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Autism linked to mutations in mitochondrial DNA

A study of 903 affected children shows inherited, spontaneous mutations increased their risk for autism spectrum disorder (ASD). The children who were diagnosed with autism had greater numbers of harmful mutations in their mitochondrial DNA than other family members.

Increasingly, studies point to malfunctions in mitochondria — powerhouses of the cell — as a cause for autism spectrum disorder, but the biological basis for this relationship is unclear. To see if a genetic link exists between mitochondrial malfunction and ASD, scientists analyzed mitochondrial DNA sequences from 903 children with ASD, along with their unaffected siblings and mothers. The report by Zhenglong Gu of Cornell University in Ithaca, New York, and colleagues, is published in the October 28th, 2016 in PLOS Genetics.

They discovered a unique pattern of heteroplasmic mutations, where both mutant and normal mitochondrial DNA sequences exist in a single cell. Children with ASD had more than twice as many potentially harmful mutations compared to unaffected siblings, and 1.5 times as many mutations that would alter the resulting protein. The researchers went on to show that these mutations can be inherited from the mother, or the result of spontaneous mutation during development.

Scientists noted the risk associated with these mutations is highest in children with lower IQ and poor social behavior compared to their unaffected siblings.

Carrying harmful mutations in mitochondrial DNA is also associated with increased risk of neurological and developmental problems among children with ASD. Because mitochondria play a central role in metabolism, these findings may help explain the metabolic disorders commonly associated with ASD and other neurodevelopmental disorders. Evaluating mutations in the mitochondrial DNA of high-risk families could help improve the diagnosis and treatment of these diseases.

Zhenglong Gu says "The result of our study synergizes with recent work on ASD, calling attention to children diagnosed with ASD who have one or more developmental abnormalities or related co-morbid clinical conditions for further testing on mitochondrial DNA and mitochondrial function. Since many neurodevelopmental disorders and related childhood disorders show abnormalities that converge upon mitochondrial dysfunction, and may have mtDNA defects as a common harbinger, future research is needed to elucidate the mitochondrial mechanisms underpinning to these diseases. Ultimately, understanding the energetic aspects of neurodevelopmental disorders may lead to entirely new kinds of treatments, and preventative strategies that would target mitochondria."

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.

Author Summary
Mitochondria contain their own genome, the mitochondrial DNA (mtDNA), and are abundant in the brain where they produce energy and intracellular signals required for normal brain function and cognition. Mitochondrial dysfunction has been proposed as a cause of Autism Spectrum Disorder (ASD), but the genetic basis has not been established. By analyzing mtDNA sequences from 903 ASD children along with their unaffected siblings and mothers, we found a unique pattern of heteroplasmic mtDNA mutations (the coexistence of both mutant and wide-type mtDNA molecules in a cell) associated with increased risk of ASD. A large fraction of these mtDNA heteroplasmies are pathogenic and can be either inherited maternally or acquired during development. Our findings unveil an important issue about pathogenic mtDNA heteroplasmy transmission between mothers and children, which could underlie many neurodevelopmental disorders in children that are shown to involve mitochondrial dysfunction. Evaluating mtDNA heteroplasmies in high-risk families could help diagnosis and treatment of these diseases.


1. Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders?: a systematic review and meta-analysis. Mol Psychiatry. Nature Publishing Group; 2011;17: 290-314. doi:10.1038/mp.2010.136
2. Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS. Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: evidence from brain imaging. JAMA psychiatry. 2014;71: 665-71. doi:10.1001/jamapsychiatry.2014.179

Competing Interests: The authors have declared that no competing interests exist.

Citation: Wang Y, Picard M, Gu Z (2016) Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder. PLoS Genet 12(10): e1006391. doi:10.1371/journal.pgen.1006391

Funding: This work was supported by various funds from Cornell University, NSF MCB-1243588, NIH 1R01AI085286, and a grant for ENN science and technology development to ZG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Nov 8, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Autism spectrum disorder linked to mutations in some mitochondrial DNA.
Darryl Leja, NHGRI, Flickr

Image Credit:
Darryl Leja, NHGRI, Flickr


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