Rare genetic condition manifesting as autism and its management

"We report the case of a young boy with nonverbal autism and intellectual disability, with a rare de novo 1q21.3 microdeletion."

That was the starting point of the article published by Cora Cravero and colleagues [1] (open-access available here). Researchers describe in some detail how a diagnosis of autism spectrum disorder (ASD) was made "on communication and social interaction impairments and restricted, repetitive patterns of behaviour and interests" and what followed: "The patient had early and extreme self-injurious behaviours that led to blindness, complicated by severe developmental regression."

Detailing how "comparative genomic hybridization array identified a de novo 1.4 Mb microdeletion of chromosome 1q21.3" and various associated physiological findings, the Cravero report provides some rather intriguing evidence that the sentence 'science does not know what causes autism' might not necessarily ring true for everyone (see here for other examples). As the authors note: "The 1q21.3 microdeletion seems associated with ID [intellectual disability], dysmorphic features, and early SIB [self-injurious behaviour] and can be a cause of syndromic autism."

One or two particular details are noteworthy in the Cravero findings outside of the idea that the N=1 might be an important concept in relation to the autism spectrum.

First, is the quite extreme effects that self-injurious behaviour (SIB) in the context of autism can have on a person. This child was blinded by their extreme SIB: "intense and repeated mutilations of cheekbones and eyes, culminating in a bilateral blindness at the age of 4 years by intumescent white cataract after numerous surgical complications." As I've mentioned before on this blog, SIB can in some cases lead to some very complicated adverse health outcomes (see here) that are not uncommon to the autism spectrum (see here). There is however a brighter note to add to the SIB experienced by this child as the authors noted that a range of interventions seemed to help alleviate some of the challenging behaviours linked to such actions. I note for example that naltrexone - the opiate antagonist - was utilised to "decrease the endorphin sensation seeking procured by SIB and diminish SIB." This follows something of a resurgence in interest in this medicine (see here) and is music to my own research ears (see here).

Second, is a little detail mentioned about the eating habits of this child: "a diet almost exclusively made up of dairy products." Alongside some accompanying details on how "intestinal transit was altered, with episodes of diarrhoea (false constipation), encopresis, and coprophagia" and I'll just say that this is something I've heard quite a bit down my years of autism research. Alongside the use of lactulose to aid the bowel issues and the anti-opioid effect of naltrexone (yes, the protein in dairy products does break down into opioid-like compounds), I'm wondering whether some of the research I've been involved with down the years looking at casein-free diets might also be relevant too (see here)?

Finally, I need to draw your attention to the increasingly popular idea that regression is a part of quite a few cases of autism (see here). Indeed the pattern of autism + ID particularly being over-represented when it comes to regression in the context of autism (see here) seems to be borne out by the case report detailed by Cravero et al.

It is good to hear that after "a year of hospitalization" the outcomes reported on this child were quite a bit more favourable than where he began. So: "His mood was stable, without tantrums or irritability, and he felt pleasure without crippling stereotypes. The SIB were limited to small low intensity fists against his helmet or his cheekbone, occurring from time to time." Further: "During the best of times he wandered half-days without helmet, smiling and exploring his environment using tactile gestures."

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[1] Cravero C. et al. Management of Severe Developmental Regression in an Autistic Child with a 1q21.3 Microdeletion and Self-Injurious Blindness. Case Rep Psychiatry. 2017;2017:7582780.

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Vitamin D genes and autism

"Vitamin D deficiency is a putative environmental risk factor for autism spectrum disorder (ASD)."

And...

"We provide straightforward genetic evidences for the first time that VDRGs [vitamin D-related genes] with a strong degree of DNM [de novo mutations] burden in ASD and DNMs of VDRGs could be involved in the mechanism underlying in ASD pathogenesis."

That was the research bottom line reported on by Jinchen Li and colleagues [1] examining an important part of the whole 'vitamin D - autism' link (see here). Specifically, how outside of just looking at functional levels of vitamin D in relation to autism (see here) and implying that groups on the autism spectrum may not be getting enough vitamin D through sunlight exposure or diet, there may be other underlying issues to consider. As other authors have hinted, the genetics of vitamin D metabolism may also be part and parcel of the autism - vitamin D story (see here).

This time around, researchers "analyzed publicly-available DNMs from 4,327 ASD probands and 3,191 controls." Among those DNMs - alterations to the genetic code present in probands but not extended family members - "18 of the VDRGs were found to harbor recurrent functional DNMs in the probands, compared with only one in the controls." In other words, small 'glitches' in the genes thought to be involved in vitamin D metabolism were more frequently present in the autism group than the not-autism group. Said glitches *may* have the ability to affect the working of those vitamin D metabolising genes with onward effects.

This is interesting work. It kinda reiterates that (i) vitamin D and the metabolism of vitamin D might be important for at least some parts of the autism spectrum and, (ii) issues with deficiency or insufficiency of vitamin D metabolites in relation to autism may be the product of both genetic and environmental issues. We obviously need to see more investigations done in this area; not least to define how widespread said genetic issues affecting vitamin D metabolism might be in relation to the very wide and very heterogeneous autism spectrum. I'd put a bet on such issues perhaps affecting only part of the autism spectrum and perhaps related to one or more phenotypes. Other authors seem to think so too [2].  I'd also wager that something quite important might emerge when it comes to the specificity of any findings too (see here).

The other question that needs to be answered is what can be done as and when issues with vitamin D metabolising genes are detected. Does this mean that additional supplementation of vitamin D (in it's typically supplemented form(s)) is unlikely to be of use (bearing in mind the recent data in this area) as a result of those DNMs? As with everything related to autism, simple answers to seemingly simple questions are very, very unlikely...


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[1] Li J. et al. Vitamin D-related genes are subjected to significant de novo mutation burdens in autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet. 2017 Apr 13.

[2] Gillberg C. et al. The role of cholesterol metabolism and various steroid abnormalities in autism spectrum disorders: A hypothesis paper. Autism Res. 2017 Apr 12.

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Li J, Wang L, Yu P, Shi L, Zhang K, Sun ZS, & Xia K (2017). Vitamin D-related genes are subjected to significant de novo mutation burdens in autism spectrum disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics PMID: 28407358

"early medical events are associated with clinical ASD phenotypes"

The paper by Charlotte Willfors and colleagues [1] (open-access) provides some food for thought today and the observation that various individual and cumulative medical events - "early medical events likely to be caused by environmental factors" - may be important to at least some autism.

Researchers "scrutinized the early medical histories of a rare and informative sample of 13 MZ [monozygotic] twin pairs discordant for clinical ASD [autism spectrum disorder]" also including "13 MZ typically developing (TD) control pairs (n=52) matched for sex" as an 'exploratory step. Discordant for autism means that one twin had autism and the other did not.

This research first step looked at medical events (likely to be caused by environmental factors!) included things like delivery and neonatal variables (e.g. foetal distress, hypoxia), minor and frequent infections (e.g. ear infections), allergy and epilepsy to name a few. Data was acquired from a few sources including medical records and medical history "assessed from a parent reported questionnaire." They examined exposure to the medical events "in relation to either quantitative or qualitative discordance for ASD." Qualitative discordance referred to when "only one twin within a pair meeting the diagnostic criteria of ASD." A 'confirmatory' study was also carried out whereby a larger, independent cohort of 100 twin pairs "quantitatively discordant for autistic traits" were also quizzed and findings cross-validated.

Results: a few non-shared environmental (NSE) events seemed to be important based on their analysis. So: "Single early medical factors, likely to be caused by NSE, that discriminated between twins in qualitative ASD discordant pairs were dysregulation during the first year of life (comprising feeding and sleeping problems, excessive crying and worrying) and birth weight." Authors also reported that cumulatively, the appearance of early medical events were significantly different in MZ twins with autism compared with their non-ASD co-twin. It's worth mentioning that some of those 'dysregulation' events have been talked about in the earliest descriptions of autism (see here). Birth weight too has something of a long-standing connection to [some] autism (see here). When it came to analysis based on autistic traits (the confirmatory study) it seemed that "early dysregulation and the cumulative load of a variety of early adverse medical events" continued to be important variables (although birth weight linked to ASD traits lost its significance).

These are important findings. The focus on MZ twins (who share a common structural genetic blueprint) means that the genetics side of things is to a large extent 'controlled for' and the results are more likely to reflect some environmental or, more accurately, non-genetic influence. There is a caveat to this though, as per the authors recognition: "with the exception of putative post-twinning de novo mutations." I might also add that MZ twins are also not necessarily epigenetically the same too so gene expression can (and does) differ. What causes these epigenetic differences is still the source of some debate but I might chime in with one idea (see here) out of many possibilities.

"Our data indicate that taking into account the cumulative load of early medical factors might strengthen or discourage a suspicion of ASD, at least in a minority of cases." This is an interesting thought provided by the authors based on their findings. It ties in well with the idea that although behavioural presentation is core to autism presentation and diagnosis, behaviour might not be the only important feature present in relation to autism. I do have to express a degree of caution however with such an approach based on the idea that various types of regression have been noted in the peer-reviewed literature to accompany some autism (see here) and with it, the concept of 'acquired autism' should really be properly recognised (see here for example) in these days of the plural 'autisms'. Indeed, there's a research study idea for anyone out there: looking at MZ twins discordant for autism with onset of said autism tied into a regression of skills?

Scientific replication is the name of the [future] game in this area of study, drawing on larger cohorts and perhaps based in other geographical areas outside of Sweden. We also need to find out what mechanisms might be potentially associating something like 'early dysregulation' with the onset of autism, taking into account how factors such as early feeding practices/issues for example, might provide at least one avenue for future study (see here).

To close, in light of some recent media headlines about the 'myth' that autism rates are on the up (and quite significantly so over past two decades), I offer some past posts suggesting that the word 'myth' should be reserved for other [non-peer-reviewed] matters (see here and see here and see here) and not this particular branch of epidemiological science. As to what may be 'causing' the upswing in numbers of diagnosed cases, well, it's likely to be very, very, very complicated (and without any need for sweeping generalisations please)...

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[1] Willfors C. et al. Medical history of discordant twins and environmental etiologies of autism. Transl Psychiatry. 2017 Jan 31;7(1):e1014.

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Willfors C, Carlsson T, Anderlid BM, Nordgren A, Kostrzewa E, Berggren S, Ronald A, Kuja-Halkola R, Tammimies K, & Bölte S (2017). Medical history of discordant twins and environmental etiologies of autism. Translational psychiatry, 7 (1) PMID: 28140403

Offspring autism risk and advancing parental age (differences)

Parental age at offspring conception/birth in relation to offspring autism risk has been a recurrent theme in autism research circles for quite a few years now. I've covered it more than once on this blog (see here for example) and the various suggestions that advancing parental age in particular, might elevate the risk of offspring autism.

Set in this context, the paper by Sven Sandin and colleagues [1] (open-access) (a name not unfamiliar to this blog) adds to the research evidence based on their analysis of some 5.7 million children born between 1985 - 2004 resident in one of five countries (Denmark, Israel, Norway, Sweden and Western Australia). Including data on some 30,000 children diagnosed with an autism spectrum disorder (ASD): "Parental ages, sex and birth year were obtained from birth or civil registers."

After quite a bit of statistical modelling and controlling for various potentially confounding variables, several findings were reported pertinent to the authors' data being "the strongest evidence to date supporting the hypothesis that advanced parental ages at the time of birth are independently associated with risk for ASD in the offspring." Outside of "no support for any modification by the sex of the child" researchers also noted a "combined parental age effect" whereby there "was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages."

A few of the finer details of this study have been covered elsewhere (see here). I'll draw your attention to one or two statistics unearthed during the study:

• "relative to fathers aged 20–29 years, fathers 50 years or older had a statistically significantly increased risk for offspring with ASD (RR=1.66 95% CI:1.49–1.85)",
• "Relative to mothers aged 20–29 years, mothers younger than 20 years had a statistically significantly increased risk for offspring with ASD (RR=1.18 95% CI:1.08–1.29)" and 
• the "lowest risk corresponded to couples that generated the majority of births, specifically, 29–39-year-old fathers and 25–35-year-old mothers." 

Those estimates of relative risk (RR) statistics translate into an estimated 66% increased risk for offspring autism if a dad was over 50 years old compared with a dad in their 20s, an 18% increased risk for offspring autism for teen mums compared to 20-something mums and the lowest statistical risk of offspring autism being reported when dads conceive in their 30s coupled with a mid-20 to mid-30 year old mum. The authors also note that "Similar patterns of association, but with slightly higher RRs for the highest parental ages, were evident for AD [autistic disorder]" so completing the message about older parental ages at conception and differing parental ages being relevant across the autism spectrum.

Accepting that this was a huge study in terms of participant numbers and spanning different geographical locations, the authors rightly offer a few words of caution about their methods and data. So: "we lack information about potentially confounding variables such as SES [socio-economic status] and parental psychiatric history" is something to keep in mind [2]. Further: "We cannot rule out the possibility that other factors associated with parental age (for example, length of marriage or partnership, obstetric complications, gestational age and birth weight) have an important role in explaining our results" and "We did not have individual level information on co-morbid ID [intellectual disability] in ASD cases." I'd also suggest that given the growing emphasis on autism or ASD not existing in some sort of diagnostic vacuum (see here) one might reasonably ask whether other comorbidity outside of ID might also play a role in risk estimates.

As to the possible mechanism(s) of effect, well, the authors go through the usual older parents - older sperm and eggs mantra although perhaps bypassing an emerging area outside of just de novo mutations based on the role of epigenetic mechanisms (see here). They do suggest that the 'difference in parental age' factor might suggest "that the increase in risk is not attributable to advancing parental age per se, and that the risk increase cannot be explained solely by an accumulation of point mutations or other genomic alterations in the parents" but say little more on the basis of their collected data.

I might be wrong but I also didn't seem too much in the way of discussion of how parental nutrition might impact on offspring autism risk as per the proposed factor from other work by authors on the Sandin paper in relation to the inter-pregnancy interval (IPI) and autism risk (see here and see here). Although the idea that parental age might affect autism offspring risk, I'd be minded to suggest that this is only the first stage in a journey towards elucidating the particular mechanisms of any effect.

Music: The Pixies - Gigantic.

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[1] Sandin S. et al. Autism risk associated with parental age and with increasing difference in age between the parents. Mol Psychiatry. 2015 Jun 9.

[2] Lehti V. et al. Maternal socio-economic status based on occupation and autism spectrum disorders: A national case-control study. Nord J Psychiatry. 2015 Mar 3:1-8.

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Sandin S, Schendel D, Magnusson P, Hultman C, Surén P, Susser E, Grønborg T, Gissler M, Gunnes N, Gross R, Henning M, Bresnahan M, Sourander A, Hornig M, Carter K, Francis R, Parner E, Leonard H, Rosanoff M, Stoltenberg C, & Reichenberg A (2015). Autism risk associated with parental age and with increasing difference in age between the parents. Molecular psychiatry PMID: 26055426

Increasing parental age and autism severity?

An interesting paper by David Geier and colleagues [1] (open-access here) caught my eye recently, concluding that there was a lack of support for the suggestion that: "increasing parental age was associated with increasing autism spectrum disorder phenotypic severity".

"the snozzberries taste like snozzberries".

Before progressing through the paper and its possible implications, the eagle-eyed out there might have already spotted the name Dr Brian Hooker on the authorship list of the Geier paper. Outside of his other peer-reviewed work [2], I probably only need to mention the letters 'CDC' and everything that has [so far] followed including (at the time of writing) a removal statement retraction statement (updated: 04/10/14) for another paper [3]...

Anyhow, the idea behind the Geier paper stems from the quite widely disseminated notion that there may be a connection between increasing parental age at conceiving and an increased risk of offspring autism. I've covered it a few times on this blog (see here and see here). The authors elaborate about a recent hypothesis suggesting that "there must be a linkage between increasing genetic load and increasing parental age in autism spectrum disorder pathogenesis" based on studies like the one from Kong and colleagues [4] (covered in a previous post) and Lampi and colleagues [5]. Further, that as a consequence of an increasing genetic load (all those SNPs et al), "there should be a significant relationship between increasing parental age and increasing autism spectrum disorder phenotypic severity of subjects diagnosed with an autism spectrum disorder".

The paper is open-access but maybe a few details are in order:

• Participants (N=351), diagnosed with DSM-IV autism, were drawn from "patients presenting for outpatient genetic consultations at the ASD Centers, LLC". Mean age was approximately 9 years of age, most male and most reporting developmental regression following birth. Details of age of parents at time of offspring birth were analysed alongside use of the ATEC (Autism Treatment Evaluation Checklist) at initial clinical presentation. These variables formed the crux of the study.
• Results: "Overall, it was observed that no significant relationships were observed between increasing autism spectrum disorder phenotypic severity and increasing maternal or paternal age". Except, that is, for something that seemed to suggest that older maternal age at birth of child seemed to correlates with "improved sociability" in offspring. The authors report that their observations: "provide important insights into the apparent lack of a relationship between increasing parental age and increasing autism spectrum disorder phenotypic severity".

Of course one has to be careful with any study of correlation/association, particularly when it comes to something as simple as just looking at ATEC scores of severity of behaviours in the autism domains and parents age at time of birth of their children. I personally would also have liked to see some further discussion on whether the broader autism phenotype (BAP) for example, might have been an influencing variable too in light of studies like the one from Hasegawa and colleagues [6]. Also, the participant group is quite large - as the authors note - but even there I think back to the sort of sample numbers that those [big data] studies in Taiwan are including (see here) as to where we should be heading.

That all being said, I don't want to downplay the Geier results. Another quote might be useful here: "most observed de novo genetic events are unconnected to an autism spectrum disorder diagnosis, and those that do confer risk are distributed across many genes and are not necessarily sufficient for disease". This ties in rather nicely with the recent discussions on common variations and autism risk (see here) and how Gaugler and colleagues [7] questioned how much weight to give to de novo mutations in the grand scheme of autism 'causation'. This also might imply that non-genetic events, or at least non-structural genetic events headed under the general banner of environment might also play some contributory role to at least some cases of autism. Again, something which has cropped up on this blog before (see here).

Music to close. Given the recent vote near these parts, one of Scotland's most famous exports... Franz Ferdinand and Do You Want To.

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[1] Geier DA. et al. An Evaluation of the Effect of Increasing Parental Age on the Phenotypic Severity of Autism Spectrum Disorder. J Child Neurol. 2014 Aug 27. pii: 0883073814541478.

[2] Hooker B. et al. Methodological issues and evidence of malfeasance in research purporting to show thimerosal in vaccines is safe. Biomed Res Int. 2014;2014:247218.

[3] Hooker BS. Measles-mumps-rubella vaccination timing and autism among young african american boys: a reanalysis of CDC data. Transl Neurodegener. 2014; 3: 16.

[4] Kong A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012 Aug 23;488(7412):471-5.

[5] Lampi KM. et al. Parental age and risk of autism spectrum disorders in a Finnish national birth cohort. J Autism Dev Disord. 2013 Nov;43(11):2526-35.

[6] Hasegawa C. et al. Broader autism phenotype in mothers predicts social responsiveness in young children with autism spectrum disorders. Psychiatry Clin Neurosci. 2014 Jun 6. doi: 10.1111/pcn.12210.

[7] Gaugler T. et al. Most genetic risk for autism resides with common variation. Nature Genetics. 2014. July 20.

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Geier DA, Hooker BS, Kern JK, Sykes LK, & Geier MR (2014). An Evaluation of the Effect of Increasing Parental Age on the Phenotypic Severity of Autism Spectrum Disorder. Journal of child neurology PMID: 25163730

Common variation and the genetics of autism

The paper by Trent Gaugler and colleagues [1] reporting that the genetic architecture of the autism spectrum disorders (ASDs) seems in the most part to be due to "common variation" over and above "rare variants or spontaneous glitches" adds to the quite voluminous literature in this area.

Everything in proportion? @ Wikipedia 

Based on an analysis of "a unique epidemiological sample from Sweden" researchers looked at DNA variations in some 3000 individuals with autism and asymptomatic controls. They were able to model their findings "based mostly on combined effects of multiple genes and non-shared environmental factors" including some "synthesis of results from other studies".

Their results: "Most genetic risk for autism comes from common inherited gene variations that can be found in many individuals without the disorder" as per one write-up of the study results. Spontaneous mutations - those so-called de novo mutations which seem to be of growing interest to autism research - were reported to only 'modestly' increase risk of the condition (2.6% of the total risk). About 40% of the risk was unaccounted for, but combined with those common inherited gene variations, made up about 90% of the total risk or liability for ASD.

Quite a lot of the discussion about these results has focused on the issue of tiny genetic effects which many people not on the autism spectrum have present in their genome adding up into something with "substantial impact" when present together. Other research has hinted at similar things as for example, in the paper by St Pourcain and colleagues [2] looking at the genetics of social communication issues.

Whilst I do think that the Gaugler paper is an important one, I am minded to suggest a few words of caution. First and foremost is the reliance on observed genetic variation in the current paper. Although no expert in genetics, my very basic knowledge is that such variations are structural in nature as per issues like single-nucleotide polymorphisms (SNPs). The presence of such mutations (which we all have by the way, dotted around our genomic landscape) whilst of interest, don't actually though tell you an awful lot about the function of particular genes as a consequence of those point mutations unless further studies are conducted. Genes for example expressing protein can be affected by such mutations but, as we've come to realise in the past few decades, gene expression is also to some degree affected by other variables, as per the rise and rise of the science of epigenetics and the focus on non-structural effects on the genome. It's beyond the scope of this post to go too heavily into epigenetics and autism, but the research forays so far have provided some interesting data on issues like DNA methylation and autism (see here) and potential knock-on effects (see here). Importantly, structural variations might not necessarily be the same, or have the same effects, as epigenetic variations although the two may work synergistically.

Second, and I hate to bang on about this, but autism or ASD does not normally appear in some sort of diagnostic vacuum. As per the Gillberg work on the ESSENCE of autism (see here) or the 'big data' studies from the likes of Kohane and colleagues (see here), not only is autism an extremely heterogeneous condition in terms of presentation, but also a condition more than likely to co-exist alongside some heightened risk of certain comorbidity. It's all well and good saying that cumulative common genetic variants raise the risk of autism but, as per other biomarker discussions, we might very well replace the word autism with something like attention-deficit hyperactivity disorder (ADHD) or epilepsy or even something more somatic along the lines of the various work looking at autoimmune conditions appearing alongside autism. In short, genetic risk might be related to other things outside of just autism or its individual traits, and as I was reminded recently: "correlation is not the same as causation" (thanks Natasa). Oh, and then there is the RDoC initiative to consider...

Finally, it is a glaring omission in quite a bit of the coverage of this paper that the 41% of risk "unaccounted for" does not receive more interest than it has. I don't want to speculate on what might be included in the array of factors involved in this category (outside of my previous chatter on possible epigenetic factors) but will again draw your attention to other work on the old genetics-environment relationship with autism in mind and the question of heritability (see here and see here). That also one media piece talking about the Gaugler study is quoted as saying: "On their own, none of these common variants will have sufficient impact to cause autism" is an important detail which implies both cumulative effects and possibly the input of some external force(s). And those effects may very well cross the nature-nuture debate in some instances as per the results from Mitchell and colleagues talked about in a previous post.

Deciphering the genetic architecture of autism is still very much a work in progress. This latest contribution to the issue is important not least for the conclusions arrived at with talk of an additive model and it's intersection with common genetic mutations present in the general population. That being said, I still want to see more from the discipline. I'd like to see a more comprehensive analysis taking into account both genetic and epigenetic factors crossing environmental contributions too. I'd also like to see more focus on smaller groups on the autism spectrum as a function of things like developmental trajectory (see here) or response to certain interventions (see here). And for those who seem to be using this work as a hammer against environment being related to cases of autism, just remember, there may be many, many routes towards a clinical diagnosis...

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[1] Gaugler T. et al. Most genetic risk for autism resides with common variation. Nature Genetics. 2014. July 20.

[2] St Pourcain B. et al. Common variation contributes to the genetic architecture of social communication traits. Mol Autism. 2013 Sep 18;4(1):34.

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Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, & Buxbaum JD (2014). Most genetic risk for autism resides with common variation. Nature genetics PMID: 25038753

IACC and summary of research advances in autism 2012

I'm very much an outsider looking in when it comes to the goings-on at the US Interagency Autism Coordinating Committee (IACC). I'm a Limey working here in Blighty (translation: Brit working in the UK) not in the States and as far as I can see we don't have such an agency here in the UK. Yes, we do have the NICE review which is coming to a close shortly but nothing like the IACC which seems to orchestrate many autism-related activities in the States, including research.

Annually, the IACC produce a summary of autism research which kinda brings together the great and the good of progress in understanding what might constitute autism (the autisms). They've just released the 2012 review of autism research (see here) which contains some interesting studies including those covered on this blog.

A few choice studies and posts are presented for your attention:

Six developmental trajectories.... by Fountain and colleagues.
The branched chain amino acid phenotype.... by Novarino and colleagues.
De novo mutations and paternal age.... by Kong and colleagues.
Kum-ba-arbaclofen... by Berry-Kravis and colleagues.
Wandering.... by Anderson and colleagues.
Mortality.... by Bilder and colleagues.
1 in 88.... by the CDC.

'Nuff said.

De novo mutations, older dads and autism (again)

Those with an interest in autism (and/or schizophrenia) will have probably already seen the headlines discussing the study by Augustine Kong and colleagues* on  the rate of de novo genetic mutations and a father's age as being potentially important for conditions like autism and schizophrenia. For those like me who are still struggling with all things mutation, quite a nice summary of the current research is offered in this Nature commentary accompanying the study.

I'm going to briefly focus on the potential implications specifically for autism in this post, accepting that (a) de novo mutations have been looked at with schizophrenia in mind (see here) and (b) increasing parental (and grand-parental) age has been linked to an increased risk of schizophrenia (see here).

This is not the first time this year that findings related to de novo mutation and paternal age in relation to autism have surfaced in Nature as discussed in this post. The latest study from Kong and colleagues suggests a few things:

• The entire genome of 78 families (mum, dad, child) of Icelandic-origin was sequenced.
• They studied the small genetics changes, SNPs, in and between mums and dads and their children, taking into account the age of the parents. Apparently of the offspring included for study, 44 had received a diagnosis of an autism spectrum disorder and 21 diagnosed with schizophrenia.
• Their analysis suggested (i) fathers passed on about four times more mutations than mothers, (ii) approximately 2 new mutations were present in children for every year of increase in the father's age at conception - so a father conceiving at 20-years old passed on 25 random mutations compared with a father conceiving at 40-years old who passed on 65 mutations, (iii) mums were reported to pass on about 15 mutations irrespective of age; thought due to the fact that women carry their eggs through life whilst sperm is constantly being produced and therefore potentially subject to the rigours of ageing and environment.

There has, understandably, been some discussion about the implications of this research with regards to autism and more generally about the trend towards couples starting families when they're getting on a bit. Kari Stefansson, lead author on the paper discusses the trend (in Iceland) towards increasing paternal age when conceiving a child - 27.9 years in 1980 to 33 years in 2011 - as a case in point and potentially what implications this may have. That being said, I have to say that I raised a smile when reading about this recent research which suggested that children with older fathers might actually be genetically-programmed to live longer as a function of increasing teleomere length with age in sperm**. I am comparing apples and oranges here but want to show how such things are never straight-forward.

Another debate has also seemingly arisen from the Kong study with regards to the numbers of children with autism being currently diagnosed/estimated, and whether the figures reflect better case ascertainment, etc. or are reflective of a true increase in the numbers of people with autism. To quote from Fred Volkmar (here) "This study provides some of the first solid scientific evidence for a true increase in the condition of autism". Earlier this year I discussed the latest estimates of autism in the United States produced by the CDC and how an estimated 1 in 110 8-year olds with autism became 1 in 88 8-year olds with autism. If accurate, what Dr Volkmar seems to be suggesting is a kind of bridge between the genetics-environment camps which will almost certainly impact on the autism numbers game: older parents, older fathers passing on a greater number of mutations potentially increasing the risk of autism or schizophrenia. I pass no judgement on this proposal by the way.

There are a few final comments to make on this research and the area in general. Regular readers of this blog might already know that I am becoming a bit of a fan of the area of epigentics and the promise that it might hold for conditions like autism. Noting the recent research from Richard Anney and colleagues ("no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level") it's all well and good suggesting that older fathers might increase the risk of autism, but without such details as to which SNPs are consistently and reliably at work, there is likely to be a whole lot more involved in the aetiology of autism than just the structure of the genome. That and my continuing questioning as to whether age is the only factor in causing mutation or whether other environmental 'exposures' might also exert an effect.

Additionally and finally, I've said it before and I'll say it again: autism is not a homogeneous condition. We might talk about autism as being diagnostically homogeneous insofar as a person presents with this triad (soon to be dyad) of symptoms and the autism diagnosis box is ticked, but symptom onset and presentation varies from person to person (endophenotype to endophenotype?) and is further complicated by elevated risk for various comorbidity, psychological, cognitive and also more somatic comorbidity. I see nothing in the current research that rules out the possibility that more mutations passed to offspring as a result of older dads might not also be tied into an increased risk for other things (autoimmune features and conditions, epilepsy, learning disability, depression, anxiety, etc., etc.). Until we can, with some degree of confidence, peel back the diagnostic and risk layers, this issue will be in the background of any autism research.

Don't get me wrong, I am very interesting in the latest results from Kong and the now replicated findings of advancing paternal age and risk in some cases of autism. I do however believe that within the context of all the other research published and on-going in autism, this might be but one small piece of a much larger puzzle on aetiology and underlying pathology.

To finish, Jim Morrison has been on my musical radar of late, so how about some Riders on the Storm?

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* Kong A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012; 488: 471-475.

** Eisenberg DTA. et al. Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. PNAS. 2012; 109: 10251-10256.

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Augustine Kong, Michael L. Frigge, Gisli Masson, Soren Besenbacher, Patrick Sulem, Gisli Magnusson, Sigurjon A. Gudjonsson, Asgeir Sigurdsson, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Wendy S. W. Wong, Gunnar Sigurdsson, G. Bragi Walters, Stacy Steinberg, Hannes Helgason, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Agnar Helgason, Olafur Th. Magnusson,, Unnur Thorsteinsdottir, & Kari Stefansson (2012). Rate of de novo mutations and the importance of father’s age to disease risk Nature DOI: 10.1038/nature11396

Dust settled: autism, de novo mutations and older dads

On purpose I have left it a few days to post about the trio of studies published in Nature by Sanders and colleagues*, O'Roak and colleagues** and Neale and colleagues*** which have created big headlines like this one and this one on quite a few de novo mutations - as in not present in parents but present in children - being linked to the diagnosis of autism. A fourth study picked up by Time magazine (here) by Kerin and colleagues**** on moesin adds to the flavour. This last study coincidentally being in the same publication that contains an article suggesting that the predictive power of personal genome sequencing is likely to be a little bit more limited than many initially suspected. Who'd have thought it?

Back to the Nature articles, I let the dust settle a little for two main reasons: (1) just about everyone has an opinion about this work and its meaning, and (2) my first instinct was to say 'add them to the 2193 genes, 2806 SNPs/VNTRs, 4544 copy number variations, etc' already found and discussed in relation to autism.

I've talked about mutation and genes already quite a bit on this blog and how, whether diagnosed with autism or anything else or nothing at all, we are all a product of mutation and individually carry our own store of genetic mutations. Quite by chance I just saw one of the latest Marvel film adaptations, 'Thor' complete with cameo performance from the magnificent Stan Lee, who has whether knowingly or not, popularised mutation and in some respects relieved it of its quite negative connotations. After all, every kid wants to be Wolverine or Spiderman don't they?

Anyway a very, very short summary of the papers in question:

• Sanders and colleagues* discussed exome sequencing for nearly a thousand individuals, including 200 people with a diagnosis of autism. Exome sequencing, I am reliably informed, relates to the analysis of exons, the parts of DNA which get translated into functional proteins. There is quite a good background description here. Their results identified several de novo mutations in brain-expressed genes to be present, with one mutation in the same gene present in 2 unrelated participants with autism but not in asymptomatic controls among other findings.
• O'Roak and colleagues** carried out similar exome analysis for a couple of hundred parent - child trios (trios implying mum, dad and child with autism, N=677). Their analysis suggested quite a few of the 248 de novo mutations, 126 classified as 'severely disruptive', they found were paternal in origin - from dads - and showed a positive correlation with paternal age consistent with other work on older dads perhaps being a risk factor for autism. I was interested in some elements of the last sentence of this paper abstract which talked about 'extreme locus heterogeneity' but at the same time providing ".. a target for future discovery, diagnostics and therapeutics". Make of that what you will.
• Neale and colleagues*** again sequenced exomes in 175 trios. They reported finding de novo mutations in less than half of their cases (46.3%) stating that ".. the overall rate of mutation is only modestly higher than the expected rate". Nevertheless, some clever proteomics work looking at how these mutation might fit together revealed some interesting interactions between the proteins encoded by the genes being looked at. They also suggested that carrying these mutations might up the risk of autism between 5 - 20 times compared with not having them. I was also interested in one of the gene candidates identified in this study, KATNAL2, which has been tentatively correlated with 'conscientiousness' as a personality trait (assuming you believe that personality is genetic). Dr Ben Neale, the lead author, has also summarised his team's results on a guest blog post here and done to my mind, quite a good job outside of all the hype.

I have probably not been able to do justice to the complexity and obvious work that has gone into these studies with this very short summary. There was some overlap in the genetic areas of interest across the studies which, given the statistical odds involved, might be potentially very important. I must admit that I raised an eyebrow when these papers all came out pretty much simultaneously and only a few days after the CDC reported another increase in their estimates of prevalence of autism in the United States, up from 1 in 110 to 1 in 88 8-year olds - indeed 1 in 32 boys apparently in the State of Utah. I'm sure that the timing was just coincidence though.

I've said it before and will say it again, I am not a molecular biologist or anything related, so am very much an amateur when it comes to decoding the precise meaning of exomes and de novo mutations outside of some background reading. With this in mind, I translate these collective works as suggesting a few things (but don't quote me on this):

1. The genetics of autism are getting more and more complicated with every study published. It probably doesn't help that the diagnosis of autism is a subjective experience from a clinical viewpoint and autism is often surrounded by other comorbidities which are also likely to exert an effect on results. Exactly how this might change if and when the new 'sliding scale' DSM-V autism diagnostic criteria comes out will be interesting.
2. These were studies on de novo mutations meaning that they did not originate from parents. I read one comment on a blog (here) by a commentator who drops by this blog now and again, RAJ, asking the very important question: where did all the heritability go? Does this mean that the autism of today is different from the autism of yester-year or is it all a question of technology, participant numbers, etc.?
3. How and why do these de novo mutations appear is a question that should be on everyone's lips. Random is a word that crops us time and time again in relation to these mutations but with due respect, if we are talking about these mutations showing cause and effect in relation to autism risk, saying they just randomly appear leaves quite a big gap in the knowledge base. Again with my amateur status as a caveat, I do wonder about the involvement of environment and judging by the latest blog from Tom Inset at the NIMH, I'm not the only one. The paternal spotlight and in particular the older dads suggestion from the O'Roak study has put sperm in the cross-hairs, and lets face it, that opens up a myriad of possible environmental factors outside of just 'old sperm' as potentially showing some association (something again that RAJ has commented on in other posts on this blog).
4. As per other studies on mutation in areas such as ADHD, whilst these are impressive studies utilising some impressive technologies, one perhaps needs to ask how common these mutations were in terms of autism as a whole. Yes, there were some interesting areas coming to light and yes, these should be priorities for future studies. As the paper from Neale and colleagues reported however, the overall rate of mutation was only marginally higher than what would be normally expected and one should perhaps not discount the influence of things like intellectual disability as accounting for at least some results (see here).

With the onset of epigenetics (changes to gene expression without changes to the genome), things are changing in the world of genetics. Autism research at the same time continues its fascination with this area of endeavour. The concept of an 'autism gene' covering everyone with autism (and the BAP?) is a distant memory (as are the millions of pounds/dollars/other currency pumped into this area down the years) to be replaced by an altogether more complicated picture emerging of spontaneous mutations, differing genetic profiles for individuals and genes and environment potentially acting variably but synergistically.

To finish, the UK is awash with Britain's Got Talent at the moment, and aside from asking 'where me keys, where me phone' a group called the Zimmers got me reminiscing about an old Beastie Boys classic... fight for your right to [fill in the blank].

* Sanders SJ. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. April 2012.
DOI: 10.1038/nature10945

** O’Roak BJ. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature. April 2012.
DOI: 10.1038/nature10989

*** Neale BM. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 2012.
DOI: 10.1038/nature11011

**** Kerin T. et al. A noncoding RNA antisense to moesin at 5p14.1 in autism. Science Translational Medicine. April 2012.
DOI: 10.1126/scitranslmed.3003479