Rare variants in the outcome of social skills group training for autism

BackgroundExome sequencing has been proposed as the first-tier genetic testing in autism spectrum disorder (ASD). Here, we performed exome sequencing in autistic individuals with average to high intellectual abilities (N = 207) to identify a molecular diagnosis of ASD and genetic modulators of intervention outcomes following social skills group training (SSGT) or standard care. MethodsWithin a randomized controlled trial of SSGT, we performed exome sequencing to prioritize variants of clinical significance (VCSs), variants of uncertain significance (VUSs) and generated a pilot scheme to calculate genetic scores representing the genetic load of rare and common variants in the synaptic transmission pathway (GSSyTr and GSSyTc). The association with the primary outcomes (parent-reported autistic traits, Social Responsiveness Scale) was computed using a mixed linear model. Behavioral and genetic features were combined in a machine learning (ML) model to predict the individual response within the cohort. ResultsIn total, 4.4% (n = 9) and 11.3% (n = 23) of the cohort carried VCSs and VUSs, respectively. Compared to non-carriers, individuals with VCS or VUS together tended to have limited improvements of the interventions ({beta} = 9.22; CI (-0.25, 18.70); P = 0.057) and improved significantly less from standard care ({beta} = 9.35; CI (0.70, 18.00); P = 0.036), but not from SSGT ({beta} = -2.50; CI (-13.34, 8.35); P = 0.65). In addition, both GSSyTr and GSSyTc were associated with differential outcomes in standard care and SSGT groups. Our ML model showed the importance of rare variants for outcome prediction. ConclusionsAutistic individuals with likely pathogenic rare variants identified by exome sequencing might benefit less from the standard care. SSGT could therefore be of heightened importance for this subgroup. Further studies are needed to understand genetic predisposition to intervention outcomes. Trial registrationSocial Skills Group Training ("KONTAKT") for Children and Adolescent With High-functioning Autism Spectrum Disorders (KONTAKT-RCT), NCT01854346. Submitted 20 April 2013 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT01854346?view=record