Previous studies have shown that maternal smoking during pregnancy increases risk for neurobehavioral problems including autism spectrum disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD. It is thought that risk for neurobehavioral disorders in offspring is attributable to in utero exposure of the fetus to nicotine. We propose an alternative genetic mechanism to explain the increased risk of ASD to the offspring of chronic smokers. We hypothesize that cumulative tobacco consumption by men and women prior to pregnancy could result in increased rates of germline mutation in parental germ cells and lead to increased risk for genetic diseases such as ASD in offspring. Preliminary results in our NIMH-funded study of ASD show that maternal tobacco consumption is associated with higher rates of de novo mutations in offspring. Our results suggest that some environmental risk factors for ASD could be mediated in part by a genetic mechanism. To replicate and further characterize our findings, we propose to (1) confirm the effect of smoking on germline mutation in an Illumina WGS dataset of >350 families from cohorts that have been previously characterized by the Simons Foundation and (2) to determine the differing effects of maternal and paternal smoking by direct quantification of maternal and paternal mutation by nanopore sequencing. This study would be the first to document and quantify an effect of parental tobacco consumption on the rates of germline mutation. Such a finding would have significant implications for understanding the interplay between genes and environment in determining risk for developmental disorders in children.