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.

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Classical Cornelia de Lange syndrome (CdLS) is a rare genetic disorder which is associated with distinctive facial features, growth retardation, significant intellectual disability and global developmental delay, hirsutism, and upper-limb reduction defects. Classical CdLS is associated with pathogenic variants in NIPBL. We present a clinical diagnosis of classical CdLS made in a second trimester male fetus with advanced maceration who had undergone intrauterine death at 15 + 6 weeks gestation. The diagnosis was suspected after multiple congenital anomalies were identified on fetal postmortem examination. These included intrauterine growth retardation, upper limb anomalies, ventricular septal defect and diaphragmatic hernia, and skeletal and genitourinary abnormalities. Related prenatal screening findings included a raised nuchal translucency and low maternal serum pregnancy-associated plasma protein-A. Targeted molecular sequencing of genes associated with CdLS identified a novel de novo frameshift pathogenic variant in NIPBL, which confirmed the diagnosis. This report describes our case and reviews the current literature on prenatal diagnosis of CdLS. In summary, we demonstrate that clinical diagnosis of CdLS in a second trimester fetus, through postmortem examination findings, is possible, with confirmation through molecular testing.

Introduction National surveys report that transition care in inflammatory Bowel Disease is still not well developed. Although the general principles guiding transition of adolescents with chronic illnesses from paediatric to adult health care have been established, there are no studies to assess the transfer needs and concerns of adolescents with IBD and their carers. We aimed to gauge the perspectives of adolescents with IBD and their parents to determine their issues, concerns and expectations. Methods A cross sectional survey of IBD patients starting transition process in a dedicated transition clinic and their parents was undertaken using a semi-structured questionnaire designed for self completion. Along with demographic and clinical information, respondents were asked to rate on a scale of 1e5 (using Likert scale anchored by 1-least important and 5-very important and essential) their responses on their perceived importance on the aspects of preparation, self management skills, concerns regarding transfer and value of support services. Results 20 patients (12 Crohn's and 8 Ulcerative Colitis) and their parents completed the survey independently. There was concordance in the responses of patients and their parents in rating highly the need for information, education and co-ordination of transfer process (Abstract PTU-133 table 1). The knowledge, empathy and accessibility were identified as key attributes for the transferring adult team (Abstract PTU-133 table 2). The highest rated concern for both adolescents and their parents was the perceived differences in performing tests such as endoscopy (mean score of 4.5560.17 and 4.6560.23 respectively). The adolescents favoured to attend appointments without parents before transfer (mean score 3.6561.18) as opposed to their parents (mean score 1.961.16). In addition parents were concerned whether they will become less involved in care following transfer (mean score 4.15. The adolescents' favoured younger age of transition and transfer when compared to their parents. While dedicated adolescent services were described as beneficial by patients and their parents, only 50% of patients preferred to have joint appointments. Conclusion This first pilot study demonstrates significant concerns about transition process needing addressing among adolescent IBD patients and their parents. Patients and parents differ in their rating of independence and self advocacy needed at the time of transfer. Tailoring transition to individual patient and parent needs without dedicated transition care teams may be challenging. Introduction At present, there are guidelines from the US and Europe regarding the formation of transition clinics for adolescents with IBD. This includes a UK Inflammatory Bowel Disease (IBD) Standards guidance on optimal service provision for paediatric and adolescent care. However most of these guidelines come from intuitive reasoning and opinion, as there is a lack of data on what constitutes an ideal service for young patients with IBD. The aim of this study was ...