Although autism spectrum disorders (ASDs) are traditionally described as disorders of the central nervous system, there is emerging evidence suggesting the presence of systemic physiological abnormalities, such as mitochondrial dysfunctions, in individuals with ASD. Mitochondrial dysfunction can be caused by maternally inherited or sporadic defects in the mitochondrial oxidative phosphorylation system, which is encoded by genes in both nuclear DNA and mitochondrial DNA (mtDNA). In a previous secondary analysis of the whole exome sequencing data sets of the Simons Simplex Collection (SSC), Zhenglong Gu and his colleagues took advantage of off-target reads aligned to mtDNA to determine mtDNA mutations, including homoplasmies and heteroplasmies, in 903 simplex families and identified increased rates of predicted pathogenic and/or disease-associated mtDNA heteroplasmies in ASD probands compared to their unaffected siblings¹.

Zhenglong Gu’s team plans to further their exploration of the link between mtDNA and ASD by using the newly generated whole-genome sequencing SSC data sets. With an ultra-deep and uniform sequencing coverage on mtDNA, their proposed study will more than double the sample size and increase the sensitivity of detecting low-fraction mtDNA mutations. They also plan to analyze mtDNA variations in postmortem brains from individuals with ASD and to team up with Xiaobin Wang at Johns Hopkins University to assess mtDNA in fetal and maternal samples of ASD/intellectual disability child-mother and typically developing child-mother pairs recruited in the Boston Birth Cohort. In doing so, Gu’s team will gain a greater understanding of intergenerational changes and temporal dynamics of mtDNA heteroplasmies in fetal and peripheral tissues in individuals with ASD. Overall, their study will reveal the contribution of mtDNA mutations to ASD, allowing better diagnosis for individuals with ASD with certain mitochondrial dysfunctions.