Autism spectrum disorder (ASD) has a strong genetic component, including gene changes that are passed on from parents (inherited) and changes that occur spontaneously in an affected individual (de novo). De novo genetic mutations are a known cause of ASD in “simplex” families, families in which there is a single individual with autism and the overall familial risk for the condition is low. Prior estimates have suggested that de novo mutations may contribute to perhaps 40 percent of ASD in such families. Individuals in families with multiple affected members are considered high risk, with causal genetic changes often inherited from parents. De novo mutations are expected to contribute to risk in these multiplex families as well, but the extent to which this is the case has been unclear. Additionally, the reported degree to which de novo mutations contribute to simplex ASD may be an underestimation, as prior studies have not taken into consideration all types of gene mutations. A recent study from SFARI Investigators Ivan Iossifov, Michael Wigler and their colleagues provided a rigorous assessment of the impact of de novo mutations in both simplex and multiplex families (Yoon et al., Commun. Biol., 2021).
Supported in part by SFARI funding, the researchers looked at whole genome sequencing data from simplex families enrolled in the Simons Simplex Collection (SSC) and data from multiplex families enrolled in the Autism Genetic Resource Exchange (AGRE). This allowed them to detect gene changes not previously examined, including intronic mutations, and to compare the impact of de novo mutations in both low- and high-risk families. Preliminary results suggest that de novo mutations contribute to 52–67 percent of ASD in low-risk families, but only 9–11 percent in high-risk families, supporting the view that spontaneous genetic changes are much more likely to be a cause of ASD in low-risk than in high-risk individuals.