6/12 at #UCDavis: Stephen Scherer on “Detection of Clinically Relevant Genetic Variants in Autism Spectrum”

UC Davis MIND Institute’s 2012-2013 Distinguished Lecturer Series

SPEAKER: Stephen Scherer, PhD, DSc
Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder
Wednesday, June 12, 2013
TIME: 4:30 pm – 6:00 pm
MIND Institute Auditorium (2825 50th Street, Sacramento)

Background Information ( see attached and below)

Bio Info: Stephen Scherer, PhD, DSc, FRSC, holds the GlaxoSmithKline-Canadian Institutes of Health Research Endowed Chair in Genome Sciences at The Hospital for Sick Children and University of Toronto. Dr. Scherer is director of the University of Toronto’s McLaughlin Centre and The Centre for Applied Genomics. He has made numerous contributions to medical genetics including mapping, sequencing and disease gene studies of human chromosome 7. In 2004, his team co-discovered global gene copy number variation (CNV) and has since shown that CNV is the most abundant type of genetic variation of human DNA. His group then identified CNV that contribute to the etiology of autism and many other disorders. The Database of Genomic Variants that he founded facilitates hundreds of thousands of clinical diagnoses each year. His work is documented in over 300 publications and patents and cited more than 20,000 times, ranking him as one of the top cited scientists over the past decade worldwide. Dr. Scherer has won numerous honors such as the 2004 Steacie Prize, an International Howard Hughes Medical Institute Scholarship, and the Premiers Summit Award for Medical Research. He is a distinguished Fellow of the Canadian Institute for Advanced Research, the American Association for the Advancement of Science, and the Royal Society of Canada.

Presentation: (Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder )
Autism Spectrum Disorder (ASD) demonstrates high heritability, familial clustering and ~4:1 male to female bias, yet the causes are only partially understood, due to extensive clinical and genetic heterogeneity. Whole genome sequencing (WGS) promises added value to identify novel ASD risk genes, as well as new mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. In a pilot study, we used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in 6 of 32 (19%) and X-linked or autosomal inherited alterations in 10 of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such mutations was larger than has been previously reported, a yield that is in part due to the more comprehensive coverage afforded by WGS. Deleterious mutations were found in four novel, 9 known, and 8 candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to the FMR1 gene that is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (also linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough informatic analyses may improve the detection of genetic variants likely associated with ASD or its associated clinical symptoms

Scherer_ Bioabstract_05282013.pdf

Velasquez-Manoff opinion piece in the NY Times on autism, parasites & inflammation; nice ideas; not enough caveats

There is a very interesting “Opinion” piece in the New York Times today: Immune Disorders and Autism – NYTimes.com.  By Moises Velasquez-Manoff is details some recent work that the author believes relates to autism and a variety of other human ailments with an autoimmune connection.

The general logic/key points seem to be as follows:

  • Some autism cases look like a form of inflammatory diseases with the immune system overactive (inflammation on high, anti-inflammation on low, or some combination thereof)
  • Infection of a mother during pregnancy increases the risk of having a child with autism.
  • In animal models, inducing inflammation in the mother (even without an infection) leads to an increased risk of behavioral “problems” in her offspring
  • Inflammatory and/or autoimmune diseases (e.g., asthma) have increased in incidence along with autism.
  • If a mother has automimmune or inflammatory diseases such as rheumatoid arthritis celiac disease she has a higher risk of having a child with autism.  Similarly if a mother has allergies or asthma during the second trimester, there is a higher risk of having children with autism.  
  • Many automimmune and inflammatory disorders and autism are all more prevalent is the developed world.
  • The developed world is generally cleaner that the developing world.  
  • There are many fewer parasites in people in the developed world.
  • Parasites are known to suppress inflammation.
  • Therefore, we may be able to stop/limit autism, asthma, and other inflammatory diseases by purposefully infecting people with parasites from our evolutionary past. 

Now, personally, I like the general hypothesis here.  It makes complete sense.  But alas, it is suffers from this issue that is spreading almost as fast as these diseases – a lack of a discussion of the distinction between correlation and causation.  I have been obsessing about this a bit recently with studies of the microbiome.   Overall, I do like this current article.  It mixes human epidemiological studies with controlled animal studies with discussion of conceptual models.  But alas there is really no discussion of the challenges if disentangling correlations vs. causation. And I think it is a bit dangerous in the latter parts with the jump to potentially curing these various ailments by purposeful infection with parasites.  Again, I like the idea.  But a few caveats would have been nice.  I am glad it was marked as an opinion piece but even when one states an opinion about a medical issue, one can still say “there are reasons why this might not be true .. such as …”.  Too bad that wasn’t done here.

UPDATE – Emily Willingham has written a VERY detailed critique of the article that I think everyone interested in anything related to this topic should read: Emily Willingham: Autism, immunity, inflammation, and the New York Timeswww.emilywillinghamphd.com.

Put down what you are doing & read this article: Amy Harmon "Autistic & seeking a place in an adult world"

Some people out there complain about the death of great scientific and medical writing. Well, I say to them “What exactly have you been reading?” Sure there is crummy stuff out there. But there are some masterpieces. And yesterday night I found one – Amy Harmon has an article that was released online last night and published in the Sunday New York Times Today: Autistic and Seeking a Place in an Adult World.
It is a spectacular piece of work – captivating, heartbreaking (in ways), inspiring (in others) and just brilliant in many ways. I have just read it for the third or fourth time. And probably about to go back for another look. I recommend everyone and anyone give it a look.