Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability

Background: Autism spectrum disorder (ASD) is characterised by impairments in social communication and by a pattern of repetitive behaviours, with learning disability (LD) typically seen in up to 70% of cases. A recent study using the PPL statistical framework identified a novel region of genetic linkage on chromosome 16q21 that is limited to ASD families with LD. Methods: In this study, two families with autism and/or LD are described which harbour rare >1.6 Mb microdeletions located within this linkage region. The deletion breakpoints are mapped at base-pair resolution and segregation analysis is performed using a combination of 1M single nucleotide polymorphism (SNP) technology, array comparative genomic hybridisation (CGH), long-range PCR, and Sanger sequencing. The frequency of similar genomic variants in control subjects is determined through analysis of published SNP array data. Expression of CDH8, the only gene disrupted by these microdeletions, is assessed using reverse transcriptase PCR and in situ hybridisation analysis of 9 week human embryos. Results: The deletion of chr16: 60 025 584-61 667 839 was transmitted to three of three boys with autism and LD and none of four unaffected siblings, from their unaffected mother. In a second family, an overlapping deletion of chr16: 58 724 527-60 547 472 was transmitted to an individual with severe LD from his father with moderate LD. No copy number variations (CNVs) disrupting CDH8 were observed in 5023 controls. Expression analysis indicates that the two CDH8 isoforms are present in the developing human cortex. Conclusion: Rare familial 16q21 microdeletions and expression analysis implicate CDH8 in susceptibility to autism and LD

A clinical and cost-effectiveness trial of a parent group intervention to manage challenging restricted and repetitive behaviours in young children with autism spectrum disorder: study protocol for a randomised controlled trial

Background Restricted and repetitive behaviours vary greatly across the autism spectrum, and although not all are problematic some can cause distress and interfere with learning and social opportunities. We have, alongside parents, developed a parent group based intervention for families of young children with autism, which aims to offer support to parents and carers; helping them to recognise, understand and learn how to respond to their child’s challenging restricted repetitive behaviours. Methods The study is a clinical and cost-effectiveness, multi-site randomised controlled trial of the Managing Repetitive Behaviours (MRB) parent group intervention versus a psychoeducation parent group Learning About Autism (LAA) (n = 250; 125 intervention/125 psychoeducation; ~ 83/site) for parents of young children aged 3–9 years 11 months with a diagnosis of autism. All analyses will be done under intention-to-treat principle. The primary outcome at 24 weeks will use generalised estimating equation (GEE) to compare proportion of children with improved RRB between the MRB group and the LAA group. The GEE model will account for the clustering of children by parent groups using exchangeable working correlation. All secondary outcomes will be analysed in a similar way using appropriate distribution and link function. The economic evaluation will be conducted from the perspective of both NHS costs and family access to local community services. A ‘within trial’ cost-effectiveness analysis with results reported as the incremental cost per additional child achieving at least the target improvement in CGI-I scale at 24 weeks. Discussion This is an efficacy trial to investigate the clinical and cost-effectiveness of a parent group based intervention designed to help parents understand and manage their child’s challenging RRB. If found to be effective, this intervention has the potential to improve the well-being of children and their families, reduce parental stress, greatly enhance community participation and potential for learning, and improve longer-term outcomes

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

What constitutes successful commissioning of transition from children's to adults' services for young people with long-term conditions and what are the challenges? An interview study.

OBJECTIVE: We explored what constitutes successful commissioning for transition and what challenges are associated with this. We aimed: (1) to identify explicit and implicit organisational structures, processes and relationships that drive commissioning around transition; (2) to identify challenges faced by commissioners; and (3) to develop a conceptual model. DESIGN: A qualitative interview study. SETTING: Commissioning and provider organisations across primary and secondary care and third sector in England, UK. PARTICIPANTS: Representatives (n=14) from clinical commissioning groups, health and well-being boards and local authorities that commission national health services (NHS) for transition from children's to adults' services in England; NHS directors, general practitioners and senior clinicians (n=9); and frontline NHS and third sector providers (n=6). RESULTS: Both commissioners and providers thought successful transition is personalised, coordinated and collaborative with a focus on broad life outcomes and actualised through building pathways and universal services. A multitude of challenges were described, including inconsistent national guidance, fragmented resources, incompatible local processes, lack of clear outcomes and professional roles and relationships. No single specific process of commissioning for transition emerged-instead complex, multi-layered, interactive processes were described. CONCLUSIONS: The findings indicate a need to consider more explicitly the impact of national policies and funding streams on commissioning for transition. Commissioners need to require care pathways that enable integrated provision for this population and seek ways to ensure that generalist community providers engage with children with long-term conditions from early on. Future research is needed to identify a core set of specific, meaningful transition outcomes that can be commissioned, measured and monitored

Study protocol: longitudinal study of the transition of young people with complex health needs from child to adult health services

Background: Young people with complex health needs have impairments that can limit their ability to carry out day-to-day activities. As well as coping with other developmental transitions, these young people must negotiate the transfer of their clinical care from child to adult services. The process of transition may not be smooth and both health and social outcomes may suffer. Increasingly, policy-makers have recognised the need to ensure a smoother transition between children's and adult services, with processes that are holistic, individualised, and person-centred; however, there is little outcome data to support proposed models of care. This study aims to identify the features of transitional care that are potentially effective and efficient for young people with complex health needs making their transition. Methods/Design: Longitudinal cohort study. 450 young people aged 14 years to 18 years 11 months (with autism spectrum disorder and an additional mental health problem, cerebral palsy or diabetes) will be followed through their transition from child to adult services and will contribute data at baseline, 12, 24 and 36 months. We will collect data on: health and wellbeing outcomes (participation, quality of life, satisfaction with services, generic health status (EQ-5D-Y) and condition specific measure of disease control or management); exposure to proposed beneficial features of services (such as having a key worker, appropriate involvement of parents); socio-economic characteristics of the sample; use of condition-related health and personal social services; preferences for the characteristics of transitional care. We will use regression techniques to explore how outcomes vary by exposure to service features and by characteristics of the young people. These data will populate a decision-analytic model comparing the costs and benefits of potential alternative ways of organising transition services. In order to better understand mechanisms and aid interpretation, we will undertake qualitative work with 15 young people, including interviews, non-participant observation and diary collection. Discussion: This study will evaluate the effect of service components of transitional care, rather than evaluation of specific models that may be unsustainable or not generalisable. It has been developed in response to numerous national and international calls for such evaluation

Characteristics of young people with long term conditions close to transfer to adult health services

Background - For many young people with long term conditions (LTC), transferring from paediatric to adult health services can be difficult and outcomes are often reported to be poor. We report the characteristics and representativeness of three groups of young people with LTCs as they approach transfer to adult services: those with autism spectrum disorder with additional mental health problems (ASD); cerebral palsy (CP); or diabetes. Methods - Young people aged 14 years-18 years 11 months with ASD, or those with diabetes were identified from children’s services and those with CP from population databases. Questionnaires, completed by the young person and a parent, included the ‘Mind the Gap’ Scale, the Rotterdam Transition Profile, and the Warwick and Edinburgh Mental Wellbeing Scale. Results - Three hundred seventy four young people joined the study; 118 with ASD, 106 with CP, and 150 with diabetes. Participants had a significant (p < 0.001) but not substantial difference in socio-economic status (less deprived) compared to those who declined to take part or did not respond. Condition-specific severity of participants was similar to that of population data. Satisfaction with services was good as the ‘gap’ scores (the difference between their ideal and current care) reported by parents and young people were small. Parents’ satisfaction was significantly lower than their children’s (p < 0.001). On every domain of the Rotterdam Transition Profile, except for education and employment, significant differences were found between the three groups. A larger proportion of young people with diabetes were in a more independent phase of participation than those with ASD or CP. The wellbeing scores of those with diabetes (median = 53, IQR: 47–58) and CP (median = 53, IQR: 48–60) were similar, and significantly higher than for those with ASD (median = 47, IQR: 41–52; p < 0.001). Conclusions - Having established that our sample of young people with one of three LTCs recruited close to transfer to adult services was representative, we have described aspects of their satisfaction with services, participation and wellbeing, noting similarities and differences by LTC. This information about levels of current functioning is important for subsequent evaluation of the impact of service features on the health and wellbeing of young people with LTCs following transfer from child services to adult services

Facilitating transition of young people with long-term health conditions from children's to adults' healthcare services - implications of a 5-year research programme.

BACKGROUND During transition from children's to adults' healthcare, young adults with long-term conditions may show delays in psychosocial development compared to their peers without long-term conditions, and deterioration of their conditions' medical control. METHODS This paper integrates the findings, already published in 10 separate papers, of a 5-year transition research programme. IMPLICATIONS There is an important role for funders (commissioners) of adults' services to fund transitional healthcare, in addition to funders of children's services who currently take responsibility.It is important that healthcare provider organisations adopt an organisation-wide approach to implementation to ensure that good practice is adopted in children's and adults' services, not just adopted by enthusiasts in some specialties. This includes provision of 'developmentally appropriate healthcare' which recognises the changing biopsychosocial developmental needs of young people.Three features of transitional healthcare were associated with improved outcomes: appropriate parent involvement, promotion of young people's confidence in managing their health and meeting the adult team before transfer. These should be maintained or introduced as a priority.Child and adult healthcare providers should routinely explore with a young person how they approach transition and personalise their clinical approach thereafter.These implications are relevant for a range of stakeholders, including funders of transitional healthcare, organisations providing transitional healthcare and clinical practitioners

Facilitating transition of young people with long-term health conditions from children's to adults' healthcare services - implications of a 5-year research programme.

BACKGROUND: During transition from children's to adults' healthcare, young adults with long-term conditions may show delays in psychosocial development compared to their peers without long-term conditions, and deterioration of their conditions' medical control. METHODS: This paper integrates the findings, already published in 10 separate papers, of a 5-year transition research programme. IMPLICATIONS: There is an important role for funders (commissioners) of adults' services to fund transitional healthcare, in addition to funders of children's services who currently take responsibility.It is important that healthcare provider organisations adopt an organisation-wide approach to implementation to ensure that good practice is adopted in children's and adults' services, not just adopted by enthusiasts in some specialties. This includes provision of 'developmentally appropriate healthcare' which recognises the changing biopsychosocial developmental needs of young people.Three features of transitional healthcare were associated with improved outcomes: appropriate parent involvement, promotion of young people's confidence in managing their health and meeting the adult team before transfer. These should be maintained or introduced as a priority.Child and adult healthcare providers should routinely explore with a young person how they approach transition and personalise their clinical approach thereafter.These implications are relevant for a range of stakeholders, including funders of transitional healthcare, organisations providing transitional healthcare and clinical practitioners