Tolstoy rides again: Autism spectrum disorder

“Happy families are all alike; every unhappy family is unhappy in its own way”.  Thus beginneth Anna Karenina. That wasn’t supposed to happen with hereditary disease.  The examples we had before large scale DNA sequencing became cheap were basically one gene causing one disease.  Two of the best known cases were sickle cell anemia and cystic fibrosis (CF).  Not so for schizophrenia, in which a variety of individually rare genetic defects has been found each confined to 1 or 2 families. For details see my post on this subject a few months ago (

But schizophrenia at least looks pretty much like one disease (just like sickle cell anemia and CF).  Autism spectrum disorder is clearly a collection of disorders with a similar constellation of symptoms.  Before going much further, it’s time for a few facts about the distribution of IQ in the general population.  The standard deviation of IQ is 15 points, and, except at the tails, the distribution of IQ falls on the famous Bell Curve (Gaussian distribution).   This means (with an average IQ of 100 — by definition really) that between 2 and 3 % of the population will have IQs higher than the average (e.g. IQ over 130) and a similar amount of the population will have IQs of 70 or below.  So there are a lot of kids around who are what used to be called mentally retarded (I’m not up on the latest euphemisms).

The definition of autism and autism spectrum disorder have radically changed over the years, and what was rare, is now common, as diagnostic criteria have become looser (or more inclusive if you wish).

Autism spectrum disorder is really a group of diagnoses.  Here is the state of play 6 years ago. [ Cell vol. 119 p. 28 ’04 ] 

     l. autism
    2. Asperger’s syndrome
    3. childhood disintegrative disorder (whatever that is)
    4. Rett syndrome — this one has a known mutation causing it. 
    5. Pervasive developmental disorder not otherwise specified
Particularly note #5 — it lets in a lot of kids, and, as noted above,  between 2- 3% of the population has an IQ 70 or below. 

       [ Cell vol. 135 pp. 401 – 406 ’08 ] A variety of known genetic defects have features of autism. All of them together account for 5 – 15% of patients with autism spectrum disorder [ Nature vol. 466 pp. 368 – 373 ’10 ] .
  l.  Fragile X — 15 – 30% are autistic 
  2. Tuberous Sclerosis 25% – 60% autistic (I really doubt this based on experience)
  3. PTEN hamartoma syndrome
  4. Neurofibromatosis type I (said to be 4% — disagree ! ! !)
  5. Rett’s 100%
  6. Angelmann’s syndrome (said to be 4%  — disagree)
  7. Timothy syndrome 60%
  8. Familial autism spectrum disorders with known genetic defects 
    a. NLGN3/4
    b. NRX1 (neurexin 1 ?)
    c. SHANK3 (#22q13 microdeletion syndrome)

Sorry to be so technical, but you have to appreciate the heterogeneity of autism spectrum disorder to understand a recent editorial [ Neuron vol. 67 pp. 8 – 10 ’10 ] concerning a paper appearing elsewhere.   If you need help with some of what follows, look at the two posts on Molecular Biology Survival Guide for chemists.  The improvement in DNA sequencing and genome interrogating technology in the past few years is just incredible. Nearly 1000 individuals with autism spectrum disorder and 876 of their parents and 1287 controls were studied.  The authors were looking for large deletions and/or insertions in the genome.  By large, they mean over 30,000 nucleotides.  Now our genome is full of insertions and deletions when one of us is compared to another. 11,700 sites where the population varies in how many copies of a particular sequence are known presently (these are called copy number variations, aka CNVs).  The technology is such that the authors were able to use a chip with 1,000,000 sequences (which, if evenly spread through the genome, would be one every 3,200 nucleotides).  So it is unlikely that the chip missed many insertions or deletions (aka indels) over 30,000 nucleotides long (but see later)

Some of the CNVs are common, and the authors decided to look for CNVs, affecting less than 1% of the population (e.g. the rare ones), a perfect set up for Tolstoy. In the controls an average of 3.6 genes were intersected by the rare CNVs, while the autism spectrum disorder (ASD) had a higher number (4.3 genes).  Not much different, but because, of the large number of people in the study, definitely significant.  Because some parents of autism spectrum disorder kids were also studied, they could tell whether the CNV was new to the child (assuming BOTH parents were studied, because infidelity is always possible).  Some 5.7% of the ASDs had a de novo event (a CNV which wasn’t present in the parent(s) ).

Lots of people have been looking for genes implicated in ASD, and some have been found in other studies– the names are all acronyms (SHANK2, SynGAP, DGLAP2).  Even studying nearly 1000 ASD individuals  CNVs in these (already known) genes were found only in one or two cases out of the nearly 1000 ASDs.  So Tolstoy is right in spades, unhappy families with an ASD kid really are all different, each in their own way.  Of interest to drug design chemists, NONE of the protein coding genes affected by the CNVs involved neurotransmitters or their receptors.  (Probably anything messing with them would be lethal, but I’m pretty sure that some neurotransmitter receptor mutants have been found).

Since just about everyone has a rare (appearing in under 1% of the population) large (over 30,000) CNV — recall that the average number in controls was over 3, it’s going to be difficult if not impossible to pick out the culprits.

Now I’ve written a lot about how protein-centric molecular biology was.  It still is.  What did the authors focus the assay chip’s 1,000,000 interrogating sequences on?   The sequences were not randomly distributed throughout the genome, but rather on the 20,000 or so protein coding genes that humans possess.  Recall that the actual amount of DNA coding for amino acids is a mere 1.5% of the 3.2 megaBase genome.  They literally ignored the dark matter of the DNA (the part not coding for protein).  For details see  The editorial conflates the term gene, with protein coding genes.  This just won’t do.

I’ve said this before, but it bears repeating.  At one point it was stated that humans and chimps should really be considered one species, because our proteins are so similar.  This is like saying Monticello and Independence Hall are just the same because they’re both made out of bricks.  One could chemically identify Monticello bricks as coming from the Virginia piedmont, and Independence Hall bricks coming from the red clay of New Jersey, but the real difference between the buildings is the plan.

It’s not the proteins, but where and when and how much of them are made.  The control for this (plan if you will) lies outside the genes for the proteins themselves, in the rest of the genome.  The control elements have as much right to be called genes, as the parts of the genome coding for amino acids. Granted, it’s easier to study genes coding for proteins, because we’ve identified them and know so much about them.  It’s like the drunk looking for his keys under the lamppost because that’s where the light is. We’re only beginning to understand the controlling elements.  It would be fascinating to see how many indels the ASDs, parents and controls had in the  98.5% of the genome not studied.   Since we have the sequence of the human genome in hand, it shouldn’t be too hard to design a 1,000,000 sequence chip, with the interrogating sequences spread 3,200 nucleotides apart. The problem is we’re not exactly sure what we’re looking for.  The de novo CNVs may be a new lamppost.  Stay tuned.

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  • lona  On March 4, 2016 at 12:53 pm


    First if all, I have to say that your paper is over my head and very scientific. As a layman, I tried to understand your final point but was lost in the scientific data LOL.

    However, if I may, I would like to ask your opinion on my very simplified, and simple minded “theory”.

    I’m very interested in Aspergers. And it seems to me that it is very common among scientists and geniuses. But also perhaps more common than we think among the general population, especially in academic, medical, and technical fields. And when we think about it, perhaps also more common among certain ethnicities such as Asians, Indians, and Northern Europeans.

    So here is my theory:

    I wonder if there are two types of human beings:

    The ones with a certain brain wiring which we’ll call type X and others with another type of brain we’ll call Z.

    Type X (ASD) is more analytical, sensitive, scientific, philosophical. In other words, uses analytical thinking, has stronger senses, therefore is more reclusive, needs more alone time, more sleep, is physically less affectionate, less needy, less playful, less hateful, more into being good, loves nature and animals, science, space and exploration, justice, clear cut rules and order.

    Type Z is more affectionate, more social, loves physical closeness and contact. Hates to be alone, is less analytical and uses abstract thinking, is more social, enjoys conversations and company of others. Loves group activities, games, teams, sports, religion, politics, management, sales, big cities and big parties.

    Both types have a whole spectrum of intelligence from highly intelligent to poor intelligence as well as personality disorders. ( Although maybe Type X is more susceptible to personality disorders because of the mistreatment and ridicule it receives from type Z for being different than them).

    Could we be wrong in calling one type (Z) normal, and the other ( X or ASD ) abnormal???

    In your opinion, is it conceivable to use this approach in research for ASD?

    Thank you,

  • luysii  On March 4, 2016 at 4:23 pm

    Lona: Thanks for commenting.

    It is a natural human tendency to split things into two categories — true/false, black/white, right brain/left brain, male/female — but life is more complex than that. The point of the article is that there are many different genetic ’causes’ of autism not just one or two, and in fact there are many different types of autism.

    It is also worthwhile being aware of the fact that the criteria for diagnosis have changed markedly over the past 40 years (allowing far more people to fit the diagnosis) This is why it was thought to be rare in the 70’s (around 1/10,000) and common now (under 1/100).

    • lona  On March 4, 2016 at 5:07 pm

      Thank you so much for your response. I agree.
      Like normal/abnormal.
      I know my view is very simplistic. But I hate being considered “abnormal” as having a “disorder” because I have Aspergers. Just hoping for a day where there is more tolerance out there for sensory and processing differences.
      Thanks again!!!

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