Systematic analysis of copy number variation associated with congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to identify CNVs within 140 regions in 196 patients and 987 healthy controls, and identified six significant CNVs that were either unique to patients or enriched in patients compared with controls. These CDH-associated CNVs reveal high-priority candidate genes including HLX, LHX1, and HNF1B We also discuss CNVs that are present in only one patient in the cohort but have additional evidence of pathogenicity, including extremely rare large and/or de novo CNVs. The candidate genes within these predicted disease-causing CNVs form functional networks with other known CDH genes and play putative roles in DNA binding/transcription regulation and embryonic development. These data substantiate the importance of CNVs in the etiology of CDH, identify CDH candidate genes and pathways, and highlight the importance of ongoing analysis of CNVs in the study of CDH and other structural birth defects.

De novo frameshift mutation in COUP-TFII (NR2F2) in human congenital diaphragmatic hernia.

COUP-TFII (NR2F2) is mapped to the 15q26 deletion hotspot associated with the common and highly morbid congenital diaphragmatic hernia (CDH). Conditional homozygous deletions of COUP-TFII in mice result in diaphragmatic defects analogous to the human Bochdalek-type hernia phenotype. Despite evidence from animal models however, mutations in the coding sequence of COUP-TFII have not been reported in patients, prompting the speculation that additional coding or non-coding sequences in the 15q26 locus are necessary for diaphragmatic hernias to develop. In this report, we describe a case of a patient with a heterozygous de novo COUP-TFII frameshift mutation, presenting with CDH and an atrial septal defect. The p.Pro33AlafsTer77 mutation specifically disrupts protein isoform 1 which contains the DNA binding domain. In addition, we review other COUP-TFII sequence variations and deletions that have been described in cases of CDH. We conclude that COUP-TFII mutations can cause diaphragmatic hernias, and should be included in the differential diagnosis of CDH patients, particularly those with comorbid congenital heart defects. © 2016 Wiley Periodicals, Inc.

A pilot evaluation of therapist training in cognitive therapy for psychosis: therapy quality and clinical outcomes.

BACKGROUND: Historically, it has been difficult to demonstrate an impact of training in psychological interventions for people with psychosis on routine practice and on patient outcomes. A recent pilot evaluation suggested that postgraduate training in Cognitive Behavioural Therapy for Psychosis (CBTp) increased the delivery of competent therapy in routine services. In this study, we evaluated clinical outcomes for patients receiving therapy from therapists who successfully completed training, and their association with ratings of therapist competence and therapy content. AIMS: To characterize the therapy delivered during training and to inform both a calculation of effect size for its clinical impact, and the development of competence benchmarks to ensure that training standards are sufficient to deliver clinical improvement. METHOD: Paired patient-reported outcome measures (PROMS) were extracted from anonymized therapy case reports, and were matched with therapy ratings for each therapist. RESULTS: Twenty clients received a course of competent therapy, including a high frequency of active therapy techniques, from nine therapists. Pre-post effect size for change in psychotic symptoms was large (d = 1.0) and for affect, medium (d = 0.6), but improved outcomes were not associated with therapist competence or therapy content. CONCLUSIONS: Therapists trained to research trial standards of competence achieved excellent clinical outcomes. Therapy effect sizes suggest that training costs may be offset by clinical benefit. Larger, methodologically stringent evaluations of training are now required. Future research should assess the necessary and sufficient training required to achieve real-world clinical effectiveness, and the cost-effectiveness of training.