Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

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.)

Problem-oriented policing in violent crime places: A randomized controlled experiment

Over the past decade, problem-oriented policing has become a central strategy for policing. In a number of studies, problem-oriented policing has been found to be effective in reducing crime and disorder. However, very little is known about the value of problem-oriented interventions in controlling violent street crime. The National Academy of Sciences' Panel on the Understanding and Control of Violent Behavior suggests that sustained research on problem-oriented policing initiatives that modify places, routine activities, and situations that promote violence could contribute much to the understanding and control of violence. This study evaluates the effects of problem-oriented policing interventions on urban violent crime problems in Jersey City, New Jersey. Twenty-four high-activity, violent crime places were matched into 12 pairs and one member of each pair was allocated to treatment conditions in a randomized block field experiment. The results of the impact evaluation support the growing body of research that asserts focused police efforts can reduce crime and disorder at problem places without causing crime problems to displace to surrounding areas