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.
Highlights
Autism Spectrum Disorder (ASD) refers to a broad collection of complex, neurodevelopmental disorders, characterized by impairment of communicative and social interactions [1]
Mitochondrial dysfunction has been proposed as a cause of Autism Spectrum Disorder (ASD), but the genetic basis has not been established
By analyzing mitochondrial DNA (mtDNA) sequences from 903 ASD children along with their unaffected siblings and mothers, we found a unique pattern of heteroplasmic mtDNA mutations associated with increased risk of ASD
Summary
Autism Spectrum Disorder (ASD) refers to a broad collection of complex, neurodevelopmental disorders, characterized by impairment of communicative and social interactions [1]. ASD usually manifests at an early stage of development in pre-pubertal children [2]. The current prevalence of ASD in the United States according to the 2014 annual report from The Centers for Disease Control and Prevention (CDC) is 1 in 68 children (1.47%), with a skewed gender ratio of 4 affected boys to 1 affected girl [3]. Population-based studies suggest an even higher prevalence of 2.24% in the United States [4]. Treatment for ASD mostly relies on behavioral interventions with specialized training to lessen social, verbal and cognitive deficits. The effectiveness varies widely among children with ASD and mild forms of symptoms such as attention deficit and social difficulties may persist throughout life [5]
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