I am cross-posting to here my comment and questions regarding a recent paper on Autism genetics, discussed here: http://www.genomesunzipped.org/2012/04/guest-post-by-ben-neale-evaluating-the-impact-of-de-novo-coding-mutation-in-autism.php
My comment (as of April 2012, I had not received a response):
Thanks very much to Ben for taking the time to post to Genomes Unzipped about his very nice paper in Nature, which I just read. One question: can you direct us to the best source of information on what fraction of all autistic cases are definitely de novo, where an ADI/ADOS ruled out any manifestations of autism, Apserger’s or any other major psychiatric illness in the parents? I assume that this was done rigorously for the Simons Simplex collection, but I’d like to know what fraction of “autism” this actually includes? From my own experience as a child psychiatrist, it seems to be often the case that the father or mother of children with autism or other severe mental illness themselves have subthreshold symptoms, which of course might be due to decreased expressivity of the disorder in these parents, due to environment, genetic background, or other effects. Also, if one extends the family to grandparents, uncles, aunts, cousins, etc…. one finds often that there are other family members with psychiatric symptoms, which I believe has also been documented epidemiologically. One criticism would therefore be that a de novo design automatically eliminates these inherited variants, so one must of course be absolutely certain that the parents are unaffected and that there isn’t evidence for a recessive disorder manifesting itself but with variable expressivity, hence not found easily in low-resolution linkage studes, particularly if the rare variants are unique to single families. Anyway, I’d be very interested to have you direct us to the best sources about the fraction of autism arising from parents and extended family members with zero evidence of major psychiatric illness, as you have focused on in your paper. Of course, this has relevance for all major psychiatric illness.
Just as an aside, I will post below something I am writing now of relevance to the above discussion. Any comments on this are welcome:
It is very likely that there will be a continuum of disease, with a blending of oligogenic into polygenic modes of inheritance. This is in part simply a semantic argument, given that the “penetrance” or “effect size” of any particular mutation will obviously vary according to genetic background and environment, as demonstrated repeatedly in model organisms (1). Thus, while a mutation causing hemochromatosis or breast cancer might have high penetrance in one particular pedigree or clan, that same mutation may have very low penetrance in another pedigree, clan or group of unrelated individuals (2). The reasons for variable penetrance can be quite variable and are currently a mystery in many instances. For example, although tri-allelism has been advocated to explain variable penetrance in Bardet-Biedl syndrome, this has recently been strongly called into question due to what we consider to have been low penetrance (or, as per those authors, low expressivity) of the disease in certain members of families (3). This is due to the fact that in the original report two brothers with the same two mutations in one gene were classified as one “affected” and the other “unaffected”, prompting a search for a third mutation in another allele to account for this perceived penetrance issue (4). However, variable penetrance could easily explain this, if one of the brothers maybe had retinitis pigmentosa or some other subthreshold symptom of Bardet-Biedl syndrome, leading to an incorrect classification as “unaffected”. Only time will tell on this, however, as the families in the two reports are different, so we await further phenotypic clarification.
Thanks again for posting to this great blog forum! and I hope you can take the time to respond to this question too.
1 Casanueva, M. O., Burga, A. & Lehner, B. Fitness trade-offs and environmentally induced mutation buffering in isogenic C. elegans. Science 335, 82-85, doi:10.1126/science.1213491 (2012).
2 Kohane, I. S., Hsing, M. & Kong, S. W. Taxonomizing, sizing, and overcoming the incidentalome. Genet Med, doi:10.1038/gim.2011.68 (2012).
3 Abu-Safieh, L. et al. In search of triallelism in Bardet-Biedl syndrome. Eur J Hum Genet, doi:10.1038/ejhg.2011.205 (2012).
4 Katsanis, N. et al. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science 293, 2256-2259, doi:10.1126/science.1063525 (2001).