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[–]childpsychMD|PhD|Neuroscience 6 points7 points  (7 children)

I will preface my comments with the fact that I’m a psychiatrist and do research in ASD.

I believe that these studies are a great step in the right direction but the results should be interpreted in the context of the data sets they were derived from. This is especially true for the study employing the Simons Simplex Collection (SSC). SSC is exclusively made up of children with ASD WITHOUT any siblings or first degree relatives with ASD. It is highly enriched for individuals with concurrent intellectual disability (ID). It is also highly skewed in terms of male to female ratio, with a ratio of 1 female to 7 males, about 2+x higher than the current community estimates. ASD females accounted for only 13.5% of the SSC. Additionally, the vast majority of the females in the SSC had concurrent ID. Very few high IQ females were included. As a result, some of the study conclusions are not well substantiated for this sub-population.

Need to take a break for clinic, more to come.

Edit:

Ok, I’m back.

Historically, ASD used to be split up into classic autism, aspergers, and pervasive disorder NOS (PDD NOS). Aspergers was differentiated from autism only by the absence of significant language delay. Individuals with normal language acquisition generally have normal-range IQs but the converse is not true, that is, you can have language delay in high IQ individuals for unrelated reasons. Over time it became increasingly clear that a language-based distinction did not correlate with any clear functional differences and consequently autism was combined with aspergers into the new ASD umbrella in DSM V. PDD NOS morphed into social communication disorder, which is no longer considered to fall under the autism spectrum and IMHO correctly so given the fact that these same symptoms can be seen in a variety of other disorders/conditions.

What’s interesting about the SSC study is that it actually suggests that the (formerly diagnosed) aspergers population may indeed be slightly overlapping but generally distinct from the autism population. The real difference between the populations being IQ, not language. In the SSC, there was relatively little overlap between the genes affected in individuals with ID vs those without. Although there are some difficulties inherent to measuring IQs in autists, I think that IQ is less liable to be influenced by extraneous factors like hearing or apraxia.

I believe this population distinction applies to BOTH males and females. As I mentioned earlier, the SSC is highly skewed against females and doubly so for high IQ females, where the ratio of males to females increases even further to ~10:1 (there were only 32 higher IQ females in the whole study). With such low numbers, it’s next to impossible to separate out a high IQ female population. Despite this, the same trends in mutation types and affected genes are seen. Of course, when you lump everyone together, the low IQ females predominate and consequently females as a group end up overlapping with low IQ males. This is an artifact of the database. As our identification of high IQ females improves (we are terrible at this currently), I believe that the genetic data from females will increasingly resemble that obtained in males.

Another interesting finding is the very high overlap between genes causing low IQ autism, ID, and schizophrenia. This fits with clinically observed comorbidities but also suggests that it may be difficult to distinguish between social/executive function deficits/odd behaviors in those with low IQs causing those individuals to get lumped into the same category. In my clinical experience, this tended to be PDD NOS. I anticipate this type of diagnostic ambiguity may improve as we switch over to the more stringent DSM V criteria.

[–]SirT6PhD|MBA|Biology|Biogerontology[S] 4 points5 points  (5 children)

Thanks for the thoughtful response. I think you make a really important point when you say that these results need to be interpreted with context.

The way I conceptualize the results is like this:

There is very clearly a strong genetic component to autism. It tends to run in families, and identical twins are more likely to both have autism than fraternal twins. Boys are more likely to have ASD than girls. These are all classic signs that genetics are at play (to some degree). That said, the genetics are complicated - and that scares people, given the prevalence of the disorder.

The best genetic framework I have seen (in my opinion) for autism recognizes that there are sporadic and inherited forms of the disease. This fits the basic observation that some families are more likely to have multiple children with ASD than others. Sporadic mutations are caused mainly by de novo mutations/changes in copy number, which affect males with high penetrance. High risk families often consist of a female carrier of a highly penetrant mutation which can drive ASD in a dominant fashion in her children (especially male children). Why male children are more susceptible is still unclear.

So what does that mean in the context of this study? As you point out the SSC is a collection of ASD families with only one autistic child (and no autistic siblings). This means that most likely then, that patients in this collection have a sporadic form of ASD. The big caveat, however, is that some patients may come from high risk/pseudo-multiplex families, but this will be unclear to researchers because of family planning (i.e. not having subsequent children after one child is diagnosed with ASD) or just small family size.

So for the most part, I would say this study tells us about pathways which are susceptible to de novo mutation and likely to drive sporadic forms of ASD.

The two big (admittedly optimistic) take-homes from these studies is that:

1) as whole exome sequencing becomes cheaper and our knowledge of risk factors for ASD becomes better, we are getting closer to being able to early diagnosis (and maybe even in utero teseting). So big implications for family planning.

2) from a therapeutic perspective, a lot of the mutations cataloged in this study hit only one copy of the allele, presumably creating a haploinsufficiency of sorts. This raises the possibility of dosage compensation as a therapeutic mechanism.

An added nuance, that I don't think these studies address particularly well is getting at the genetics underlying the severity of ASD. Given that ASD is a spectrum disorder, linking genotype to phenotype remains a big goal for the field. I am not sure how well this paper contributes to that effort.

[–]childpsychMD|PhD|Neuroscience 4 points5 points  (4 children)

The best genetic framework I have seen (in my opinion) for autism recognizes that there are sporadic and inherited forms of the disease. This fits the basic observation that some families are more likely to have multiple children with ASD than others. Sporadic mutations are caused mainly by de novo mutations/changes in copy number, which affect males with high penetrance. High risk families often consist of a female carrier of a highly penetrant mutation which can drive ASD in a dominant fashion in her children (especially male children). Why male children are more susceptible is still unclear.

I agree ASD likely arise through a combination of sporadic and inherited genetic alterations. Most of the identified genes influence neuronal microstructure, including connections, and /or signal transmission. Through a downstream effect of sorts, disparate changes produce similar appearing phenotypes in affected individuals. Growth/development and environmental conditions will also influence the phenotype. Some combinations may exacerbate symptoms while others ameliorate or mark them from outside observation.

There has historically been a huge bias against diagnosis of ASD in females. The majority of ASD diagnostic criteria were defined around the typical male presentation and it is only relatively recently that a different presentation of ASD in females is recognized. European large-scale population studies are steadily decreasing the male to female ratio, with some showing male to female ratios closer to 1:1 in siblings of an already identified autistic individual. Given these trends, I believe that it's premature to debate putative mechanisms of "increased male susceptibility."

[–]tuppence- 2 points3 points  (3 children)

Thanks for hitting home the point on females throughout this thread. I'm a female with a high IQ on the spectrum and I appreciate recognition of this issue.

[–]childpsychMD|PhD|Neuroscience 2 points3 points  (2 children)

I'm also female and autistic, so increasing awareness of ASD in females is of personal as well as professional importance to me.

[–]tuppence- 0 points1 point  (0 children)

Well, I've been to a lot of gynecologists who didn't seem to respect female opinions or feelings, so....still, thanks. :)

[–]SirT6PhD|MBA|Biology|Biogerontology[S] 0 points1 point  (0 children)

Thanks for bringing that to my attention. I was actually just having a discussion about the historical tendency to normalize male symptoms in medicine. I had no idea this trend extended to autism as well.

Would you be able to recommend an article on this issue? I work on the academic side of things, and from my experience the male:female ratio is commonly referenced in talks as an indication of the genetic nature of ASD.

[–]phame 2 points3 points  (0 children)

My family has autism spectrum disorders. It shows up in about 25% of us on both maternal and paternal sides.

Myself, father, 2 grandfathers, uncle, 2 sons, grandson, nephew, 3 grand-nephews, grand-niece, 3 cousins, cousin's child. About 1/2 are diagnosed. The others very likely based on many obvious traits. Also several people who married into the family are autistic, too.

[–]SirT6PhD|MBA|Biology|Biogerontology[S] 0 points1 point  (0 children)

The two articles were published in Nature.

Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability–transcription coupling, as well as histone-modifying enzymes and chromatin remodellers—most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.