"There is broad parent interest in a genetic/epigenetic test for ASD"

The quote heading this post - "There is broad parent interest in a genetic/epigenetic test for ASD [autism spectrum disorder]" - comes from the findings reported by Kayla Wagner and colleagues [1]. As per the observation that most parents of those diagnosed with an ASD, or developmental delay (DD) or asymptomatic controls "had positive perceptions toward genetic/epigenetic research in ASD", far from being the 'danger' that it is sometimes portrayed as, the science of genetics seems to have an important standing among many parents.

The Wagner results came about as a result of this research group publishing studies "that demonstrate the utility of RNA sequencing technology (non-coding RNA) to identify children with ASD." They did what few genetic studies have done: asked parents participating in their studies whether what they were doing/finding was of interest to them. This was achieved via the use of a questionnaire which included six themes: "(1) reasons for participating in the epigenetic study; (2) prior knowledge of genetics/epigenetics, and the source of this information; (3) overall interest in genetic/epigenetic testing for ASD; (4) concerns about genetic/epigenetic testing for ASD; (5) preferences about the approach for genetic/epigenetic testing (including age of administration and biofluid of choice); and (6) extent of results to be returned." You'll probably have noted that alongside their use of the term 'genetics' they also talk about a still up-and-coming branch of genetics called epigenetics. I've talked about epigenetics and autism before on this blog (see here and see here) but the description Wager et al use just about says it all: "changes in gene expression, where the changes are not due to modification of the actual DNA sequence, but instead result from modifications that regulate DNA structure and expression." Gene expression seems to be particularly important to the science of epigenetics as per the notion that we don't all walk around with all our genes permanently switched to the 'on' or 'off' position.

Results: quite a few important points emerged from the obtained data. Most parents understood at least a little bit about genetics and some of the processes involved. Epigenetics wasn't as well known about or understood (something which is probably not so surprising). Other points also emerged: "There were no parents (0%, 0/244) concerned about a lack of scientific evidence supporting genetic and epigenetics." But that's not to say that some parents weren't concerned about the implications of genetics and epigenetics, as mention about issues like privacy and insurance status were raised during the Wagner study.

Also: "Nearly all parents (96%, 235/244) indicated that if there were genetic testing for ASD, they were interested in learning results about their child’s risk for ASD." And when it came to results, over three-quarters of all parents expressed a preference for "all epigenetic/genetic results, regardless of whether they were implicated in health and disease" and not just an overview or interpretation of any results. People want data not overviews.

And then to some important but potentially controversial findings: "The majority of parents (71%, 164/231) desired results of a genetic/epigenetic test for ASD when their child was 12 months of age or younger. Over half of parents were interested in receiving results at conception (34%, 78/231) or at birth (37%, 86/231), while fewer requested results at 12 months (17%, 40/231) or at 2 years of age (12%, 27/231)." You can perhaps see where this might be going - particularly 'receiving results at conception' - even if the authors seem to have chosen not to pursue it any further in their discussions.

I'm no bioethicist and so am nowhere near qualified to talk about the ins-and-outs of genetic testing in the context of autism and what implications this could have. I note other commentators have approached this subject previously based on some of the peer-reviewed science in this area (see here) and various points have been raised. One of the important things to bear in mind is that, as it currently stands, there is no single genetic test for all autism. Indeed, allied to the idea that the concept of 'a universal autism gene' is fast becoming a distant memory, genetic studies are serving to further highlight how complex autism actually is.

But there is always the possibility that some day someone will potentially deliver a genetic/epigenetic 'test for some autism'. The question then is how will it be used? What checks and balances will be in place to ensure that it is not misused?

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[1] Wagner KE. et al. Parent Perspectives Towards Genetic and Epigenetic Testing for Autism Spectrum Disorder. Journal of Autism & Developmental Disorders. 2019. March 22.

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Prenatal hormone involvement in autism risk?

The findings reported by Gayle Windham and colleagues [1] caught my eye recently and their observations based on the examination of mid-pregnancy serum hormone and protein markers for some 2500 mothers of children diagnosed with an autism spectrum disorder (ASD) compared with 600,000 controls.

Detailing results based on: "Second trimester levels of unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and maternal serum alpha-fetoprotein (MSAFP)", researchers reported that their results: "further support prenatal hormone involvement in ASD risk."

I perhaps need to do a little 'defining' before progressing any further with this post. Unconjugated estriol (uE3) refers to an estrogen. It becomes the dominant oestrogen during pregnancy; produced by the baby's liver and placenta. Measured levels of uE3 during the 2nd trimester of pregnancy have been linked to various 'outcomes' including the possibility of Down's syndrome and neural tube defects.

Human chorionic gonadotropin (hCG) is another hormone; one that is normally used to confirm pregnancy. During pregnancy, levels of hCG can also be used to determine Down's syndrome. Serum alpha-fetoprotein (MSAFP) is the most abundant plasma protein found in the developing foetus. During pregnancy, extremes in levels of MSAFP can indicate issues in pregnancy. Combined together, these various hormones/proteins make up the so-called triple test, that when added to information such as maternal age and stage of pregnancy, can classify a pregnancy as being high or low risk for chromosomal abnormalities. That being said, the test is by no means perfect.

Windham et al report some rather complicated results based on adjusted odds ratios (AOR) when it came to autism vs control samples. So: "Lower uE3 (AOR for < 10th percentile vs. 25th-74th percentiles = 1.21, 95 % CI 1.06-1.37), and higher MSAFP (AOR = 1.21, 95 % CI 1.07-1.37 for > 90th percentile) were significantly associated with ASD. A U-shaped relationship was seen for hCG (AOR = 1.16, 95 % CI 1.02-1.32 for < 10th percentile; AOR = 1.19, 95 % CI 1.05-1.36 for > 90th percentile)." Lower uE3 is a trend found in relation to Down's syndrome. Higher MSAFP however runs slightly counter to what has been discussed in relation to Down's syndrome. By contrast, elevations in MSAFP tend to be more readily linked to pregnancies where neural tube defects may be present. What this all means is that yes, these results could indicate the involvement of prenatal hormones and chromosomal issues in relation to 'some' autism, but science still needs to go a little way before anyone talks about a triple test being applied to autism (and the ethical issues that this might bring).

I think it's also worthwhile briefly bringing in a few caveats to such pregnancy testing that could be pertinent to other autism research findings. As per other information, a mother's weight during pregnancy can affect what results you get - "Serum marker levels tend to be decreased in heavier women, and increased in lighter women." If you map this on to the research talking about maternal obesity linked to some autism (being careful not to generalise here), you can see how adjustments might have been / have to be made. Ethnicity is another factor that needs to be kept in mind. Also: "AFP and uE3 levels tend to be low (about 8% and 6% respectively) in women with insulin dependent diabetes mellitus." This is particularly interesting in view of the quite consistent literature detailing how gestational diabetes seems to show a connection to risk of offspring autism (see here). Various other factors (vaginal bleeding) can similarly affect results.

The Windham results are nevertheless interesting and are strengthened somewhat by the large participant numbers included for study. That other groups have similarly talked about elevations in MSAFP in relation to autism [2] increases the confidence that there may something further to see in this area, at least for some autism.

Music: Al Green - Tired of Being Alone.

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[1] Windham GC. et al. Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California. J Autism Dev Disord. 2015 Sep 14.

[2] Abdallah MW. et al. Autism spectrum disorders and maternal serum α-fetoprotein levels during pregnancy. Can J Psychiatry. 2011 Dec;56(12):727-34.

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Windham GC, Lyall K, Anderson M, & Kharrazi M (2015). Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California. Journal of autism and developmental disorders PMID: 26370672

Prenatal genetic testing and autism: a delicate subject

I realise that the paper by Lei-Shih Chen and colleagues [1] covers a most sensitive topic when it comes to the autism spectrum, exploring: "the attitudes toward PGT [prenatal genetic testing] and termination decisions of 42 parents of children with ASD [autism spectrum disorder]". Indeed, this is not the first time that this research group has looked at this area of autism research [2] and it seems like they will be talking about it further too (see here).

I chose to discuss the most recent paper on this blog because (a) the Chen paper is peer-reviewed science, (b) the likelihood of PGT being 'applied to autism' at some point in the future is growing (if not here in some parts of the world?), and (c) similar to the screening tests available for conditions like Down's syndrome (see here), there are going to be conversations to be had about the decisions and choices potentially offered to parents on the basis of any screening results. Charities here in the UK such as Antenatal Results and Choices (ARC) are probably going to figure in those conversations which, in some quarters, have already begun to happen (see here). I write this blog from a cold, scientific perspective so please don't get offended by some of the discussions.

The Chen paper describes the results of a qualitative study where parents of children with ASD were given "a hypothetical scenario" regarding PGT and asked their hypothetical response to using PGT and their hypothetical response to a positive test response. "Of the 31 parents who were either willing or unsure about undergoing the PGT, approximately three-fourths would continue their hypothetical affected pregnancies".

A few things struck me about the Chen paper. First is a line introducing the abstract which reads: "In the United States, prenatal genetic testing (PGT) for Autism Spectrum Disorders (ASD) is currently available via clinical genetic services". I was quite taken aback by this sentence. As far as I was aware science was still feeling around as to the underlying genetics of autism (that is, if you consider autism to be a unitary concept rather than a more plural condition and to be solely driven by structural genetics over and above environmental factors or epigenetic changes). If someone is suggesting otherwise, please do point me towards the peer-reviewed science for that prenatal genetic test outside of something like just screening for Fragile X syndrome [3] or the preliminary results reported by Wapner and colleagues [4] mentioned with autism in mind...

The next thing that caught my eye was the high number of parents who, if faced with the hypothetical PGT situation, said they would continue with their pregnancy. I'm not so surprised at this, given that researchers were asking parents who already had a child with autism and so perhaps knew a little bit about both the good and not-so-good times which go with raising a child with a developmental disability. I also emphasise the word 'child' there before their condition/label. If the questions were put to parents with no personal experience of autism, one wonders whether similar outcomes would have been reported. Likewise if parents were for example, offered differing scenarios under such experimental conditions with other conditions outside of autism, such as Down's syndrome, the question remains about what results might have shown also bearing in mind the literature in this area [5].

Finally, and I again tread very carefully with this, was the observation that: "Parents who reported they would terminate the affected pregnancy in this hypothetical situation were primarily Asians". I go to great lengths on this blog not to over-generalise autism research such that not every finding has to apply to every single person with autism. In this instance I'd also point out that the sample size for the Chen results was very small and outside of cultural differences and representations [6], one similarly cannot assume that every person/parent of Asian origin is going to report like this. Neither however should judgement be passed on those parents who did choose this hypothetical option and the road(s) which might have led them to this hypothetical decision. This might however suggest that as per other examples, autism is looked at in very different ways according to factors such geography and culture.

As I mentioned at the top of this post, prenatal testing (genetic or otherwise) is always going to be a sensitive subject when applied to autism and will inevitably stir up considerable emotions for many people, not least those who are themselves on the autism spectrum. I'm going to leave you with some more discussion about this area from Prof. Andrew Whitehouse - he of the 'Is autism one or multiple disorders?' paper - and a very sensible post he wrote (see here) which covers most of the important issues well.

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[1] Chen LS. et al. Autism Spectrum Disorders: A Qualitative Study of Attitudes toward Prenatal Genetic Testing and Termination Decisions of Affected Pregnancies. Clin Genet. 2014 Sep 24.

[2] Chen LS. et al. Autism genetic testing: a qualitative study of awareness, attitudes, and experiences among parents of children with autism spectrum disorders. Genet Med. 2013 Apr;15(4):274-81.

[3] Gutiérrez JF. et al. Prenatal screening for fragile x: carriers, controversies, and counseling. Rev Obstet Gynecol. 2013;6(1):e1-7.

[4] Wapner RJ. et al. Chromosomal Microarray versus Karyotyping for Prenatal Diagnosis. NEJM. 2012; 367: 2175-2184.

[5] Scott CJ. et al. Prenatal diagnosis and termination of pregnancy: perspectives of South African parents of children with Down syndrome. J Community Genet. 2013 Jan;4(1):87-97.

[6] Bie B. & Tang L. Representation of Autism in Leading Newspapers in China: A Content Analysis. Health Commun. 2014 Jul 29:1-10.

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Chen LS, Xu L, Dhar SU, Li M, Talwar D, & Jung E (2014). Autism Spectrum Disorders: A Qualitative Study of Attitudes toward Prenatal Genetic Testing and Termination Decisions of Affected Pregnancies. Clinical genetics PMID: 25251361