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Heteroplasmic Mitochondrial Mutations More Common in Autism Spectrum Disorder Cases

NEW YORK (GenomeWeb) – Pathogenic mutations affecting a subset of an individual's mitochondria may be behind some forms of autism spectrum disorder (ASD), particularly cases marked by more severe intellectual and social deficits, according to a study published online today in PLOS Genetics.

Researchers from Cornell University analyzed exome sequencing data from 933 families with one ASD-affected children. Although heteroplasmic mutations affecting the DNA in some mitochondria were relatively common, they found that children with ASD were far more likely to carry potentially deleterious, heteroplasmic mitochondrial DNA mutations than were their unaffected siblings or mothers.

"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 these diseases," senior author Zhenglong Gu, a nutritional sciences researcher at Cornell University, said in a statement.

Gu and his colleagues started with exome sequence data for simplex families from the SFARI Simons Collection who were sequenced at Cold Spring Harbor Laboratory, Yale, and the University of Washington. They whittled the collection down to CSHL-sequenced samples with sufficient mitochondrial DNA coverage for the desired analysis.

From the 933 families, they further narrowed in on 903 families that met quality control criteria and contained protein-coding sequences for an ASD-affected child, an unaffected sibling, and their mother. For the more than 2,700 family members in the set, the team noted that mitochondrial genomes were covered to 141-fold, on average, making it possible to see mutations present across an individual's mitochondria, and find those that were heteroplasmic.

Across individuals with ASD and their family members, the researchers detected almost 68,700 homoplasmic mutations or variants, and fewer than 700 heteroplasmic mutations at 366 sites. About one-fifth of individuals had at least one heteroplasmic mitochondrial sequence, including 229 individual-specific heteroplasmies and 323 heteroplasmic variants specific to families. More than half of the heteroplasmies fell at sites that are typically polymorphic, though the sequence differences occurring outside of polymorphic sites appeared more prone to being pathogenic.

Heteroplasmic mitochondrial mutations that were predicted to be pathogenic were also more common in individuals with ASD than in their unaffected family members, the team noted, despite a similar overall mitochondrial mutation burden compared with unaffected siblings.

"The enrichment of predicted pathogenic mutations in autistic probands was not affected by the pathogenicity scores used," the authors wrote, "and was further confirmed by the analysis of disease-associated mutations."

When they folded in information on children's IQ, social responsiveness scores, and clinical features, the researchers also found that the heteroplasmic and pathogenic mutations in mitochondrial DNA were more common in children with ASD who had more pronounced intellectual problems, severe social deficits, and/or symptoms suspected of stemming from a mild mitochondrial disorder.

Though additional research is needed to explore such relationships, the investigators believe these results may inform future approaches for treating a subset of ASD cases. 

"Ultimately, understanding the energetic aspects of neurodevelopmental disorders may lead to entirely new kinds of treatments, and preventative strategies that would target mitochondria," Gu added in the statement.