NEW YORK – New research suggests rare inherited or de novo mutations (DNMs) have similar impacts on autism spectrum disorder (ASD) risk in girls and boys, despite ASD diagnoses occurring roughly four times more often in males.
"Understanding the genetic basis of autism is crucial for developing better diagnostic tools and providing more personalized support," Wellcome Sanger Institute researchers Hilary Martin and Mahmoud Koko, and University of Cambridge researcher Varun Warrier said in an email.
"This study challenges previous assumptions that rare genetic mutations have a stronger effect in one sex over the other," they explained, "instead showing that differences in the frequency of their occurrence arise due to differences in the diagnostic threshold of autism and co-occurring conditions between the sexes."
As they reported in the American Journal of Human Genetics on Friday, Martin, Koko, Warrier, and colleagues brought together data from the Autism Sequencing Consortium (ASC) and the Simons Foundation Powering Autism Research for Knowledge (SPARK) initiative — including exome or targeted sequence data for 47,061 individuals with ASD and more than 84,900 unaffected siblings or control individuals — to search for rare, inherited, or de novo variants associated with ASD.
"Given that a larger proportion of autistic females than males have co-occurring cognitive impairment, potentially because of an underdiagnosis of autistic females with otherwise typical cognitive development, it is unclear if the observed sex differences in rare variant rates is simply a reflection of differences in the proportion of individuals with cognitive impairment between sexes," the authors wrote.
In contrast to prior research hinting at an overrepresentation of rare ASD-linked variants in females with ASD, the team did not see sex-related differences in rare variant contributions to ASD risk in males and females. Instead, the results suggested that excess ASD diagnoses in males may stem from other potential clinical, biological, and social differences, the researchers explained — from potential common variant contributors to sex-related differences in ASD presentation or detection.
"Previous studies suggested that females require a higher genetic likelihood to be diagnosed with autism," they noted. "This study refines that understanding, demonstrating that the effect on autism predisposition conveyed by a rare protein-coding variant is similar across sexes."
The team found that the de novo mutations detected were overrepresented in genes with male-biased expression in the brain's cortex region, while de novo mutations predicted to truncate proteins encoded by genes with ties to syndromic forms of ASD turned up more frequently in female participants.
Even so, the investigators did not see sex-related differences in the ASD risk stemming from these or other rare or de novo mutations considered, suggesting that further work is needed to continue untangling common and rare autosomal and sex-linked alleles and other nongenetic factors that may contribute to sex-biased diagnoses in ASD.
"Future research can build on these findings to explore nongenetic influences, like other social and biological differences, and further refine diagnostic approaches in order to understand why and how males and females have different diagnostic thresholds," the investigators said.
They noted that members of the team or their collaborators "are following this up to investigate how common genetic variants and hormones may possibly contribute to sex differences in autism. We are also investigating why girls and women are diagnosed, on average, later in life."