More on Genetics and Autism
The latest issue of Nature Genetics opens with an editorial entitled All in the mind about recent discoveries of de novo mutations in some cases of autism and schizophrenia. “Exceptional rigor and caution” are called for in the search for “causative variants”:
If many genes can be perturbed to produce a related set of psychiatric phenotypes, how can we establish a causal relationship? What if the visible rearrangements are the byproduct of a mutational process? Sebat et al. (Science 316, 445–449; 2007) considered that the hypothesis positing common causation of autism and CNV [copy number variant] by a “fragile genome disorder” would predict not single de novo CNV but larger numbers clustered in affected individuals. They did not find clusters of CNVs in any individual. However, this conclusion may be open to reevaluation, as existing chip-based methods assess larger CNV and the overwhelming majority of variants smaller than 10 kb may require higher-density arrays or even sequencing to genotype them.
In an excellent review on the genetics of autism, Abrahams and Geschwind (Nat. Rev. Genet. 9, 341–355; 2008) caution that “For some of the very rare, virtually unique, mutations even large sample sizes will not be sufficient to demonstrate statistical association, although the biological significance of the mutation may be clear.” To which we add our standard warning: if these disorders of mind are oligogenic and we do not have quantitative measure of the frequency and circumstances of discovery of the mutations, as well as the genomic background on which they occurred, we have only part of the picture. Incomplete notions of “biological significance”, unsupported by statistical significance, may once again lead us back into the wilderness. [my emphases]
Perhaps we’re stumbling through a wilderness of possible causes; am glad to have some guides along the way.
Go here for the July issue of Nature Genetics.
Tags: asd, asperger, autism, autism blog, disabilities blog, disability, Family, family blog, genes, Genetics, genome, Parenting, pdd-nos, Psychiatry, schizophrenia
3 opinions for More on Genetics and Autism
Mike
Jun 27, 2008 at 10:01 pm
There is no doubt that genetic mutations, changes, etc play a part in autism. And to me, there is no doubt that a toxic assault is to blame. (ref: http://www.bodyburden.org) Be it mercury, lead, artificial chemicals and flavors, fluoride, pollution from industry, man made chemicals, (you get the idea) …it is common sense that the rise in autism, childhood asthma, childhood cancers, and illness in general is caused by our toxic society. Why doesn’t the EPA and FDA protect us? They don’t care. They are bought and paid for by industry, we all know that. They’ll tell us 20 yrs later that the chemical they approved is harmful. We have to fend for ourselves when it comes to our health. Period.
RAJ
Jun 28, 2008 at 5:24 am
“An experimental design genotyping trios is indeed feasible and informative: this is how Sebat et al. (Science 316, 445–449; 2007) found de novo CNVs in 12 of 118 individuals with sporadic autism, a tenfold higher frequency than the 1% de novo CNV found in controls”.
Sebat also stated that only 10% of CNV’s are inherited and de novo mutations account for 90% of cases.
The parents would thus be unaffected which is an interpretation that would seriouly question the whole concept of the broad autism phenotype, if 90% of cases are de novo, mild autistic-like traits in the extended pedigrees of autistic people would be incompatible with Sabat’s hypothesis.
The most detailed study of a single healthy middle aged man found thousands of genetic mutations, including CNV’s in thousands of genes. This decoding of a single human being costs millions of dollars and took more than three years to complete. Sabat’s technology was primitice compared to the technology used in this report:
http://www.technologyreview.com/Biotech/19328/
daedalus2u
Jun 28, 2008 at 8:51 am
I went to a talk on the CNV work by Sabat. What they did was look at markers all along the genome, when those markers were missing they took a closer look at that region. The deletions that they found most frequently, were in gene regions that are normally duplicated multiple times in the genome and which happen to be involved in synapse formation. It isn’t at all clear that the deletions they found were of any significance at all. They only found them in a minority of people with autism, and then assumed that a more sensitive test would find more, and that the more sensitive test would not find more in the controls.
He had no clue as to a mechanism, he only found an association and assumed causation. He was just a “gene guy”, didn’t really understand how physiology all fits together (but to be fair, no one does). I didn’t find the case he presented to be compelling. Some of the CNVs he found were inherited and had no (apparent) adverse effects in the parent.
RAJ is completely correct, a majority of autism being caused by de novo genetic events is completely incompatible with the familial associations of autism that are very well known.
Have an opinion? Leave a comment: