Title: Genome wide searches for autism.

Disclosure: work is his own, but was here as a guest of Complete Genomics.

Backround on neurodevelopmental brain disorders

• Big question: How does brain form and work?
• Recent work has been focused on autism.
  • Stats presented on autism (1:110 are autistic, using broad def of autism)
  • 8% recurrance risk for siblings.
• Cognitive imparement in 50-60%
• regression in 10-25% of cases
• Challenges to gene discovery
  • difficult to make diagnoses (especially @ genetic level where 80-95% of cases)
• Hypothesis: repressive burden
  • Nice slide: rate of cousin marriages corresponds to regions with higher birth defects and cognitive imparement.  (Mainly middle east and north Africa.)
  • over 200 pedigrees collected.
  • Focus on middle east, where cousin marriages are common and culturally appropriate.
• use 500k snp chips
  • phase I: validation and CNV discovery
  • Phase II: targetted sequencing… which migrated to whole genome
• Locus Heterogeneity
  • Many bands are implicated
  • Sequence region to identify candidate genes (mutations)
• At this point, in comes Complete Genomics.
  • 40 individuals with autism sequenced
  • Analysis for non-complete genomics data set involved wading through forest of open source tools – complete genomics, tho, you just get hard drives and the data is ready to use.   (Big contrast)
  • Coverage: 63x coverage, 95.6% bases called
• Variant calling: used rare gene model
  • 3.2M variants
  • 1k pathogenic  + novel
  • 100 pathogenic + novel + homozygous
  • 10 pathogenic + novel + homozygous + linked.
• When compared to known autism genes, they were able to identify several individuals where it WAS the causative variant.
  • Most were still not obvious, however.
• [Skipping clinical/patient data]
  • For this patient, a chr6 area identified.
    • from 3.2M snps, only 4 were consistent with recessive model, one was in PEX7.
  • All affected family members had mutation in PEX7
  • Absent in 700 controls.
• 2nd example:
  • “Mutation in known gene with atypical presentation can be autism.”

Conclusions:

• There will be no “autism gene”
• WGS will help us understand the disease
• Not all genes identified will be new, and many will have known interventions.
• There will new ones too.
• Autism is complex, but some variations will be “low hanging fruit”, such as autosomal recessive presented here.

[All in all a neat talk – similar to cancer, wading into a complex genetic landscape.]