Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder

Abstract

Increasing clinical and biochemical evidence implicate mitochondrial dysfunction in the pathophysiology of Autism Spectrum Disorder (ASD), but little is known about the biological basis for this connection. A possible cause of ASD is the genetic variation in the mitochondrial DNA (mtDNA) sequence, which has yet to be thoroughly investigated in large genomic studies of ASD. Here we evaluated mtDNA variation, including the mixture of different mtDNA molecules in the same individual (i.e., heteroplasmy), using whole-exome sequencing data from mother-proband-sibling trios from simplex families (n = 903) where only one child is affected by ASD. We found that heteroplasmic mutations in autistic probands were enriched at non-polymorphic mtDNA sites (P = 0.0015), which were more likely to confer deleterious effects than heteroplasmies at polymorphic mtDNA sites. Accordingly, we observed a ~1.5-fold enrichment of nonsynonymous mutations (P = 0.0028) as well as a ~2.2-fold enrichment of predicted pathogenic mutations (P = 0.0016) in autistic probands compared to their non-autistic siblings. Both nonsynonymous and predicted pathogenic mutations private to probands conferred increased risk of ASD (Odds Ratio, OR[95% CI] = 1.87[1.14–3.11] and 2.55[1.26–5.51], respectively), and their influence on ASD was most pronounced in families with probands showing diminished IQ and/or impaired social behavior compared to their non-autistic siblings. We also showed that the genetic transmission pattern of mtDNA heteroplasmies with high pathogenic potential differed between mother-autistic proband pairs and mother-sibling pairs, implicating developmental and possibly in utero contributions. Taken together, our genetic findings substantiate pathogenic mtDNA mutations as a potential cause for ASD and synergize with recent work calling attention to their unique metabolic phenotypes for diagnosis and treatment of children with ASD.

Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic‐Based Associations, and Non‐Energy‐Related Mechanisms

“…Autistic individuals also had 1.5 times as many non-synonymous mutations and 2.2 times as many predicted pathogenic mutations than non-autistic siblings [51]. These findings were in contrast to an earlier report in which whole mitochondrial genome sequencing of ~400 autistic children failed to identify evidence of an association between mitochondrial mutations and autism using the proband's father as a control [52].…”

An energetic view of stress: Focus on mitochondria

“…Notably, an increasing number of studies are reporting mitochondrial dysfunction in Autism Spectrum Disorder (ASD) (Gu et al, 2013; Tang et al, 2013), a neurodevelopmental disorder involving core alterations in social behaviors. Key recent evidence includes reports indicating redox metabolism abnormalities in autistic children associated with mitochondrial disease (Frye et al, 2013) and genetic evidence for pathogenic mtDNA mutations as a potential cause for ASD (Wang et al, 2016). Beyond autism, a recent study has identified an association between a mitochondrial DNA (mtDNA) single nucleotide polymorphism (SNP), which affects the regulation of mitochondrial calcium levels related to energy production, with aggression and leadership in children with attention deficiency and hyperactivity disorder (ADHD) (Hwang et al, 2017).…”

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

“…Indeed, as compared with their typically developing siblings, children with ASD are enriched in heteroplasmic mutations in nonpolymorphic mtDNA regions, suggesting that errors in mtDNA replication occurred early in life, potentially during gestation [57].…”