Thursday, January 10, 2008

Autism, Chromosome 16p11.2 and De Novo Gene Mutations

As the father of a son with Autism Disorder I have been following closely the incredible explosion of research into the nature, causes and possible treatments for autism, what I describe as the Autism Knowledge Revolution. As someone who is not a scientist or researcher I try to read the original journal articles publishing these findings but usually have to resort to other sources to translate the language and concepts downward to my own level of understanding which is basically plain English.

It is exciting to see new reports like the Association between Microdeletion and Microduplication at 16p11.2 and Autism published in the New England Journal of Medicine which identifies a Chromosome involved in 1% of autism cases. I try to read and understand the original articles but I also like to consult layman's interpretations offered by credible sources for help and certainty that I truly understand the nature of the research and the possible implications of any findings. I also check other autism bloggers but do so with the knowledge that autism bloggers have a tendency to try and cram any new studies into their own ideological take on the major autism fault lines such as the genetics versus environment causal debates.

My own view for many years based on little more than the "twins" studies and my own son's pre and post natal history was that genetics was probably more significant than environment in causing autism. But I never ruled out environmental possibilities and it is not clear to me that a truly scientific, or at least a truly open minded approach ever rules any possible factor, or set of factors, out on an absolute basis. It is with that mindset that I have read the Chromosome 16p11.2 report and various news commentaries on the report and its findings.

Any finding of a genetic basis to autism gives many of us an automatic knee-jerk thought that autism is an inherited condition, a simple "like father like son", causal relationship. But as I read the article, with my layman's limitations, I was struck by the reference to "de novo mutations" and it was difficult for me to see a simple direct inheritance relationship in what the authors were saying, although admittedly I might have misunderstood:

The abstract published in the NEJM states:

Methods As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland.

Results Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor.

Conclusions We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations.

As a practicing lawyer I am familiar, in the legal context, with the expression "de novo". In some Canadian legal processes an appeal can be done by way of "trial de novo", essentially a new trial before a higher tribunal, rather than an appeal of specific issues from the original trial. I wasn't sure what "de novo" meant in describing genes.

In What is a gene mutation and how do mutations occur? the NIMH states:

Previous pageNext page Previous pageNext page

A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome.

Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person’s life in virtually every cell in the body.

Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder.

Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation.

Every step forward in understanding autism is in itself a positive development. And popular comment on the Chromosome 16p11.2 findings argue that the findings may help lead toward development of drugs which could be aimed at treating or curing some cases of autism. I hope so.

In the meantime though I also remain curious about the nature of the de novo gene muations involved and the extent to which they are caused by environmental factors.


Anonymous said...

Harold -- Breaking news:

Ettina said...

"Every step forward in understanding autism is in itself a positive development. And popular comment on the Chromosome 16p11.2 findings argue that the findings may help lead toward development of drugs which could be aimed at treating or curing some cases of autism. I hope so."

Time and again they say that, but really only very few genetic conditions are treatable any way other than symptomatic (based on symptoms - eg surgery for heart defects, special education for delays, etc). What finding the genetic cause really means, in my experience, is a prenatal test so they can abort fetuses with that condition.
By the way, as far as I know, certain chemicals (called mutagens) can increase the frequency of de novo genetic changes, but there's a certain baseline level that will always occur. That's how we evolve. And basically any cancer-causing chemical is a mutagen, but not all affect the gonads.

Anonymous said...

The blog entry after this one metiones gene CNTNAP2 and "parent-of-origin effects". I think a more likely scenario than genetic screening for abortion will be to include this genomic mutation in fertility/genetic testing for parents before they have kids. The "triple screen" blood test given to pregnant women for Down Syndrome and Spina Bifida is non-invasive to a fetus and only indicates the possibility for increased risk (if there is increased risk for these conditions amniocentesis is advised). Unless there is a blood test for mothers that can indicate a high risk of the gene mutation (if it causes some sort of marker in the mother's bloodstream),

I don't think the general population will be undergoing amnio for autism screening anytime soon, as it carries a big risk in causing miscarriage. Probably only if genetic tests on the parents indicate the mutation (or the likelyhood of it) is present will they be advised to have it done (and given the generally despairing atmosphere surrounding autism, they probably will)

Unknown said...

"What finding the genetic cause really means, in my experience, is a prenatal test so they can abort fetuses with that condition."

ettina, with all respect, I do not think such a sweeping statement can be supported. It simply is not possible to say what future research will produce.

Anonymous said...

My son recently was diagnosed with Asperger's syndrome. The neurologist happened to do a karyotype, which revealed increased genetic material at 16p11.2. I was then tested and have the same abnormality. I do not exhibit any ASD traits, however we do have many individuals in our family that probably would have a diagnosis if they had grown up in a different time. Some one had mentioned that this new information about the 16th chromosome paves the way for aborted fetuses. In some ways you may be correct, however, I would not have changed my decision to have this child, even if I had known before birth. Children with autism have touch my life and heart for many years, as I used to do ABA before entering into the field of early intervention. I think that maybe the identification would help us reach these children at an earlier age. This is a very special group of children who are here to teach us a great deal. Every day I spend with my son is another that I wish I could see the world through his eyes. He thinks on such a different plane than the rest of us. I think we need to stop and listen to what these kids are telling us. As to the debate of genes vs. environment, how about a middle ground. I truely believe there is merit to both sides and that neither is fully to blame at anytime. We all have genes that predispose us to certain diseases, for example diabetes, however our environment ie. our diet etc. has a lot to do with if that gene is expressed. My heart goes out to all those who are struggling. Best wishes on your quest.

Anonymous said...

see other links.
not all info are close to 16p112