Analysis of Copy Number Variants identifies new candidate genes for Autism Spectrum Disorder and Intellectual Disability

Autism spectrum disorder (ASD) and Intellectual Disability (ID) are complex neuropsychiatric disorders characterized by extensive clinical and genetic heterogeneity and with overlapping risk factors. The aim of my project was to further investigate the role of Copy Numbers Variants (CNVs), identified through genome-wide studies performed by the Autism Geome Project (AGP) and the CHERISH consortium in large cohorts of ASD and ID cases, respectively. Specifically, I focused on four rare genic CNVs, selected on the basis of their impact on interesting ASD/ID candidate genes: a) a compound heterozygous deletion involving CTNNA3, predicted to cause the lack of functional protein; b) a 15q13.3 duplication containing CHRNA7; c) a 2q31.1 microdeletion encompassing KLHL23, SSB and METTL5; d) Lastly, I investigated the putative imprinting regulation of the CADPS2 gene, disrupted by a maternal deletion in two siblings with ASD and ID. This study provides further evidence for the role of CTNNA3, CHRNA7, KLHL23 and CADPS2 as ASD and/or ID susceptibility genes, and highlights that rare genetic variation contributes to disease risk in different ways: some rare mutations, such as those impacting CTNNA3, act in a recessive mode of inheritance, while other CNVs, such as those occurring in the 15q13.3 region, are implicated in multiple developmental and/or neurological disorders possibly interacting with other susceptibility variants elsewhere in the genome. On the other hand, the discovery of a tissue-specific monoallelic expression for the CADPS2 gene, implicates the involvement of epigenetic regulatory mechanisms as risk factors conferring susceptibility to ASD/ID.

Helping the most vulnerable out of the poverty trap and reducing inequality: Policies, strategies, and services for individuals with Autism Spectrum Disorder, including intellectual and neurodevelopmental disabilities: Benchmarking Autism Services Efficacy: BASE Project (Volume 3) Secondary Data analysis

1) Executive Summary
Legislation (Autism Act NI, 2011), a cross-departmental strategy (Autism Strategy 2013-2020) and a first action plan (2013-2016) have been developed in Northern Ireland in order to support individuals and families affected by Autism Spectrum Disorder (ASD) without a prior thorough baseline assessment of need. At the same time, there are large existing data sets about the population in NI that had never been subjected to a secondary data analysis with regards to data on ASD. This report covers the first comprehensive secondary data analysis and thereby aims to inform future policy and practice.
Following a search of all existing, large-scale, regional or national data sets that were relevant to the lives of individuals and families affected by Autism Spectrum Disorder (ASD) in Northern Ireland, extensive secondary data analyses were carried out. The focus of these secondary data analyses was to distill any ASD related data from larger generic data sets. The findings are reported for each data set and follow a lifespan perspective, i.e., data related to children is reported first before data related to adults.
Key findings:
Autism Prevalence:
Of children born in 2000 in the UK,
• 0.9% (1:109) were reported to have ASD, when they were 5-year old in 2005;
• 1.8% (1:55) were reported to have ASD, when they were 7-years old in 2007;
• 3.5% (1:29) were reported to have ASD, when they were 11-year old in 2011.
In mainstream schools in Northern Ireland
• 1.2% of the children were reported to have ASD in 2006/07;
• 1.8% of the children were reported to have ASD in 2012/13.

Economic Deprivation:
• Families of children with autism (CWA) were 9%-18% worse off per week than families of children not on the autism spectrum (COA).
• Between 2006-2013 deprivation of CWA compared to COA nearly doubled as measured by eligibility for free school meals (from near 20 % to 37%)
• In 2006, CWA and COA experienced similar levels of deprivation (approx. 20%), by 2013, a considerable deprivation gap had developed, with CWA experienced 6% more deprivation than COA.
• Nearly 1/3 of primary school CWA lived in the most deprived areas in Northern Ireland.
• Nearly ½ of children with Asperger’s Syndrome who attended special school lived in the most deprived areas.

Unemployment:
• Mothers of CWA were 6% less likely to be employed than mothers of COA.
• Mothers of CWA earned 35%-56% less than mothers of COA.
• CWA were 9% less likely to live in two income families than COA.

Health:
• Pre-diagnosis, CWA were more likely than COA to have physical health problems, including walking on level ground, speech and language, hearing, eyesight, and asthma.
• Aged 3 years of age CWA experienced poorer emotional and social health than COA, this difference increased significantly by the time they were 7 years of age.
• Mothers of young CWA had lower levels of life satisfaction and poorer mental health than mothers of young COA.
Education:
• In mainstream education, children with ASD aged 11-16 years reported less satisfaction with their social relationships than COA.
• Younger children with ASD (aged 5 and 7 years) were less likely to enjoy school, were bullied more, and were more reluctant to attend school than COA.
• CWA attended school 2-3 weeks less than COA .
• Children with Asperger’s Syndrome in special schools missed the equivalent of 8-13 school days more than children with Asperger’s Syndrome in mainstream schools.
• Children with ASD attending mainstream schooling were less likely to gain 5+ GCSEs A*-C or subsequently attend university.



Further and Higher Education:
• Enrolment rates for students with ASD have risen in Further Education (FE), from 0% to 0.7%.
• Enrolment rates for students with ASD have risen in Higher Education (HE), from 0.28% to 0.45%.
• Students with ASD chose to study different subjects than students without ASD, although other factors, e.g., gender, age etc. may have played a part in subject selection.
• Students with ASD from NI were more likely than students without ASD to choose Northern Irish HE Institutions rather than study outside NI.

Participation in adult life and employment:
• A small number of adults with ASD (n=99) have benefitted from DES employment provision over the past 12 years.
• It is unknown how many adults with ASD have received employment support elsewhere (e.g. Steps to Work).
•
Awareness and Attitudes in the General Population:
• In both the 2003 and 2012 NI Life and Times Survey (NILTS), NI public reported positive attitudes towards the inclusion of children with ASD in mainstream education (see also BASE Project Vol. 2).

Gap Analysis Recommendations:
This was the first comprehensive secondary analysis with regards to ASD of existing large-scale data sets in Northern Ireland. Data gaps were identified and further replications would benefit from the following data inclusion:
• ASD should be recorded routinely in the following datasets:
o Census;
o Northern Ireland Survey of Activity Limitation (NISALD);
o Training for Success/Steps to work; Steps to Success;
o Travel survey;
o Hate crime; and
o Labour Force Survey.
• Data should be collected on the destinations/qualifications of special school leavers.
• NILT Survey autism module should be repeated in 5 years time (2017) (see full report of 1st NILT Survey autism module 2012 in BASE Project Report Volume 2).
• General public attitudes and awareness should be assessed for children and young people, using the Young Life and Times Survey (YLT) and the Kids Life and Times Survey (KLT); (this work is underway, Dillenburger, McKerr, Schubolz, & Lloyd, 2014-2015).
 

Autism Spectrum Disorder: Evidence-based interventions

Autism Spectrum Disorders (ASD) are pervasive developmental disorders that are diagnosed along a continuum of behavioural variants in social interaction, communication, and imagination. Some individuals on the spectrum are ‘high-functioning’ and able to cope in every day environments, while others are severely affected, non-verbal, and may have comorbid diagnoses, such as intellectual disability, epilepsy, and/or obsessional, conduct, or mental health disorders. ASD diagnosis can be formulated from as early as 6-months to one year of age, although it is more common that children are aged 2-3 years before diagnosis is affirmed. Frequently, higher functioning individuals are not diagnosed until adolescence or even adulthood.

Creating an Inclusive Society… How Close are We in Relation to Autism Spectrum Disorder? A General Population Survey

BackgroundChildren with autism spectrum disorder are increasingly educated in mainstream classrooms in the United Kingdom (Wilkinson & Twist, Autism and Educational Assessment: UK Policy and Practice. NFER, Slough, 2010), and some employers are now specifically seeking out staff on the autism spectrum. Does that mean that we are living in an inclusive society' [United Nations Department of Economic and Social Affairs (UNDESA), Creating an Inclusive Society: Practical Strategies to Promote Social Integration 2008], in the sense that inequalities are reduced and full economic, social and cultural participation is advanced for individuals with autism?

MethodsA general population survey was conducted to assess how close we, as a society, are to an inclusive society for individuals with autism in Northern Ireland. Public attitudes were examined to (i) visibility and social interaction, (ii) aetiology, needs and interventions, and (iii) rights and resources.

ResultsA stratified, representative sample of 1204 adults took part in the survey; of these, 989 were aware of autism and their attitudes and behavioural projections reflected a mix of acceptance and denunciation. The level of confusion with regard to interventions reflected the general uncertainty within UK policy regarding meeting the needs of individuals on the autism spectrum (International Journal of Disability, Development and Education 61, 134, 2014a).

ConclusionTherefore, it seems that inclusion is working to an extent, but more clarity is needed with regard to adequate education, intervention and support for individuals with autism.

Helping the most vulnerable out of the poverty trap and reducing inequality: Policies, strategies, and services for individuals with Autism Spectrum Disorder, including intellectual and neurodevelopmental disabilities: BASE Project Report (Volume 2) NILT Survey Autism Module

The primary purpose of the BASE Project was to establish how to help individuals with Autism Spectrum Disorder out of poverty by promoting social inclusion. In order to achieve this, a range of methodologies were utilised that aimed to provide a baseline against which the effect of the Autism Act (NI) 2011 and the associated Autism Strategy (2013-2020) and Action Plans can be measured. The BASE Project is reported in 5 volumes. Volume 2 reports on the analysis of the autism module of the Northern Ireland Life and Times (NILT) Survey that assessed public awareness, attitudes, knowledge, and projected behaviours with regard to individuals with ASD (all primary data and technical reports are available at www.ark.ac.uk/nilt/).

The NILT (2012) survey first ever autism module (n=1204) offered a baseline against which the impact of new autism legislation, policies, and strategies can be measured. Key findings:

• 82% awareness: Most people in Northern Ireland are aware of autism (n=989).
• 50% of all participants knew someone with autism personally (n=606).

Of those who were aware of autism:
• 19% had a close family member with autism (n=186), and/or a friends/acquaintance (n=296), and/or a work colleague (n=79) with autism.
• Autism awareness was particularly low for those from ethnic minorities and those with no internet access.
• Awareness of autism specific legislation was low (20%).
• Good levels of knowledge about autism strengths and challenges, slight tendency to overestimate the occurrence of special talents.
• Prevalence of autism was underestimated (62% thought autism was much less prevalent than official figures or did not know).
• Fairly accurate perception about causes of autism, i.e., not caused by poor parenting (84%).
• Strong support for evidence-based behavioural interventions (77%), but confusion about interventions that are not evidence-based (64%).
• Strong positive attitudes towards children and adults in social, educational and employment settings.
• Autism not viewed as necessarily ‘lifelong’ (58%); support for independent living (78%), e.g., driving a car (83%).
• More business for employers who employ people with autism (12%).
• Strong support for families caring rather than residential care (64%).
• Confusion about service responsibility: education (26%) health (33%) or both (28%).

Given increasing prevalence rates of ASD it is important that the general population is aware of autism and able to respond responsibly to the associated strengths and challenges. The results of the NILT (2012) first ever autism module show that the general public was well aware of autism, had positive attitudes, and was relatively knowledgeable about the issues faced by individuals and families affected directly. However, there was a lack of clarity about responsibility for effective service delivery. The NILT results show that a shift in focus is necessary from ‘awareness raising campaigns’ to an approach that delivers clarity with regard to intervention and accountability.

Motor deficits in children with autism spectrum disorder: A cross-syndrome study

Recent research suggests that children with autism spectrum disorder (ASD) experience some level of motor difficulty, and that this may be associated with social communication skills. However, other studies show that children with language impairments, but without the social communication problems, are at risk of motor difficulties as well. The aim of the present study was to determine if children with ASD have syndrome specific motor deficits in comparison to children with specific language impairment (SLI). We used an independent groups design with three groups of children (8-10 years old) matched on age and nonverbal IQ; an ASD group, an SLI group, and a typically developing (TD) group. All of the children completed an individually administered, standardized motor assessment battery. We found that the TD group demonstrated significantly better motor skills than either the ASD or SLI groups. Detailed analyses of the motor subtests revealed that the ASD and SLI groups had very similar motor profiles across a range of fine and gross motor skills, with one exception. We conclude that children with ASD, and SLI, are at risk of clinically significant motor deficits. However, future behavioural and neurological studies of motor skills in children with ASD should include an SLI comparison group in order to identify possible autism specific deficits.

Developing social interaction and understanding in individuals with autism spectrum disorder: a groupwork intervention

Background: Difficulties with social interaction and understanding lie at the heart of the communication disorder that characterises the autism spectrum. This study sought to improve social communication for individuals with autism spectrum disorder (ASD) by means of a groupwork intervention focusing on social and emotional perspective-taking, conversation skills, and friendship skills. It also aimed to address some of the limitations of previous interventions, including a lack of generalisation to other settings, so as to maximise inclusion in the community. Method A group of 46 high functioning children and adolescents with ASD (38 boys, 8 girls, age range 6-16 years) were allocated to one of 6 intervention groups. Each group met over a period of 12-16 weeks for a minimum of one 1 1/2-hour weekly session aimed at promoting key areas of social interaction and understanding, supported by home-based practice. Results: Significant gains were achieved in comparison with a normative population, and individual parent ratings showed marked and sustained changes in the key areas targeted in the group sessions. Conclusion: Social communication in children and adolescents with ASD can be enhanced through the use of a groupwork intervention addressing social interaction and understanding.

A complex chromosomal rearrangement involving chromosomes 2, 5, and X in autism spectrum disorder

Here, we describe a female patient with autism spectrum disorder and dysmorphic features that harbors a complex genetic alteration, involving a de novo balanced translocation t(2;X)(q11;q24), a 5q11 segmental trisomy and a maternally inherited isodisomy on chromosome 5. All the possibly damaging genetic effects of such alterations are discussed. In light of recent findings on ASD genetic causes, the hypothesis that all these alterations might be acting in orchestration and contributing to the phenotype is also considered. (C) 2012 Wiley Periodicals, Inc.

Neuropsychiatric disease (NPD) clustering in families with Autism Spectrum Disorder (ASD): genetic, epigenetic and environmental issues

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication/interaction and by unusual repetitive and restricted behaviors and interests. ASD often co-occurs in the same families with other neuropsychiatric diseases (NPD), such as intellectual disability, schizophrenia, epilepsy, depression and attention deficit hyperactivity disorder. Genetic factors have an important role in ASD etiology. Multiple copy number variants (CNVs) and single nucleotide variants (SNVs) in candidate genes have been associated with an increased risk to develop ASD. Nevertheless, recent heritability estimates and the high genotypic and phenotypic heterogeneity characteristic of ASD indicate a role of environmental and epigenetic factors, such as long noncoding RNA (lncRNA) and microRNA (miRNA), as modulators of genetic expression and further clinical presentation. Both miRNA and lncRNA are functional RNA molecules that are transcribed from DNA but not translated into proteins, instead they act as powerful regulators of gene expression. While miRNA are small noncoding RNAs with 22-25 nucleotides in length that act at the post-transcriptional level of gene expression, the lncRNA are bigger molecules (>200 nucleotides in length) that are capped, spliced, and polyadenylated, similar to messenger RNA. Although few lncRNA were well characterized until date, there is a great evidence that they are implicated in several levels of gene expression (transcription/post-transcription/post-translation, organization of protein complexes, cell– cell signaling as well as recombination) as shown in figure 1.

Teaching children who have a diagnosis of Autism Spectrum Disorder

Best practice dictates that the Autism Spectrum Disorder (ASD) diagnostic process is informed by experienced professionals from at least two disciplines, for example psychology or speech pathology, with the diagnosis ultimately provided by a specialist medical practitioner e.g. child psychiatrist, neurologist or paediatrician. Irrespective of a child’s age, diagnosis relies upon information about their early development. Current information and observations on a child’s behaviour, communication and socialisation are considered by the specialist medical practitioner against the signs and symptoms detailed in one of several diagnostic systems. Two recently used classification systems in Australia have been the fourth edition of the Diagnostic Statistical Manual of Mental Disorders (DSM-IV) published by the American Psychiatric Association (1994) and the tenth edition of the International Classification of Disease (ICD-10), published by the World Health Organisation (2003).

Vineland Adaptive Behavior Scales - II profile of young children with Autism Spectrum Disorder

Adaptive behaviour is a crucial area of assessment for individuals with Autism Spectrum Disorder (ASD). This study examined the adaptive behaviour profile of 77 young children with ASD using the Vineland-II, and analysed factors associated with adaptive functioning. Consistent with previous research with the original Vineland a distinct autism profile of Vineland-II age equivalent scores, but not standard scores, was found. Highest scores were in motor skills and lowest scores were in socialisation. The addition of the Autism Diagnostic Observation Schedule (ADOS) calibrated severity score did not contribute significant variance to Vineland-II scores beyond that accounted for by age and nonverbal ability. Limitations, future directions, and implications are discussed.

Post-school needs of young people with high-functioning Autism Spectrum Disorder

This study describes the post-school circumstances and service needs of older teenagers and adults with high-functioning Autism Spectrum Disorder, living in Queensland, Australia. The respondents were 95 parents. Results indicated that the majority of the young people lived in the family home and were unemployed. Of those who worked, 56% had unskilled jobs. They were estimated to spend a significant proportion of their time engaged in solitary, technology-based activities, and comparatively little time in employment or socialising. Parents rated employment support as the greatest service priority for their sons and daughters, followed by specialised support to assist with completing post-school education and training, assistance to support the transition from high school to adulthood, and social skills training.