Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in etiology of ACDMPV.

Aims/hypothesis This study aimed to determine the characteristics and pregnancy outcomes across different subtypes of gestational diabetes mellitus (GDM) based on insulin resistance. Methods GDM subtypes were defined in 1813 pregnant women from a multicentre prospective cohort study, stratified according to insulin resistance, based on Matsuda index below the 50th percentile of women with normal glucose tolerance (NGT), during a 75 g OGTT at 24-28 weeks' gestation. GDM was diagnosed in 12.4% (n = 228) of all participants based on the 2013 WHO criteria. Results Compared with women with NGT (1113 [61.4%] of the total cohort) and insulin-sensitive women with GDM (39 [17.1%] women with GDM), women with GDM and high insulin resistance (189 [82.9%] women with GDM) had a significantly higher BMI, systolic BP, fasting plasma glucose (FPG), fasting total cholesterol, LDL-cholesterol and triacylglycerol levels in early pregnancy. Compared with women with NGT, insulin-sensitive women with GDM had a significantly lower BMI but similar BP, FPG and fasting lipid levels in early pregnancy. Compared with women with NGT, women with GDM and high insulin resistance had higher rates of preterm delivery (8.5% vs 4.7%, p = 0.030), labour induction (42.7% vs 28.1%, p < 0.001), Caesarean section (total Caesarean sections: 28.7% vs 19.4%, p = 0.004; emergency Caesarean sections: 16.0% vs 9.7%, p = 0.010), neonatal hypoglycaemia (15.4% vs 3.5%, p < 0.001) and neonatal intensive care unit admissions (16.0% vs 8.9%, p = 0.003). In multivariable logistic regression analyses using different models to adjust for demographics, BMI, FPG, HbA 1c , lipid levels and gestational weight gain in early pregnancy, preterm delivery (OR 2.41 [95% CI 1.08, 5.38]) and neonatal

Table 1-Sensitivity and specificity of the GCT across different thresholds Threshold GCT Abnormal GCTs, % (n)Prevalence of GDM, % (n) Sensitivity, % (95% CI), n/N Specificity, % (95% CI), n/N LR1 (95% CI) LR2 (95% CI)Positive posttest probability, % (95% CI) Negative posttest probability, % (95% CI) Conversion factor for SI units for glucose in mmol/L:

AcknowledgementsThis investigator-initiated study was funded by the Belgian National Lottery, the Fund of Academic studies of UZ Leuven and the Fund Yvonne and Jacques François -de Meurs of the King Boudewijn Foundation. The sponsors of the study had no role in the design of the study; or in the collection, handling, analysis; or interpretation of the data; or in the decision to write and submit the manuscript for publication KB and RD are the recipient of a 'Fundamenteel Klinisch Navorserschap Fonds Wetenschappelijk Onderzoek (FWO) Vlaanderen'.We thank Dr. Inge Beckstedde from the UZA site and Dr. Sylva Van Imschoot from the AZ St Jan Brugge site for their help with the recruitment and study assessments. We thank the research assistants, paramedics and physicians of all participating centers for their support and we thank all women who participated in the study.

This study determines if a modified two-step screening strategy with a glucose challenge test (GCT) ≥ 7.2 mmol/L and clinical risk factors improves the diagnostic accuracy for gestational diabetes mellitus (GDM), based on 2013 WHO criteria, while limiting the number of oral glucose tolerance tests (OGTT). This was a prospective multicentric cohort study with 1811 participants receiving both GCT and 75 g OGTT in pregnancy. Participants and health care providers were blinded for GCT. Characteristics were analyzed across four glucose tolerance groups: abnormal (≥7.2 mmol/L), GCT GDM (n = 165), normal GCT GDM (n = 63), abnormal GCT normal glucose tolerant (NGT) (n = 472); normal GCT NGT (n = 1113). Compared to normal GCT NGT women, normal GCT GDM women had increased rates of obesity (23.8% vs. 10.5%, p < 0.001), ethnic minority background (19.3% vs. 8.2%, p < 0.001) and a history of GDM (13.8% vs. 4.6%, p = 0.03). By combined screening of GCT ≥ 7.2 mmol/L with these risk factors, sensitivity increased to respectively, 74.1–78.1% using one risk factor, and to 82.9% using any of these risk factors with a specificity of 57.5%. By using a modified two-step screening strategy, the number of women needing both a GCT and OGTT would be reduced to 25.5%, and 52.6% of all OGTTs could be avoided, compared to a universal one-step approach.