Functional impact of global rare copy number variation in autism spectrum disorders.

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

A genome-wide scan for common alleles affecting risk for autism.

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

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.

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.

Development and Initial Utility of the Autism Clinical Interview for Adults: A New Adult Autism Diagnostic Measure.

Background: Clinicians use diagnostic interviews to help them gather and organize information collected in the assessment of autism. Most instruments are developed for children and few measures have been developed that are reliable, valid, and appropriate for use in adulthood. This is a significant barrier to providing a high-quality, timely service for adults. The aim of this development study was to assess the initial utility of the recently developed Autism Clinical Interview for Adults (ACIA) for use in autism diagnostic clinical services before further large-scale testing and evaluation. Methods: We invited adults who had received an autism spectrum diagnosis through a U.K. National Health Service (NHS) multidisciplinary adult autism assessment to participate. Seventeen autistic adults (8 women and 9 men, mean age of 37 years) and four relatives agreed to an interview. The semistructured ACIA interview comprises subject and informant versions, and a self-report preinterview questionnaire. In combination, the ACIA components cover topics relevant to autism and co-occurring condition assessment. We evaluated clinical utility and content validity via comparison with the Diagnostic and Statistical Manual Fifth Edition (DSM-5) and NHS diagnostic reports. Results: Each interview took between 60 and 90 minutes to complete. Comparison with DSM-5 and the NHS autism diagnostic report demonstrated that the ACIA accurately identified information on core autism characteristics needed for a diagnosis, and identified co-occurring conditions. In response to participant suggestions we revised the interview. Conclusions: These initial findings support the potential utility and validity of the ACIA for adult autism diagnostic clinical services. Further investigations of the acceptability, utility, and validity of this interview are planned. Lay summary: Why was this study done?: Clinicians use diagnostic interviews during assessments to help gather and record information both from a person suspected to be on the autism spectrum and from an informant (someone who knows them well). However, most autism diagnostic interviews were originally developed for assessing autism in childhood, and few have been developed for use with adults. The lack of diagnostic interviews developed specifically for use with adults makes it difficult to provide a good-quality, consistent assessment.What was the purpose of this study?: The study tested a new semistructured diagnostic interview called the Autism Clinical Interview for Adults (ACIA). The ACIA includes a questionnaire for people to complete before their interview. This is followed by an interview that can be conducted with the person themselves and a separate version to be used with someone who knows them well (if permitted). The interview covers autism traits, strengths and difficulties, and co-occurring physical and mental health conditions. We wanted to find out if the interview is useful for autism diagnostic services by comparing information collected using the ACIA with clinical diagnostic reports.What did the researchers do?: We invited people who had received a diagnosis of autism from a U.K. National Health Service (NHS) assessment to take part in an interview. We asked them if we could also interview someone who knew them well, and if we could compare their NHS autism diagnostic report with information gathered using the ACIA.What were the results of the study?: Seventeen autistic adults (average age 37 years; 8 women and 9 men) and 4 relatives/supporters (2 parents, a spouse, and a cohabiting partner) agreed to be interviewed. Each interview took 60 to 90 minutes to complete. A comparison with clinical reports showed the ACIA identified autism traits relevant for a diagnosis, as well as co-occurring conditions (e.g., depression). Participants suggested some ways to improve the interview, and revisions were made.What do these findings add to what is already known?: There are few diagnostic interviews designed specifically for use with adults seeking a diagnosis of autism. The findings from this study show that the ACIA is a promising new interview.What are the potential weaknesses of the study?: The study is small. However, it is important to run an initial test study before involving more people and resources in larger studies. Building on these results, we aim to undertake further studies on the acceptability and usefulness of the new interview with a larger number of people, including people from a range of backgrounds.How will these findings help autistic people now or in the future?: The ACIA has potential for use in adult autism clinical assessment services and as a resource for research and training. The semistructured format helps gather important and relevant information, and the interview length supports feasibility in clinical and research settings. The ACIA has the potential to streamline autism assessments and speed up the process for adults who currently wait a long time for their diagnosis.

Psychometric properties of questionnaires and diagnostic measures for autism spectrum disorders in adults: A systematic review.

Accurately diagnosing autism spectrum disorders in adulthood can be challenging. Structured questionnaires and diagnostic measures are frequently used to assist case recognition and diagnosis. This study reviewed research evidence on structured questionnaires and diagnostic measures published since the National Institute for Health and Care Excellence evidence update. The Cochrane library, Medline, Embase and PsycINFO were searched. In all, 20 studies met inclusion criteria. Sensitivity and specificity of structured questionnaires were best for individuals with previously confirmed autism spectrum disorder diagnoses and reduced in participants referred for diagnostic assessments, with discrimination of autism spectrum disorder from mental health conditions especially limited. For adults with intellectual disability, diagnostic accuracy increased when a combination of structured questionnaires were used. Evidence suggests some utility of diagnostic measures in identifying autism spectrum disorder among clinic referrals, although specificity for diagnosis was relatively low. In mental health settings, the use of a single structured questionnaire is unlikely to accurately identify adults without autism spectrum disorder or differentiate autism spectrum disorder from mental health conditions. This is important as adults seeking an autism spectrum disorder diagnostic assessment are likely to have co-existing mental health conditions. Robust autism spectrum disorder assessment tools specifically for use in adult diagnostic health services in the presence of co-occurring mental health and neurodevelopmental disorders are a research priority.