-11:03:39 AM

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hal-02565169 , version 1 (06-05-2020)

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HAL Id : hal-02565169 , version 1
DOI : 10.1056/NEJMoa1609009
PUBMED : 28121514
PUBMEDCENTRAL : PMC5559731

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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⟩

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Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

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