Autism, Genetic Risk Factors, & Ultrasound


It’s been a few months since the paper by Webb et al. (2016) came out, reporting a possible link between first trimester ultrasound exposure and increased autism severity in those individuals with rare copy number variations (CNV). If you’re a follower of this blog, you may already be familiar with my and my husband’s stance on ultrasound safety in the United States and potential risk for neurodevelopmental conditions. I can tell you that from a research standpoint, it’s a taboo subject: few people in medicine, science, or even the media are interested in considering the possibility that prenatal ultrasound may be more risky than we once thought. (A science writer from Forbes tried to tear down the recent article, although I was unimpressed with her inexpert arguments, which the original authors graciously and professionally answered in the Comments section.)

In a previous blog several years ago I gave a mini-course on Ultrasound Biology 101. If you’re interested in the background I highly recommend a read. However, here I’m going to delve into the study itself, followed by a description of one of our upcoming collaborative projects with the folks at University of Washington to expand their findings and, if positive, lend credence to our calls for more stringent regulations on prenatal ultrasound use.

Method Summary

Webb et al. accessed data contained within the Simons Simplex Collection (SSC). This is a database full of clinical and genetic data on single-incidence autism families. The team weeded out all the probands who didn’t have ultrasound history, who hadn’t gone through genetic testing, or who didn’t have the necessary battery of behavioral and cognitive test results. This left them with a group total of 1,749 people to study.

From this data, they were able to look at the relationship (co-variance) between:

  1. symptom severity as gauged by behavioral/cognitive test results
  2. the presence of CNVs
  3. exposure to first trimester ultrasound

Autism Incidence Vs. Autism Severity

Before I delve into the results, I have to say one of the great things about this paper is that it doesn’t look at autism incidence at all. That’s been a huge problem in studies like Grether et al. (2010). Instead, they looked at differences in autism severity. And though the numbers are small (let’s face it, rare CNVs are called “rare” for a reason), there are still some significant differences across groups in relation to early ultrasound exposure.

So, What’s All the Hubbub?

Although the authors didn’t mention it in the abstract, they did identify a relationship between first trimester ultrasound exposure and poorer social affective scores/higher restricted and repetitive behaviors across the entire group, regardless of the presence of CNVs. This suggests that early ultrasound exposure may increase risk for autism severity across a wide variety of genetic backgrounds. Further study is needed, however, to determine if this is the case.

Webb et al. went on to study 133 cases with CNVs (males and females), some of whom had first trimester ultrasound exposure and the rest who did not. They found that there was a significant relationship between CNVs, early exposure, and symptom severity. In particular, the researchers discovered that individuals with CNVs who had been exposed to ultrasound within the first trimester tended to have lower nonverbal IQ scores compared to those with CNVs who hadn’t been exposed.

When the investigators went on to study the 111 males with CNVs, they found similar results as above. In addition, however, they also found that males with CNVs/early exposure exhibited significantly more restricted/repetitive behaviors than those without exposure. (Females in the SSC tend to have lower restricted/repetitive behavior scores than the males, suggesting this measurement may not be especially sensitive for gauging complex effects in females.[1])

The authors also addressed potential statistical issues related to reliability of parental reporting (e.g., maternal recall), none of which significantly affected the final results.

Why Focus on Males, You Ask?

Unfortunately, there is an extreme male bias in both the SSC and autism in general; therefore, researchers often restrict their studies to a single sex (males) when numbers are small. It’s also in an effort to homogenize their samples as much as possible.

However, researchers often study SSC males for another reason: boys who don’t have rare loss-of-function mutations have significantly higher nonverbal IQs than males with these kinds of mutations (see below). Meanwhile, there’s no significant difference in nonverbal IQ in females regardless of gene background. So, males in the SSC have become a popular focus for genetics studies because they split into two subgroups that appear to be driven in large part by their divergent genetic backgrounds.

Screen Shot 2016-10-30 at 4.52.32 PM.png

Future Directions

Currently we’re starting a collaborative project with the University of Washington to hopefully extend these results a bit further. Since much of my work of the last few years has been focused on investigating trends in functional enrichment across risk genes, I had proposed to Sara Webb that we look at potential trends in functional gene enrichment across CNVs according to symptom severity.

If we do ultimately find significant enrichment trends linked with severity, that may help us determine if there are subgroups of individuals with specific types of mutations that are more vulnerable to early ultrasound exposure. If we can then expand this to mutations in functionally overlapping gene classes through protein interaction network analysis, this could allow us to predict what types of gene mutations may predispose towards vulnerability to ultrasound exposure. That in turn could lead to genetic testing in early pregnancy, which may help the doctor determine whether the use of ultrasound is safe or not. Personalized Medicine FTW.*

This is how science works. You don’t throw away a tool simply because you didn’t know how to use it properly. Ultrasound will undoubtedly fulfill an important role in obstetric care for a long time to come. But with better research comes the ability to refine its use so that safety and quality of life can be maximized.

*As a much simpler solution, we could just avoid ultrasound altogether within the first trimester, since it’s typically only used for pregnancy confirmation and dating, neither of which pose significant threat to the fetus.

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