We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype–phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that occurs within the first 3 years of life, which is marked by social skills and communication deficits along with stereotyped repetitive behavior. Although great efforts have been made to clarify the underlying neuroanatomical abnormalities and brain-behavior relationships in adolescents and adults with ASD, literature is still limited in information about the neurobiology of ASD in the early age of life. Brain images of 50 toddlers with ASD and 28 age, gender, and developmental quotient matched toddlers with developmental delay (DD) (control group) between ages 2 and 3 years were captured using combined magnetic resonance-based structural imaging and diffusion tensor imaging (DTI). Structural magnetic resonance imaging was applied to assess overall gray matter (GM) and white matter (WM) volumes, and regional alterations were assessed by voxel-based morphometry. DTI was used to investigate the white matter tract integrity. Compared with DD, significant increases were observed in ASD, primarily in global GM and WM volumes and in right superior temporal gyrus regional GM and WM volumes. Higher fractional anisotropy value was also observed in the corpus callosum, posterior cingulate cortex, and limbic lobes of ASD. The converging findings of structural and white matter abnormalities in ASD suggest that alterations in neural-anatomy of different brain regions may be involved in behavioral and cognitive deficits associated with ASD, especially in an early age of 2–3 years old toddlers.

Response inhibition, an important domain of executive function (EF), involves the ability to suppress irrelevant or interfering information and impulses. Previous studies have shown impairment of response inhibition in high functioning autism (HFA) and attention deficit hyperactivity disorder (ADHD), but more recent findings have been inconsistent. To date, almost no studies have been conducted using functional imaging techniques to directly compare inhibitory control between children with HFA and those with ADHD. Nineteen children with HFA, 16 age- and intelligence quotient (IQ)-matched children with ADHD, and 16 typically developing (TD) children were imaged using functional near-infrared spectroscopy (NIRS) while performing Go/No-go and Stroop tasks. Compared with the TD group, children in both the HFA and ADHD groups took more time to respond during the No-go blocks, with reaction time longest for HFA and shortest for TD. Children in the HFA and ADHD groups also made a greater number of reaction errors in the No-go blocks than those in the TD group. During the Stroop task, there were no significant differences between these three groups in reaction time and omission errors. Both the HFA and ADHD groups showed a higher level of inactivation in the right prefrontal cortex (PFC) during the No-go blocks, relative to the TD group. However, no significant differences were found between groups in the levels of oxyhemoglobin concentration in the PFC during the Stroop task. Functional brain imaging using NIRS showed reduced activation in the right PFC in children with HFA or ADHD during an inhibition task, indicating that inhibitory dysfunction is a shared feature of both HFA and ADHD.

Earlier studies have suggested abnormal brain volumes in autism, but inconsistencies exist. Using voxel-based morphometry, we compared global and regional brain volumes in 17 high-functioning autistic children with 15 matched controls. We identified significant reduction in left white matter volume and white/gray matter ratio in autism. Regional brain volume reductions were detected for right anterior cingulate, left superior parietal lobule white matter volumes, and right parahippocampal gyrus gray matter volume, whereas enlargements in bilateral supramarginal gyrus, right postcentral gyrus, right medial frontal gyrus, and right posterior lobe of cerebellum gray matter in autism. Our findings showed global and regional brain volumes abnormality in high-functioning autism.