Last month, my colleagues and I published two large studies that sequenced the genes or exomes of thousands of families with a history of autism. These studies identified several dozen ‘high-confidence’ autism genes that show spontaneous, harmful mutations in multiple affected (and unrelated) individuals.
Picking the ripest of these low-hanging fruits — through ‘brute-force’ genomics and discovery of spontaneous, or de novo, mutations — has brought us much closer to understanding the genetics of autism than we were just five years ago. But to optimize what we can learn, our studies must be informed by what we have already discovered. We certainly need many more sequences from more families with autism. But these sequences need to be of the right kind.
When large-scale genomic analysis began on cohorts of people with autism, we hoped — and expected — to discover many, if not most, of the underlying genes. We have undoubtedly found many, and perhaps even most, using the broadest criteria for an autism gene.
We can now put forth a statistically sound estimate of the overall genetic contribution of de novo mutations of different categories to autism. (These categories include loss-of-function mutations — which prevent full protein production — and missense variants, which have a less clear effect on protein function.) There is little doubt that this approach remains the most powerful weapon in today’s arsenal —not just for autism spectrum disorders, but other neuropsychiatric and sporadic genetic disorders as well.
But we still cannot pinpoint the causal mutations for many cases of autism because the genomic background noise remains high: More than half of even the most damaging single hits to a protein are present in an individual by chance and are not linked to autism. Given this, it is not always clear what to tell clinicians and genetic counselors who are on the front line and wish to make use of these data.
So what is the future of family-based genomic studies of autism, with detection of de novo mutations as the central focus?
Read full, original article: Future of autism genetics should learn from its past