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Loss-of-Function Genetic Variants Associated With Autism

In a new study appearing in Nature Medicine, the researchers from the Institut Pasteur and elsewhere studied whole-exome sequencing data of more than 13,000 individuals with autism and 210,000 individuals who have not been diagnosed with autism. Prior to this study, little is known about the prevalence of rare loss-of-function (LoF) variants within autism related genes in individuals without a diagnosis of autism. Using the exome sequencing data, the researchers estimated the odds ratio (OR) that rare LoF variants in 185 genes were associated with autism. They additionally focused on a subset of LoF variants they dubbed stringent LoFs (S-LoFs), as many known autism-associated genes are intolerant to LoF variants. "The reasons why some individuals carrying the S-LoF will have a diagnosis of autism, and some do not, probably depend on additional genetic, societal, and environmental factors," the authors write.  Additionally, in brain imaging data from 21,040 individuals from the UK Biobank, the researchers could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. The findings highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis, the authors note.