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.
- For this patient, a chr6 area identified.
- 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.]
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