Differences in the Genetic Background Contribute to Risk and Resilience to Autism

Background: In the last 20 years, there was a tremendous progress in identifying genes associated to autism spectrum disorders (ASD). The genetic architecture of ASD is complex, ranging from apparently monogenic forms of the disorder to highly polygenic forms. However, if rare deleterious mutations affecting approximately 100 genes are now well accepted as risk factors for ASD, the role of the genetic background on their variable penetrance remains poorly understood.

Objectives: To identify resilient individuals, carrying rare deleterious mutations in ASD susceptibility genes without being diagnosed with the condition, and study the genetic factors influencing their clinical trajectories.

Methods: We designed a framework to assess the risk associated to more than 11,000 rare deleterious mutations in parents and children of 1,786 quadruplet families with one affected and one unaffected child of the Simons Simplex Collection. We investigated hallmarks of mutation intolerance (haploinsufficiency, probability of loss-of-function mutation intolerance, z-score for missense mutation or deletion intolerance) to discriminate mutations likely to affect gene function. We also used clinical records available for each family to focus on mutations identified in children displaying a clear discordance in ASD phenotype (SRS and VABS-II scores).

Results: The fraction of resilient individuals among siblings and parents was surprisingly high, with approximately 7% of individuals carrying rare deleterious mutations in ASD-associated genes without displaying ASD symptoms. By stratifying resilient children from other unaffected children, we confirm a significant role of polygenic risk in ASD etiology. In addition, we observe significant differences in polygenic risk between affected and unaffected children who inherited the same rare deleterious mutations and between affected children with rare inherited deleterious mutations and affected children without.

Conclusions: The genetic background significantly influences the clinical trajectory of siblings carrying similar deleterious mutations in ASD-associated genes. Our results highlight the importance of investigating rare deleterious mutations in ASD susceptibility genes in the context of the genetic background, as well as the clinical heterogeneity of both diagnosed and undiagnosed individuals. Understanding the genetic factors contributing to resilience to ASD provides new insights into the molecular mechanisms of ASD, ultimately allowing the development of novel therapeutic strategies.