Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

On-line preparatory information for children and their families undergoing dental extractions under general anesthesia: A phase III randomized controlled trial.

BACKGROUND: Family-centered interactive on-line games are increasingly popular in healthcare, but their effectiveness for preoperative preparation needs further research. www.scottga.org is the new on-line version of a proven nonweb-based game for children and parents/caregivers. AIMS: The aim of this study was to evaluate if www.scottga.org improved children's anxiety and families' satisfaction compared with controls. METHODS: In this phase III double-blind randomized controlled trial, children/parents/caregivers received (i) www.scottga.org, (ii) standard care, or (iii) a placebo hand-washing game. The intervention and placebo games were available online for home usage and provided again on the ward before surgery. All children were accompanied by parent/caregivers at induction and observed and scored using validated measures. Stratified randomization and generalized linear models were used. An intention-to-treat approach was adopted. RESULTS: Overall, 52/176 children had baseline "psychological disturbance." Children's anxiety increased preinduction, but there were no differences between groups (Facial Image Scale: video-standard OR = 1.08, P = .82, 95% CI [0.56, 2.1]; video-placebo OR = 0.9, P = .77 95% CI [0.46, 1.8]). There were no differences in induction behavior (visual analog scale: video mean = 3.5; standard care mean = 3.5; placebo mean = 3.7: video-standard OR = 2.0, P = .42, 95% CI [-0.6, 1.3]; video-placebo OR = 1.53, P = .65, 95% CI [-0.8, 1.1]) or induction anxiety (modified Yale Preoperative Anxiety Scale: video-standard OR 1.02, P = .97, 95% CI [0.61, 2.6]; video-placebo OR 1.38, P = .49, 95% CI [0.87, 3.81]). Families favored the intervention regarding the "child handling the visit better" (Treatment Evaluation Inventory: video-standard OR = 12; 95% CI 4.7-32; P < .001; video-placebo OR = 8.2; 95% CI 3-22; P < .001) and "improving the child's ability to cope" (Treatment Evaluation Inventory: video-standard OR = 21; 95% CI 8-56; P < .001 and video-placebo OR = 13; 95% CI 5-34; P < .001). CONCLUSION: Families believed that a video-game preparation helped their child's perioperative anxiety, but there were no objective measures of behavioral improvement associated with this intervention.

How families prepare their children for tooth extraction under general anaesthesia: Family and clinical predictors of non-compliance with a 'serious game'.

OBJECTIVE: To explore family and clinical factors for usage of an online serious game designed to prepare children with ECC for dental treatment under general anaesthesia. DESIGN: Observational study. Secondary data of 60 children, aged 5-to-7, randomised to the intervention group in a phase-III randomised controlled trial [NIHR Portfolio 10006, ISRCTN: 18265148] testing the efficacy of the serious game http://www.scottga.org (available online). Usage was captured automatically, with each click, in real time. The total number of replays and total number of missing slides per game-run performed by the child, were recorded and used to monitor usage. Compliance outcomes were: total time running the game and number of completely missed slides. RESULTS: 57/60 played the game. Median age of parent/carer was 32. For 74% of the families, fathers resided at home and for 65% the parent/carer had A-levels-to-university education. At recruitment, 70% of the children were reported as anxious/highly-fearful and 37% as "significantly psychologically disturbed". CONCLUSIONS: Factors for non-compliance were absence of a father at home (P = 0.01) and higher child-anxiety (P = 0.01) and, to a lesser extent, a low parent/carer education level (P = 0.09). Interactive cartoons featuring dental assessment, oral health messages and modelling featured in the more popular slides.

Expression of the guanine nucleotide exchange factor, RAPGEF5, during mouse and human embryogenesis.

Rap GTPases mediate fundamental cellular processes, including cell adhesion, migration and intracellular signal transduction. The subcellular activity of these GTPases is regulated by dedicated activators (guanine nucleotide exchange factors, GEFs) and deactivators (GTPase-activating proteins, GAPs). RAPGEF5 is a potent activator of Rap proteins and mutations in RAPGEF5 have been linked to both neurological disorders and congenital heart disease. In the frog model, Xenopus tropicalis, Rapgef5 is a critical regulator of the canonical Wnt signalling pathway and is required for normal gastrulation and correct establishment of the left-right body axis. However, requirements for RAPGEF5 in other developmental contexts, and in mammalian embryogenesis in particular, remain undefined. Here, we describe RAPGEF5 mRNA expression patterns during mouse (E9.5 - E16.5) and human (Carnegie stage 21) development, as an initial step towards better understanding its developmental functions.

Improving access to preparatory information for children undergoing general anaesthesia for tooth extraction and their families: study protocol for a Phase III randomized controlled trial.

BACKGROUND: Children can find anaesthesia induction especially distressing and postoperative psychological and physical morbidity are common. Preparation programmes for general anaesthesia (GA) are highly effective in reducing this distress. A Phase II study has already verified the effectiveness of a prototype preoperative GA-coping computer game to help children cope with induction in a dental GA setting. The biggest patient users of pediatric GA services in the UK are children who need to have teeth removed (estimated to be 100,000 yearly). Tooth decay is the most common disease in children worldwide. This study is a Phase III randomized controlled trial (RCT) and will evaluate the effectiveness of the new internet version of this game. METHODS/DESIGN: The Phase III RCT will use a double-blind three-armed design. The clinical trial will recruit up to 210 children and will compare the web-based game against standard care and another non-medical game. At least 53 patients in each group will be required for 90% statistical power. Distress will be assessed through an evaluation of the child's behaviour during the visit and later parental reports of physical and psychological morbidity. The satisfaction of parents and children will be measured; the mode of usage of the web-based game will be automatically recorded and the impact on the service (for example, recovery time and throughput) will be reported.The Phase III study primary outcome will measure: (1) patient experience: acceptance of anaesthetic induction, child cooperation and distress, reduction of peri- and postoperative morbidity, child and family satisfaction, and (2) service improvement: anaesthetic time and improvement in throughput. Measures will be administered at baseline, at the time of the GA treatment visit, and at 48 hours and one week postoperatively. DISCUSSION: This study aims to determine the effectiveness of an online GA-coping game for children and families undergoing tooth extraction under GA. TRIAL REGISTRATION: ISRCTN18265148 (registered 24 November 2013).