On Wed June 14, we had the chance to listen to a talk by Dr. Steven Scherer, a key researcher at Sick Kids hospital about his research on ASD. I attempted to summarize the talk below.
To begin, ASD (Autism Spectrum Disorders) is a disorder that involves deficit in one of more domains of social, behavioural, and language abilities of a person. It is a broad spectrum of over 100 disorders and some notable example are Rett, Fragile X, Timothy, and XXY-kelinfelter’s syndrome. The average age of onset is about 4.5 years old.
From past research, it has been shown that genetics is involved ASD. In twin studies there is a 50-90% MZ concordance. Interesting side note; the ratio of the disorders in ASD seem to be 4:1 male to female ratio.
Key note: every ASD risk gene is associated with intellectual disability genes, however not every intellectual disability genes are associated with ASD.
In the general population, ~10% of genome are CNV, ~90% are copy number stable.
Important CNV in ASD
- rare CNV deletion at SHANK1 : only male carriers result in ASD. Density in synaptic spine volume is reduced in ASD.
- ASTN2 CNV : All maternal transmission . ASTN2 is a huge gene. risk of anxiety. Site of gene must be considered. Rare deletions at 14q23.3 affecting GPHN expos
What is Scherer lab doing now?
- MSSNG : a collaboration with Sickkids and Google that stores phenotype a and genotype data on cloud. Apparently cloud storage costs more than sequencing. I actually thought this was an interesting. Imagine each person can sequence our genes on a monthly basis (to keep track of our mutations). Do you think there would be a git system for our genes and suppose there is, how could it be implemented? (read more at https://www.mss.ng )
- Precision medicine development with WGS.
There are on average 73 spontaneous dev novo mutations consisting of 60 SNV and 13 indels & larger CNV, compared to 3 somatic exonic mutations detectable on an individual (I believe it was meant in a person with ASD). There point that was made here was that gene replication is very stable.
KEY MESSAGE :
We need to look at the whole genome, WGS is very important. Because even if we think nothing is wrong with a gene the mutations might be on another unexpected gene. WGS now only takes 2 days. Just doing exon sequencing may miss half the important genes.
Most de novo mutations come from the father’s genes. With that in mind, the highest risk factor for autism today is : advanced paternal age. Somatic mutations may lead to ASD. I believe it was meant that somatic mutations in early development stage may lead to ASD. It would be interesting to think however, as an open ended question, if a mutation in a developed brain can ever lead to ASD for adults.
It was mentioned that there was an interesting case study about a family where the dad was a carrier. Both the son and the daughter carry a severe deletion with the daughter doing a lot better than the son is. Could it be an environmental factor? Maybe, but what is for sure is that genes alone cannot explain.
- Be aware of rare variants in ASD : CNV or single gene mutation is enough to cause disorder/condition
- ASD is not being looked at at a genetic level with NGS. Many classes of genetic variants in many genes : ASD is unique(gene/environment). Most of the research currently deals with de novo mutations but the next focus is on somatic mutations.
- WGS needs to become the standard test in ASD instead of the current exon sequencing.