National Children's Research Centre

NCRC group success with New England Journal of Medicine paper.

February 8, 2017

Congratulations to Prem Puri, John Darlow and David Barton for their part in the recent New England Journal of Medicine paper identifying key genetic drivers in the development of kidney disease in the DiGeorge syndrome.


The DiGeorge syndrome is a genetic disorder that affects many organs, including the heart, the nervous system, and the kidneys. The result of deletions on chromosome 22q11.2, it thought to affect at least 1 in every 4,000 children born. Although kidney problems are common in children with the DiGeorge syndrome, until now the genetic driver of these kidney defects was unknown.

Through a major international collaboration, led by teams at Columbia and Duke Universities, a genome-wide search for structural variants was conducted in 2,080 patients with congenital kidney and urinary tract anomalies and in 22,094 controls. Exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies was also performed. In addition, researchers carried out functional studies using zebrafish and mice, to substantiate their findings.

The study 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 the CRKL gene emerging as the main genetic driver. This finding also not only has implications for the DiGeorge syndrome, but also for spontaneous kidney and urinary tract defects.

This work builds on long-term research by Prem Puri, John Darlow and David Barton into the genetic cause of vesicoureteral reflux, that is the backward flow of urine from the bladder into the kidneys. Indeed, in a previous study, published in Molecular Genetics & Genomic Medicine, they showed that markers in the 22q11.2 region examined in the New England Journal of Medicine paper tended to be inherited along with vesicoureteric reflux (VUR) in some of the families in their cohort. This suggests that patients with VUR who did not have deletions detectable in the New England Journal of Medicine study (over 100 kb) may in fact have other mutations that were below the limit of detection. This is an exciting finding, and one that Prem Puri, John Darlow and David Barton are continuing to study.

The full paper can be found here.