De novo missense variants disrupting protein-protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types.
Siwei Chen, Jiebiao Wang, Ercument Cicek and 3 others
PMID 33032641WHAT IT FOUND
Rare new genetic changes that break protein contacts were more common in autism than in unaffected siblings, especially in genes active early in brain development and in neurons.
The paper gives no therapy target.
Key findings
01Predicted interaction-disrupting de novo missense variants were more common in ASD probands than in unaffected siblings.
02Disrupted interaction genes were expressed more highly in developing brain and showed the strongest differences in neuronal cell types.
03Probands carrying variants on novel DAWN genes also had reduced intelligence, impaired social ability, and delayed age of walking.
STILL TO COME
How it was doneWhat they found
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What it does not show
The study is a computational genetic and brain expression analysis, not a clinical trial or therapy study. It used existing whole-exome sequencing and brain expression datasets, so the researchers could not assign participants to treatment or control for therapy. Interaction disruption is predicted from protein structure and damage scores, not directly measured in patients. The authors state that guilt-by-association and the human interactome are imperfect. The authors also note that some novel DAWN genes could be false positives because their gene constraint scores are intermediate. The outcomes are genetic or diagnostic features, not therapy response.
Declared interests
Foundation for the National Institutes of Health, Simons Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Human Genome Research Institute funded the work.
The easy way to misread this
Do not read the new gene lists as proven causes of autism or as guides to therapy. The paper reports computational associations and candidate genes, and its own limitation says some novel genes could be false positives.