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.)
Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0 × 10 for novel LOF, increased to p = 4.1 × 10 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3 × 10). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.
BACKGROUND: Surgeons have traditionally relied on opiates after hip replacement, despite a growing epidemic of abuse. This study assessed the efficacy of multimodal analgesia and impact of conservative opiate prescribing after discharge from hip surgery. STUDY DESIGN: In this cluster-randomized trial, 235 patients undergoing hip replacement (5 surgeons) received 1 of 3 discharge pain regimens: scheduled-dose multimodal analgesia with a minimal opiate supply (group A), scheduled-dose multimodal analgesia with a traditional opiate supply (group B), or a traditional pro re nata (as needed) opiate regimen alone (group C). Each of the surgeons comprised a distinct cluster and alternated in a randomized sequence between interventions. The multimodal regimen comprised fixed-schedule doses of acetaminophen, meloxicam, and gabapentin. Primary outcomes were daily visual analogue scale pain and opiate use for 30 days. Secondary outcomes included satisfaction, sleep quality, opiate-related symptoms, hip function, and adverse events. The primary intent-to-treat analysis was performed using linear mixed models. RESULTS: Daily pain was significantly lower in group A (coefficient [Coeff] À0.81; p ¼ 0.003) and group B (Coeff À0.61; p ¼ 0.021) relative to group C. Although daily opiate use in group A (Coeff À0.77; p < 0.001) and group B (Coeff À0.30; p ¼ 0.04) was lower than group C, opiate use for group A was also lower than group B (Coeff À0.46; p ¼ 0.002). Duration of opiate use was significantly shorter for group A (1.14 weeks) and group B (1.39 weeks) compared with group C (2.57 weeks). There were fewer opiate-related symptoms, most commonly fatigue, in group A compared with C, but groups B and C were not significantly different. Both multimodal regimens improved satisfaction and sleep, and there were no differences in hip function or adverse events. CONCLUSIONS: Multimodal analgesia with minimal opiates improved pain control while significantly decreasing opiate use and opiate-related adverse effects. It is time to rethink our reliance on opiates after elective operations.
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