Lerner Research Institute News

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Study Establishes Maternal Genetics as Modulator of Autism Risk

A preclinical study led by Dr. Eng indicates that maternal genetics alone may contribute to increased risk for autism spectrum disorder in offspring.


A recent preclinical study led by Charis Eng, MD, PhD, has shown for the first time that maternal genetics alone may be a risk factor for autism spectrum disorder (ASD) in offspring. Published in Translational Psychiatry, the results suggest that genes predisposing women to inflammation may affect fetal neurodevelopment and lead to ASD-related traits in their offspring. 

“While it is well-known that inflammation in a pregnant women due to external factors like infections and toxins is associated with an increased risk for ASD in her offspring, only a few studies have focused on the role of maternal genetics and none have identified significant associations with ASD,” said Dr. Eng. “Our study is the first to elucidate the impact of maternal genetics on ASD pathogenesis during prenatal neurodevelopment in the absence of strong external inflammatory exposures.”

PTEN model demonstrates impact of maternal genetics on ASD

In this study, the researchers used a mouse model of PTEN, a tumor suppressor gene associated with ASD in patients. Mutations in PTEN have been identified in approximately two percent of all ASD cases and in 17% of those in which the child has ASD and macrocephaly (abnormally large head size).

They compared the characteristics and behaviors of offspring from female mice that had only one functional copy of PTEN to those of female mice that had both functional copies.

One maternal functional PTEN copy was associated with abnormally large heads and ASD-like tendencies, including repetitive behavior and decreased sociability, even if the offspring carried two functional gene copies. However, ASD-like behaviors were more severe in offspring with only one copy.

They also found that offspring with only one PTEN copy from female mice with both functional copies had less severe ASD-like behavior, hinting that maternal genetics could also protect against genetic predisposition to ASD.

IL-10 levels may influence maternal inflammation and fetal development

To further investigate the role of maternal inflammation in ASD development, the researchers then analyzed the levels of anti-inflammatory molecules, including IL-10, in the preclinical models during pregnancy.

They found that low levels of IL-10 in models with only one functional PTEN copy directly correlated with decreased expression of complement proteins in fetal livers and increased breakdown of the offspring’s blood-brain barrier, which protects the brain against toxins and pathogens.  

“While additional studies are needed to fully delineate the connection between maternal IL-10 levels and fetal development, there is the potential that IL-10 dysregulation during pregnancy could serve as a marker for maternal inflammation and ASD risk,” said Dr. Eng. “Altogether, our study indicates that maternal genetics predisposing to inflammation can impact the developing fetal brain and lead to ASD-like behaviors in the offspring, thus warranting further investigation into genes that predispose women to high inflammation.”

Dr. Eng is the inaugural chair of the Genomic Medicine Institute and inaugural director of the Center for Personalized Genetic Healthcare, which includes the PTEN Multidisciplinary Clinic (designated as a Clinical Center of Excellence by the PTEN Hamartoma Tumor Syndrome Foundation). She was the first to link PTEN to ASD.

Ritika Jaini, PhD, project staff in the Eng lab, is first author on the study, which was supported in part by the Cleveland Clinic Caregiver Catalyst Grant Program, the Ambrose Monell Foundation and the Zacconi Program of PTEN Research Excellence.

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