Severity of ASD symptoms and their correlation with the presence of copy number variations and exposure to first trimester ultrasound

Abstract

Scientific Abstract Current research suggests that incidence and heterogeneity of autism spectrum disorder (ASD) symptoms may arise through a variety of exogenous and/or endogenous factors. While subject to routine clinical practice and generally considered safe, there exists speculation, though no human data, that diagnostic ultrasound may also contribute to ASD severity, supported by experimental evidence that exposure to ultrasound early in gestation could perturb brain development and alter behavior. Here we explored a modified triple hit hypothesis (Williams & Casanova 2010) to assay for a possible relationship between the severity of ASD symptoms and (1) ultrasound exposure (2) during the first trimester of pregnancy in fetuses with a (3) genetic predisposition to ASD. We did so using retrospective analysis of data from the SSC (Simon's Simplex Collection) autism genetic repository funded by the Simons Foundation Autism Research Initiative. We found that male children with ASD, copy number variations (CNVs) and exposure to first trimester ultrasound had significantly decreased non-verbal IQ and increased repetitive behaviors relative to male children with ASD, with CNVs and no ultrasound. These data suggest that heterogeneity in ASD symptoms may result, at least in part, from exposure to diagnostic ultrasound during early prenatal development of children with specific genetic vulnerabilities. These results also add weight to on-going concerns expressed by the FDA about non-medical use of diagnostic ultrasound during pregnancy. Lay Abstract Variations in autism spectrum disorder (ASD) may arise through both internal and external factors. Diagnostic ultrasound is used in routine clinical practice and is generally considered safe during pregnancy. However animal models suggest that ultrasound could contribute to ASD severity as ultrasound early in prenatal development may alter brain development and behavior. We test for a possible relationship between the severity of ASD symptoms and (1) ultrasound exposure (2) during the first trimester of pregnancy in fetuses with a (3) genetic predisposition to ASD. We used data from the SSC (Simon's Simplex Collection) autism genetic repository funded by the Simons Foundation Autism Research Initiative. We found that male children with ASD and copy number variations (CNVs), which is a type of genetic vulnerability, and exposure to first trimester ultrasound had decreased non-verbal IQ and increased repetitive behaviors compared to male children with ASD and CNVs but no ultrasound. These data suggest that variation in ASD symptoms may result from exposure to diagnostic ultrasound during early prenatal development of children with specific genetic vulnerabilities. These results also add weight to on-going concerns expressed by the FDA about non-medical use of diagnostic ultrasound during pregnancy.

The joint effect of air pollution exposure and copy number variation on risk for autism

“…No interactions were observed for other air pollutants, even those that demonstrated main effects; ozone tends to be negatively correlated with the other pollutants examined. While earlier work has demonstrated interactions between the presence of a pathogenic CNV and an environmental exposure [Webb et al, 2016], these findings appear to be the first indication that global copy number variation may increase susceptibility to certain environmental factors, and underscore the need to consider both genomics and environmental exposures as well as the mechanisms by which each may amplify the risks for autism associated with the other.…”

Is Excessive Prenatal Ultrasonography a Risk Factor for Autism? A Literature Review

“…In July 2016, Webb et al 73 retrospectively analyzed a modification of Casanova's hypothesis by analyzing a possible association between ASD severity and PUS exposure within the first trimester of pregnancy with fetuses genetically predisposed to ASD. Genetic predisposition was determined, based on the presence or absence of ASD-associated copy number variations (CNVs) with structural duplications or deletions of deoxyribonucleic acid (DNA) base pairs in the genome sequence.…”

Ultrasound and Autism Spectrum Disorder

“…A recent study 1 has suggested that heterogeneity of autism spectrum disorder (ASD) may, in part, result from exposure to early ultrasound in genetically vulnerable children.…”

“…Just over 60% recalled having at least one ultrasound in the first trimester and in those children there was a statistically significant increase in one metric of parent-reported repetitive behaviours compared to unexposed children, but no difference, or one improvement, in nine other metrics of cognitive ability, social affective behaviours or repetitive behaviours. 1 There were 133 children (7.6% of the initial cohort) with ASD-associated copy number variants. In those exposed to first trimester ultrasound there was a statistically significant decrease in non-verbal IQ and, in boys only, an increase in one metric of repetitive behaviour compared to unexposed children, but no difference on the other eight metrics.…”

“…In those exposed to first trimester ultrasound there was a statistically significant decrease in non-verbal IQ and, in boys only, an increase in one metric of repetitive behaviour compared to unexposed children, but no difference on the other eight metrics. 1 The methodological concerns raised by this study include reliance on parental recall, lack of detail regarding ultrasound exposure, lack of appropriate (sibling) control group, possible confounding factors were not taken into account, regression analysis was undertaken without appropriate significance level correction for multiple comparisons (the results are not significant at the 5% level with a Bonferroni correction 10 ). Given the high risk of bias and statistical inaccuracy in this study, the conclusions are unjustified and the criteria for causation are not met.…”