Background: Why some individuals who carry similar genetic variants have different disease severity is unclear. For example, many individuals with Rett syndrome, a neurodevelopmental disorder related to autism spectrum disorder (ASD), carry mutations in the same gene, but exhibit a wide range of symptom severity which ranges from very severe to relatively mild.

What’s new: A recent article in PLoS One reported on two pairs of sisters with Rett syndrome that—despite having the same causative mutation in a gene known as MECP2—showed significant symptom variability.  In each pair, one sister lacked the ability to speak or walk and displayed severe intellectual disability, while the other sister could speak and walk and displayed moderate intellectual disability.  In order to identify additional factors in these patients that may affect disease severity, the researchers analyzed the protein-coding portions of the genome for additional genetic changes.

The girls with the more severe Rett syndrome symptoms preferentially carried potentially harmful genetic variants in genes associated with oxidative stress, muscle impairment, and autism/intellectual disability.  On the other hand, the girls with less severe symptoms showed an enrichment of potentially harmful variants in genes associated with modulation of the immune system.

Why it’s important: The findings of this study suggest that additional genetic variation affecting specific biological processes can modify the severity of disease phenotypes in individuals with the same root genetic causes of disease.  Genes identified as being responsible for modifying the overall disease severity could serve as potential therapeutic targets.

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