These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

We are performing whole genome sequencing (WGS) of families with Autism Spectrum Disorder (ASD) to build a resource, named MSSNG, to enable the sub-categorization of phenotypes and underlying genetic factors involved. Here, we report WGS of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible in a cloud platform, and through an internet portal with controlled access. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertion/deletions (indels) or copy number variations (CNVs) per ASD subject. We identified 18 new candidate ASD-risk genes such as MED13 and PHF3, and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (p=6×10−4). In 294/2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried CNV/chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

Summary Brain enlargement has been observed in children with Autism Spectrum Disorder (ASD), but the timing of this phenomenon and its relationship to the appearance of behavioral symptoms is unknown. Retrospective head circumference and longitudinal brain volume studies of 2 year olds followed up at age 4 years, have provided evidence that increased brain volume may emerge early in development.1, 2 Studies of infants at high familial risk for autism can provide insight into the early development of autism and have found that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life3,4. These observations suggest that prospective brain imaging studies of infants at high familial risk for ASD might identify early post-natal changes in brain volume occurring before the emergence of an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that cortical surface area hyper-expansion between 6-12 months of age precedes brain volume overgrowth observed between 12-24 months in the 15 high-risk infants diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep learning algorithm primarily using surface area information from brain MRI at 6 and 12 months of age predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81%, sensitivity of 88%). These findings demonstrate that early brain changes unfold during the period in which autistic behaviors are first emerging.

OBJECTIVE Evidence from prospective high-risk infant studies suggests that early symptoms of autism usually emerge late in the first- or early in the second-year of life after a period of relatively typical development. This is the first neuroimaging study to prospectively examine white matter fiber tract organization during this interval in infants who develop autism spectrum disorder (ASD) by 24 months. METHOD Participants included 92 infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months, with a majority contributing additional imaging data at either or both 12 and 24 months. At 24 months, 28 infants met criteria for ASD; 64 infants did not. Microstructural properties of white-matter fiber tracts reported to be associated with ASD or related behaviors were characterized by fractional anisotropy (FA) and radial and axial diffusivity. RESULTS FA trajectories differed significantly between infants who did versus did not develop ASD for 12 of 15 fiber tracts. Development for most fiber tracts in infants with ASD was characterized by elevated FA at 6 months followed by slower developmental change overtime relative to infants without ASD. Thus, by 24 months of age, lower FA values were evident for those with ASD. CONCLUSION These results suggest that the aberrant development of white matter pathways precede the manifestation of autistic symptoms in the first year of life. Longitudinal data are critical to characterizing the dynamic age-related brain and behavior changes underlying this neurodevelopmental disorder.