Genomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach

As next-generation sequencing (NGS) has become more widely used, germline and rare genetic variations responsible for inherited illnesses, including cancer predisposition syndromes (CPSs) that account for up to 10% of childhood malignancies, have been found. The CPSs are a group of germline genetic disorders that have been identified as risk factors for pediatric cancer development. Excluding a few “classic” CPSs, there is no agreement regarding when and how to conduct germline genetic diagnostic studies in children with cancer due to the constant evolution of knowledge in NGS technologies. Various clinical screening tools have been suggested to aid in the identification of individuals who are at greater risk, using diverse strategies and with varied outcomes. We present here an overview of the primary clinical and molecular characteristics of various CPSs and summarize the existing clinical genomics data on the prevalence of CPSs in pediatric cancer patients. Additionally, we discuss several ethical issues, challenges, limitations, cost-effectiveness, and integration of genomic newborn screening for CPSs into a healthcare system. Furthermore, we assess the effectiveness of commonly utilized decision-support tools in identifying patients who may benefit from genetic counseling and/or direct genetic testing. This investigation highlights a tailored and systematic approach utilizing medical newborn screening tools such as the genome sequencing of high-risk newborns for CPSs, which could be a practical and cost-effective strategy in pediatric cancer care

Incidence, risk factors, and feto-maternal outcomes of inappropriate birth weight for gestational age among singleton live births in Qatar : a population-based study

Background Abnormal fetal growth can be associated with factors during pregnancy and at postpartum. Objective In this study, we aimed to assess the incidence, risk factors, and feto-maternal outcomes associated with small-for-gestational age (SGA) and large-for-gestational age (LGA) infants. Methods We performed a population-based retrospective study on 14,641 singleton live births registered in the PEARL-Peristat Study between April 2017 and March 2018 in Qatar. We estimated the incidence and examined the risk factors and outcomes using univariate and multivariate analysis. Results SGA and LGA incidence rates were 6.0% and 15.6%, respectively. In-hospital mortality among SGA and LGA infants was 2.5% and 0.3%, respectively, while for NICU admission or death in labor room and operation theatre was 28.9% and 14.9% respectively. Preterm babies were more likely to be born SGA (aRR, 2.31; 95% CI, 1.45–3.57) but male infants (aRR, 0.57; 95% CI, 0.4–0.81), those born to parous (aRR 0.66; 95% CI, 0.45–0.93), or overweight (aRR, 0.64; 95% CI, 0.42–0.97) mothers were less likely to be born SGA. On the other hand, males (aRR, 1.82; 95% CI, 1.49–2.19), infants born to parous mothers (aRR 2.16; 95% CI, 1.63–2.82), or to mothers with gestational diabetes mellitus (aRR 1.36; 95% CI, 1.11–1.66), or pre-gestational diabetes mellitus (aRR 2.58; 95% CI, 1.8–3.47) were significantly more likely to be LGA. SGA infants were at high risk of in-hospital mortality (aRR, 226.56; 95% CI, 3.47–318.22), neonatal intensive care unit admission or death in labor room or operation theatre (aRR, 2.14 (1.36–3.22). Conclusion Monitoring should be coordinated to alleviate the risks of inappropriate fetal growth and the associated adverse consequences.The PEARL-Peristat study was funded by Qatar National Research Fund (Grant no NPRP 6-238-3-059) and was sponsored by the Medical Research Centre, Hamad Medical Corporation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Incidence, Risk Factors, and Outcomes of Preterm and Early Term Births: A Population-Based Register Study

Preterm birth (PTB) and early term birth (ETB) are associated with high risks of perinatal mortality and morbidity. While extreme to very PTBs have been extensively studied, studies on infants born at later stages of pregnancy, particularly late PTBs and ETBs, are lacking. In this study, we aimed to assess the incidence, risk factors, and feto-maternal outcomes of PTB and ETB births in Qatar. We examined 15,865 singleton live births using 12-month retrospective registry data from the PEARL-Peristat Study. PTB and ETB incidence rates were 8.8% and 33.7%, respectively. PTB and ETB in-hospital mortality rates were 16.9% and 0.2%, respectively. Advanced maternal age, pre-gestational diabetes mellitus (PGDM), assisted pregnancies, and preterm history independently predicted both PTB and ETB, whereas chromosomal and congenital abnormalities were found to be independent predictors of PTB but not ETB. All groups of PTB and ETB were significantly associated with low birth weight (LBW), large for gestational age (LGA) births, caesarean delivery, and neonatal intensive care unit (NICU)/or death of neonate in labor room (LR)/operation theatre (OT). On the other hand, all or some groups of PTB were significantly associated with small for gestational age (SGA) births, Apgar <7 at 1 and 5 minutes and in-hospital mortality. The findings of this study may serve as a basis for taking better clinical decisions with accurate assessment of risk factors, complications, and predictions of PTB and ETB.The study was approved by the Hamad Medical Corporation Institutional Review Board, with a waiver of consent. It was funded by Qatar National Research Fund (Grant no NPRP 6-238-3-059) and was sponsored by the Medical Research Centre, Hamad Medical Corporation. The authors want to thank their respective institutions for their continued support. The publication of this article is funded by the Qatar National Library, Doha, Qatar

Prevalence, predictors, and outcomes of major congenital anomalies : a population-based register study

Congenital anomalies (CAs) are a leading cause of morbidity and mortality in early life. We aimed to assess the incidence, risk factors, and outcomes of major CAs in the State of Qatar. A population-based retrospective data analysis of registry data retrieved from the Perinatal Neonatal Outcomes Research Study in the Arabian Gulf (PEARL-Peristat Study) between April 2017 and March 2018. The sample included 25,204 newborn records, which were audited between April 2017 and March 2018, of which 25,073 live births were identified and included in the study. Maternal risk factors and neonatal outcomes were assessed for association with specific CAs, including chromosomal/genetic, central nervous system (CNS), cardiovascular system (CVS), facial, renal, multiple congenital anomalies (MCAs) using univariate and multivariate analyses. The incidence of any CA among live births was 1.3% (n = 332). The most common CAs were CVS (n = 117; 35%), MCAs (n = 69, 21%), chromosomal/genetic (51; 15%), renal (n = 39; 12%), CNS (n = 20; 6%), facial (14, 4%), and other (GIT, Resp, Urogenital, Skeletal) (n = 22, 7%) anomalies. Multivariable regression analysis showed that multiple pregnancies, parity ≥ 1, maternal BMI, and demographic factors (mother’s age and ethnicity, and infant’s gender) were associated with various specific CAs. In-hospital mortality rate due to CAs was estimated to be 15.4%. CAs were significantly associated with high rates of caesarean deliveries (aOR 1.51; 95% CI 1.04–2.19), Apgar < 7 at 1 min (aOR 5.44; 95% CI 3.10–9.55), Apgar < 7 at 5 min (aOR 17.26; 95% CI 6.31–47.18), in-hospital mortality (aOR 76.16; 37.96–152.8), admission to neonatal intensive care unit (NICU) or perinatal death of neonate in labor room (LR)/operation theatre (OT) (aOR 34.03; 95% CI 20.51–56.46), prematurity (aOR 4.17; 95% CI 2.75–6.32), and low birth weight (aOR 5.88; 95% CI 3.92–8.82) before and after adjustment for the significant risk factors. This is the first study to assess the incidence, maternal risk factors, and neonatal outcomes associated with CAs in the state of Qatar. Therefore, a specialized congenital anomaly data registry is needed to identify risk factors and outcomes. In addition, counselling of mothers and their families may help to identify specific needs for pregnant women and their babies.Open Access funding provided by the Qatar National Library. The PEARL-Peristat study was funded by Qatar National Research Fund (Grant no NPRP 6-238-3-059) and was sponsored by the Medical Research Centre, Hamad Medical Corporation.Scopu

Natural history, with clinical, biochemical and molecular characterization, of classical homocystinuria in the Qatari population

Classical homocystinuria (HCU) is the most common inborn error of metabolism in Qatar, with an incidence of 1:1800, and is caused by the Qatari founder p.R336C mutation in the CBS gene. This study describes the natural history and clinical manifestations of HCU in the Qatari population. A single center study was performed between 2016 and 2017 in 126 Qatari patients, from 82 families. Detailed clinical and biochemical data were collected and Stanford-Binet intelligence, quality of life and adherence to treatment assessments were conducted prospectively. Patients were assigned to one of three groups, according to mode of diagnosis: 1) Late Diagnosis Group (LDG), 2) Family Screening Group (FSG), and 3) Newborn Screening Group (NSG). Of the 126 patients, 69 (55%) were in the LDG, 44 (35%) in the NSG, and 13 (10%) in the FSG. The leading factors for diagnosis in the LDG were ocular manifestations (49%), neurological manifestations (45%), thromboembolic events (4%), and hyperactivity and behavioral changes (1%). Both FSG and NSG groups were asymptomatic at time of diagnosis. NSG had significantly higher IQ, QoL, and adherence values compared with the LDG. The LDG and FSG had significantly higher Met levels than the NSG. The LDG also had significantly higher tHcy levels than the NSG and FSG. Regression analysis confirmed these results even when adjusting for age at diagnosis, current age or adherence. These findings increase understanding of the natural history of HCU and highlight the importance of early diagnosis and treatment. This article is protected by copyright. All rights reserved.Qatar National Research Fund , Grant/Award Number: 7‐355‐3‐08

Outcomes of 28+1 to 32+0 Weeks Gestation Babies in the State of Qatar: Finding Facility-Based Cost Effective Options for Improving the Survival of Preterm Neonates in Low Income Countries

In this retrospective study we did a comparative analysis of the outcome of 28+1 to 32+0 weeks gestation babies between the State of Qatar and some high income countries with an objective of providing an evidence base for improving the survival of preterm neonates in low income countries. Data covering a five year period (2002–2006) was ascertained on a pre-designed Performa. A comparative analysis with the most recent data from VON, NICHD, UK, France and Europe was undertaken. Qatar’s 28+1 to 32+0 weeks Prematurity Rate (9.23 per 1,000 births) was less than the UK’s (p < 0.0001). Of the 597 babies born at 28+1 to 32+0 weeks of gestation, 37.5% did not require any respiratory support, while 31.1% required only CPAP therapy. 80.12% of the MV and 96.28% of CPAP therapy was required for <96 hours. 86.1% of the mothers had received antenatal steroids. The 28+1 to 32+0 weeks mortality rate was 65.3/1,000 births with 30.77% deaths attributable to a range of lethal congenital and chromosomal anomalies. The survival rate increased with increasing gestational age (p < 0.001) and was comparable to some high income countries. The incidence of in hospital pre discharge morbidities in Qatar (CLD 2.68%, IVH Grade III 0.84%, IVH Grade IV 0.5%, Cystic PVL 0.5%) was less as compared to some high income countries except ROP ≥ Stage 3 (5.69%), which was higher in Qatar. The incidence of symptomatic PDA, NEC and severe ROP decreased with increasing gestational age (p < 0.05). We conclude that the mortality and in hospital pre discharge morbidity outcome of 28+1 to 32+0 weeks babies in Qatar are comparable with some high income countries. In two thirds of this group of preterm babies, the immediate postnatal respiratory distress can be effectively managed by using two facility based cost effective interventions; antenatal steroids and postnatal CPAP. This finding is very supportive to the efforts of international perinatal health care planners in designing facility-based cost effective options for low income countries

Studying carrier frequency of spinal muscular atrophy in the State of Qatar and comparison to other ethnic groups: Pilot study

Abstract Background Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations and deletions in SMN1 at exon 7. The carrier frequency for SMN1 mutations ranges from 2 to 4% in the general population. Methods We examined allelic, genotypic relatedness and copy number (CN) variations and frequencies of SMN1 and SMN2, in 13,426 samples from Qatar biobank (QBB) to provide a precise estimation of SMA carrier frequency in Qatar in comparison to other populations. Results The SMA carrier frequency was found to be (2.8%) and the rs143838139 was found in 491/13426 (3.66%) of individuals. The SNP rs121909192, which is a pathogenic risk factor, was found in 321/13500 (2.38%). In Addition 242/11379 (2.13%) had two copies of SMN1 and the rs143838139, which may explain the (2 + 0) silent carrier. Additionally, two participants were found to be SMA type 4 with 0 and 4 copy numbers in SMN1 and SMN2, respectively. Conclusion The SMA carrier frequency in Qatar was found to be comparable to Saudi Arabia and Caucasians. The likely pathogenic variant, rs121909192, was found to be significantly higher when compering with other in our study. The rs143838139 variant, which has a strong association with the silent carrier genotype, has been found. Consequently, testing for this SNP may enhance the precision of evaluating the likelihood of a patient having an affected child. We conclude that the frequency of SMA carriers varies within the Qatar population and other ethnic groups

The impact of abnormal maternal body mass index during pregnancy on perinatal outcomes: A retrospective cohort study

Background Abnormal Body mass index (BMI) during pregnancy is a growing public health concern as it has been associated with an increased risk of maternal and neonatal complications. This study aimed to investigate the impact of abnormal BMI on maternal and neonatal outcomes compared to normal BMI. Methods A total of 14,624 singleton births were included in a retrospective cohort study conducted in a tertiary maternity hospital in Qatar. Women were categorised as underweight (BMI Results Compared to women with normal BMI, women with increasing BMI had increasingly higher odds of developing specific adverse outcomes, the highest being in the class III obesity group (GDM- aOR 2.71, 95% CI 2.25-3.27, p Conclusion The findings of this study have important implications for the clinical management of pregnant women with abnormal BMI. They suggest that interventions to improve maternal and neonatal outcomes are crucial in directing prenatal care optimisation, focusing on enhancing prepregnancy BMI to minimise adverse maternal and neonatal outcomes.</p

Gestational Age Specific Neonatal Survival in the State of Qatar (2003-2008) - A Comparative Study with International Benchmarks

Objective: To analyze and compare the current gestational age specific neonatal survival rates between Qatar and international benchmarks

Prophylactic Sildenafil in Preterm Infants at Risk of Bronchopulmonary Dysplasia: A Pilot Randomized, Double-Blinded, Placebo-Controlled Trial.

Bronchopulmonary dysplasia (BPD) is the need for oxygen therapy at 36 weeks postmenstrual age (PMA). Sildenafil has been shown to enhance the lung alveolarization and vascularization in newborn animal models after lung injury and has possible therapeutic potential for the prevention of BPD. To perform a proof-of-concept, Phase II, pilot randomized, double-blind, clinical trial to study the efficacy of sildenafil in preventing BPD, in postnatal (< 24 h), extremely and very preterm infants. This Phase II, pilot randomized, double-blind, clinical trial was conducted in the Neonatal Intensive Care Unit of Women's Wellness and Research Center, Doha, Qatar during 2012-2014. Infants of 24-29 weeks' gestation were eligible if they needed respiratory or oxygen support ≥ 25% at randomization, and if they were at a postnatal age of < 24 h at randomization. Forty preterm infants were randomly assigned to receive off-label oral sildenafil (0.5 mg/kg every 6 h) or a placebo solution, for one week. The primary endpoints were the incidence of BPD and death at 36 weeks PMA, and the side effects. Secondary outcomes included the incidence of BPD and the respiratory support at day 28 of life, duration of oxygen use, fraction of inspired oxygen use at 36 weeks and 28 days of life, duration of hospitalization, and the incidence of significant retinopathy of prematurity, severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, patent ductus arteriosus, and late sepsis. No significant differences were observed between the sildenafil and placebo study groups in mortality at 36 weeks PMA (10% vs 20%, p = 1), respiratory support at 36 weeks (30% vs 25%, p = 0.57), and side effects (0% vs 0%). For all other secondary outcomes, no significant differences were detected. While not associated with side effects, off-label oral sildenafil did not demonstrate benefits in the prevention of BPD or death in the extreme and very preterm infants. Future studies of dosing and efficacy that target different regimens of sildenafil are warranted before sildenafil is recommended for the prevention of BPD.The study was supported by Medical Research Center, Hamad Medical Corporation [Grant number RP#11087/11]