Genomic landscapes of Chinese sporadic autism spectrum disordersrevealed by whole-genome sequencing

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity.In this study,we identified all classes of genomic variants from whole-genome sequencing (WGS) dataset of 32 Chinese trios with ASD,including de novo mutations,inherited variants,copy number variants (CNVs) and genomic structural variants.A higher mutation rate (Poisson test,P<2.2×10^(-16)) in exonic (1.37×10^(-8)) and 3'-UTR regions (1.42×10^(-8)) was revealed in comparison with that of whole genome (1.05×10^(-8)).Using an integrated model,we identified 87 potentially risk genes (P<0.01) from 4832 genes harboring various rare deleterious variants,including CHD8 and NRXN2,implying that the disorders may be in favor to multiple-hit.In particular,frequent rare inherited mutations of several microcephaly-associated genes (ASPM,WDR62,and ZNF335)were found in ASD.In chromosomal structure analyses,we found four de novo CNVs and one de novo chromosomal rearrangement event,including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1,which causes Angelman syndrome and microcephaly,and a disrupted TNR due to de novo chromosomal translocation t (1;5) (q25.1;q33.2).Taken together,our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes may be implicated in pathogenesis of ASD.Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum in complex disorders,such as ASD,could provide novel insights into pathogenesis,diagnosis and treatment.

Prevalence of Autism Spectrum Disorder in China:A Nationwide Multi-center Population-based Study Among Children Aged 6 to 12 Years

This study aimed to obtain the first national estimate of the prevalence of autism spectrum disorder(ASD) in Chinese children.We targeted the population of 6 to 12-year-old children for this prevalence study by multistage convenient cluster sampling.The Modified Chinese Autism Spectrum Rating Scale was used for the screening process.Of the target population of 142,086 children,88.5%(n=125,806) participated in the study.A total of 363 children were confirmed as having ASD.The observed ASD prevalence rate was 0.29%(95% CI:0.26%-0.32%) for the overall population.After adjustment for response rates,the estimated number of ASD cases was867 in the target population sample,thereby achieving an estimated prevalence of 0.70%(95% CI:0.64%-0.74%).The prevalence was significantly higher in boys than in girls(0.95%;95% CI:0.87%-1.02% versus 0.30%;95%CI:0.26%-0.34%;P <0.001).Of the 363 confirmed ASD cases,43.3% were newly diagnosed,and most of those(90.4%) were attending regular schools,and 68.8% of the children with ASD had at least one neuropsychiatric comorbidity.Our findings provide reliable data on the estimated ASD prevalence and comorbidities in Chinese children.

Modifying the Autism Spectrum Rating Scale(6–18 years)to a Chinese Context:An Exploratory Factor Analysis

The purpose of this study was to explore the psychometric properties of the Chinese version of the autism spectrum rating scale（ASRS）. We recruited 1,625community-based children and 211 autism spectrum disorder（ASD） cases from 4 sites, and the parents of all participants completed the Chinese version of the ASRS. A robust weighted least squares means and variance adjusted estimator was used for exploratory factor analysis. The3-factor structure included 59 items suitable for the current sample. The item reliability for the modi？ed Chinese version of the ASRS（MC-ASRS） was excellent. Moreover,with 60 as the cut-off point, receiver operating characteristic analysis showed that the MC-ASRS had excellent discriminate validity, comparable to that of the unmodi？ed Chinese version（UC-ASRS）, with area under the curve values of 0.952（95% CI： 0.936–0.967） and 0.948（95% CI：0.930–0.965）, respectively. Meanwhile, the con？rm factor analysis revealed that MC-ASRS had a better construct validity than UC-ASRS based on the above factor solution in another children sample. In conclusion, the MC-ASRS shows better ef？cacy in epidemiological screening for ASD in Chinese children.

Chinese Norms for the Autism Spectrum Rating Scale

This study aimed to establish norms for the modi？ed Chinese version of the Autism Spectrum Rating Scale（ASRS）. Participants were recruited from Shanghai,Harbin, Guangzhou, and Changsha, China, and their parents and teachers were invited to complete the Chinese Parent version and the Teacher version of the ASRS. In both versions, boys had signi？cantly higher sub-scale scores and total score（T-score） by 1–3 and 4–5 points respectively, than girls（both P ／ 0.001）. Age had weak correlations with some sub-scores and the T-score（r ranged from-0.1859 to 0.0738）, and some reached signi？cance（P ／ 0.03）. The correlations appeared stronger and were more common in females. The T-score based on Chinese norms ideally correlated with the score based on the United States norms in boys and girls for both versions.Norms for the Chinese version of the ASRS for children aged 6–12 years are proposed and may be helpful for screening individuals with autism spectrum disorders from the general population of children.

Cellular and Circuitry Bases of Autism:Lessons Learned from the Temporospatial Manipulation of Autism Genes in the Brain

Transgenic mice carrying mutations that cause Autism Spectrum Disorders（ASDs） continue to be valuable for determining the molecular underpinnings of the disorders. Recently, researchers have taken advantage of such models combined with Cre-lox P and similar systems to manipulate gene expression over space and time. Thus, a clearer picture is starting to emerge of the cell types, circuits, brain regions, and developmental time periods underlying ASDs. ASD-causing mutations have been restricted to or rescued speci？cally in excitatory or inhibitory neurons, different neurotransmitter systems, and cells speci？c to the forebrain or cerebellum. In addition,mutations have been induced or corrected in adult mice,providing some evidence for the plasticity and reversibility of core ASD symptoms. The limited availability of Cre lines that are highly speci？c to certain cell types or time periods provides a challenge to determining the cellular and circuitry bases of autism, but other technological advances may eventually overcome this obstacle.