Joseph Gleeson proposes to identify mechanisms and origins of de novo mutations (DNMs), which make important contributions to the risk of autism spectrum disorder (ASD). These mutations are classically thought to arise in the one-cell-stage zygote at the time of fertilization and are often assigned a low risk of recurrence. However, the risk of DNMs is directly related to paternal age, and most de novo single nucleotide variants (SNVs) arise from the father’s cells, suggesting an origin in sperm.

The Gleeson laboratory has preliminary findings from the Simons Simplex Collection (SSC) that a substantial fraction of simplex ASD cases due to DNMs have gonadal mosaicism detectable in the sperm of the father, and in at least one case, this has led to recurrence of disease. Gleeson’s team also found that approximately 5 percent of all DNMs in offspring (including ASD-related and non-ASD-related) are detectable in the sperm of the father even months or years after conception. Thus, preliminary results suggest that paternal gonadal mosaicism is an underestimated phenomenon, and that this information can be used to stratify potential fathers into risk categories for having a child with ASD.

In the current project, Gleeson proposes to expand this assessment to 50 families (using additional families from the SSC as well as families participating in a cohort at the University of California, San Diego), in order to measure gonadal mosaicism by deep sequencing of sperm samples for the presence of ASD-causative mutations. He also plans to test the variability of this ASD-relevant gonadal mosaicism across time in individual males and across men of various ages.

Finally, Gleeson proposes to calculate the risk of recurrence of ASD within single families from measurements of gonadal mosaicism in men, considering the risk attributed to certain ASD gene mutations and the allelic fraction of these mutations within sperm. This information should improve estimates from the current guidelines of a 1 percent baseline recurrence risk to the vast majority of cases with a near 0 percent recurrence risk and a small fraction with a substantially higher risk. The results of this study will also uncover basic mechanisms of gonadal mosaicism in males and a source of mutations leading to ASD.