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 = 4.5×1014). 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

Trends in Outcomes for Neonates Born Very Preterm and Very Low Birth Weight in 11 High-Income Countries

Objective To evaluate outcome trends of neonates born very preterm in 11 high-income countries participating in the International Network for Evaluating Outcomes of neonates. Study design In a retrospective cohort study, we included 154 233 neonates admitted to 529 neonatal units between January 1, 2007, and December 31, 2015, at 24(0/7) to 31(6/7) weeks of gestational age and birth weight <1500 g. Composite outcomes were in-hospital mortality or any of severe neurologic injury, treated retinopathy of prematurity, and bronchopulmonary dysplasia (BPD); and same composite outcome excluding BPD. Secondary outcomes were mortality and individual morbidities. For each country, annual outcome trends and adjusted relative risks comparing epoch 2 (2012-2015) to epoch 1 (2007-2011) were analyzed. Results For composite outcome including BPD, the trend decreased in Canada and Israel but increased in Australia and New Zealand, Japan, Spain, Sweden, and the United Kingdom. For composite outcome excluding BPD, the trend decreased in all countries except Spain, Sweden, Tuscany, and the United Kingdom. The risk of composite outcome was lower in epoch 2 than epoch 1 in Canada (adjusted relative risks 0.78; 95% CI 0.74-0.82) only. The risk of composite outcome excluding BPD was significantly lower in epoch 2 compared with epoch 1 in Australia and New Zealand, Canada, Finland, Japan, and Switzerland. Mortality rates reduced in most countries in epoch 2. BPD rates increased significantly in all countries except Canada, Israel, Finland, and Tuscany. Conclusions In most countries, mortality decreased whereas BPD increased for neonates born very preterm

Supplementary Material for: Outborns or Inborns: Where Are the Differences? A Comparison Study of Very Preterm Neonatal Intensive Care Unit Infants Cared for in Australia and New Zealand and in Canada

<b><i>Background:</i></b> Very preterm infants born outside tertiary centers are at higher risks of adverse outcomes than inborn infants. Regionalization of perinatal care has been introduced worldwide to improve outcomes. <b><i>Objective:</i></b> To compare the risk-adjusted outcomes of both inborn and outborn infants cared for in tertiary neonatal intensive care units in Australia and New Zealand and in Canada. <b><i>Methods:</i></b> Deidentified data of infants <32 weeks' gestational age from the 29 Australian and New Zealand Neonatal Network units (ANZNN; n = 9,893) and 26 Canadian Neonatal Network units (CNN; n = 7,133) between 2005 and 2007 were analyzed for predischarge adverse outcomes. <b><i>Results:</i></b> ANZNN had lower rates of outborns compared to CNN (13 vs. 19%), particularly of late admissions (>2 days of age; 5.8 vs. 22.2% of outborns) who had high morbidity rates. After adjusting for confounding variables including gestation, ANZNN inborn infants had lower odds of chronic lung disease [CLD; 17.0 vs. 23.3%; adjusted odds ratio (AOR) = 0.70, 95% CI: 0.64-0.77], severe neurological injuries on ultrasound (SNI; 4.1 vs. 6.7%; AOR = 0.62, 95% CI: 0.53-0.73), severe retinopathy (5.6 vs. 7%; AOR = 0.71, 95% CI: 0.59-0.84) and necrotizing enterocolitis (3.5 vs. 5.4%; AOR = 0.67, 95% CI: 0.56-0.79), but no difference in mortality odds. After excluding the late outborn admissions, ANZNN outborns had lower odds of SNI (AOR = 0.43, 95% CI: 0.32-0.58) and CLD (AOR = 0.63, 95% CI: 0.49-0.81) than CNN. <b><i>Conclusions:</i></b> ANZNN inborn and early admitted outborn infants had lower odds of neonatal morbidities than their CNN counterparts. However, compared to ANZNN, the higher CNN rates of outborns and their late admissions are likely related to the differences in regionalization and referral practices, and may explain differences in outcomes

Supplementary Material for: Variations in Oxygen Saturation Targeting, and Retinopathy of Prematurity Screening and Treatment Criteria in Neonatal Intensive Care Units: An International Survey

<b><i>Background:</i></b> Rates of retinopathy of prematurity (ROP) and ROP treatment vary between neonatal intensive care units (NICUs). Neonatal care practices, including oxygen saturation (SpO₂) targets and criteria for the screening and treatment of ROP, are potential contributing factors to the variations. <b><i>Objectives:</i></b><i></i> To survey variations in SpO₂ targets in 2015 (and whether there had been recent changes) and criteria for ROP screening and treatment across the networks of the International Network for Evaluating Outcomes in Neonates (iNeo). <b><i>Methods:</i></b> Online prepiloted questionnaires on treatment practices for preterm infants were sent to the directors of 390 NICUs in 10 collaborating iNeo networks. Nine questions were asked and the results were summarized and compared. <b><i>Results:</i></b> Overall, 329/390 (84%) NICUs responded, and a majority (60%) recently made changes in upper and lower SpO₂ target limits, with the median set higher than previously by 2–3% in 8 of 10 networks. After the changes, fewer NICUs (15 vs. 28%) set an upper SpO₂ target limit > 95% and fewer (3 vs. 5%) a lower limit < 85%. There were variations in ROP screening criteria, and only in the Swedish network did all NICUs follow a single guideline. The initial retinal examination was carried out by an ophthalmologist in all but 6 NICUs, and retinal photography was used in 20% but most commonly as an adjunct to indirect ophthalmoscopy. <b><i>Conclusions:</i></b> There is considerable variation in SpO₂ targets and ROP screening and treatment criteria, both within networks and between countries

Supplementary Material for: Respiratory Management of Extremely Preterm Infants: An International Survey

<b><i>Background:</i></b> There are significant international variations in chronic lung disease rates among very preterm infants yet there is little data on international variations in respiratory strategies. <b><i>Objective:</i></b> To evaluate practice variations in the respiratory management of extremely preterm infants born at < 29 weeks’ gestational age (GA) among 10 neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of Neonates collaboration. <b><i>Methods:</i></b> A web-based survey was sent to the representatives of 390 neonatal intensive care units from Australia/New Zealand, Canada, Finland, Illinois (USA), Israel, Japan, Spain, Sweden, Switzerland, and Tuscany (Italy). Responses were based on practices in 2015. <b><i>Results:</i></b> Overall, 321 of the 390 units responded (82%). The majority of units within networks (40–92%) mechanically ventilate infants born at 23–24 weeks’ GA on continuous positive airway pressure (CPAP) with 30–39% oxygen in respiratory distress within 48 h after birth, but the proportion of units that offer mechanical ventilation for infants born at 25–26 weeks’ GA at similar settings varied significantly (20–85% of units within networks). The most common respiratory strategy for infants born at 27–28 weeks’ GA on CPAP with 30–39% oxygen with respiratory distress within 48 h after birth used by units also varied significantly among networks: mechanical ventilation (0–60%), CPAP (3–82%), intubation and surfactant administration with immediate extubation (0–75%), and less invasive surfactant administration (0–68%). <b><i>Conclusions:</i></b> There are marked variations but also similarities in respiratory management of extremely preterm infants between networks. Further collaboration and exploration is needed to better understand the association of these variations in practice with pulmonary outcomes