Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits

An improved understanding of sterol and lipid abnormalities in individuals with autism spectrum disorder (ASD) could lead to personalized treatment approaches. Toward this end, in blood, we identified reduced synthesis of cholesterol in families with ≥2 children with ASD participating with the Autism Genetic Resource Exchange (AGRE), as well as reduced amounts of high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB), with 19.9% of the subjects presenting with apolipoprotein patterns similar to hypolipidemic clinical syndromes and 30% with either or both ApoA1 and ApoB less than the fifth centile. Subjects with levels less than the fifth centile of HDL or ApoA1 or ApoA1 + ApoB had lower adaptive functioning than other individuals with ASD, and hypocholesterolemic subjects had apolipoprotein deficits significantly divergent from either typically developing individuals participating in National Institutes of Health or the National Health and Nutrition Examination Survey III.

Rates of contributory de novo mutation in high and low-risk autism families

Autism arises in high and low-risk families. De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the simplex families than in their unaffected siblings. But the extent of contribution in low-risk families cannot be determined solely from simplex families as they are a mixture of low and high-risk. The rate of de novo mutation in nearly pure populations of high-risk families, the multiplex families, has not previously been rigorously determined. Moreover, rates of de novo mutation have been underestimated from studies based on low resolution microarrays and whole exome sequencing. Here we report on findings from whole genome sequence (WGS) of both simplex families from the Simons Simplex Collection (SSC) and multiplex families from the Autism Genetic Resource Exchange (AGRE). After removing the multiplex samples with excessive cell-line genetic drift, we find that the contribution of de novo mutation in multiplex is significantly smaller than the contribution in simplex. We use WGS to provide high resolution CNV profiles and to analyze more than coding regions, and revise upward the rate in simplex autism due to an excess of de novo events targeting introns. Based on this study, we now estimate that de novo events contribute to 52–67% of cases of autism arising from low risk families, and 30–39% of cases of all autism.

Measuring shared variants in cohorts of discordant siblings with applications to autism

We develop a method of analysis [affected to discordant sibling pairs (A2DS)] that tests if shared variants contribute to a disorder. Using a standard measure of genetic relation, test individuals are compared with a cohort of discordant sibling pairs (CDS) to derive a comparative similarity score. We ask if a test individual is more similar to an unrelated affected than to the unrelated unaffected sibling from the CDS and then, sum over such individuals and pairs. Statistical significance is judged by randomly permuting the affected status in the CDS. In the analysis of published genotype data from the Simons Simplex Collection (SSC) and the Autism Genetic Resource Exchange (AGRE) cohorts of children with autism spectrum disorder (ASD), we find strong statistical significance that the affected are more similar to the affected than to the unaffected of the CDS (P value ∼ 0.00001). Fathers in multiplex families have marginally greater similarity (P value = 0.02) to unrelated affected individuals. These results do not depend on ethnic matching or gender.