Severity Of Genetic Mutation May Override Female Protective Effect Against Autism: Study

An increased severity of a genetic mutation responsible for autism could override mechanisms that protect females from the neurodevelopmental disorder, a study has found.

Autism spectrum disorder affects males more frequently than females, with women thought to possess biological protective mechanisms that reduce vulnerability to the condition, which is characterised by repetitive behaviours and impaired social communication skills.

However, direct experimental evidence supporting this trend has remained limited, researchers from Korea Advanced Institute of Science and Technology (KAIST), Yonsei University and the Institute for Basic Science said.

"Our findings suggest that females may possess protective biological mechanisms against CHD8-related dysfunction, but severe mutations can overwhelm those protective effects," said author Eunee Lee, professor at Yonsei University, said.

"This provides important insight into why autism severity and sex differences can vary depending on genetic background and mutation strength," Lee said.

The gene 'CHD8' is considered among the most important risk factors for autism and other neurodevelopmental conditions. It helps regulate the activity of genes involved in brain development by remodelling chromatin structure, a complex macromolecule containing DNA, RNA, and proteins.

The researchers developed what they described as the world's first viable homozygous mouse model carrying the same CHD8 mutation inherited from both parents.

The model enabled researchers to directly compare mild and severe CHD8 mutations across brain development, neural activity, behaviour, and gene expression.

Mice carrying only one mutated CHD8 copy showed behavioural abnormalities primarily in males, consistent with previous findings and the trend of a higher prevalence of autism in human males.

In contrast, mice carrying severe mutations in both CHD8 copies displayed pronounced autism-related abnormalities in both sexes.

The homozygous mutant mice also exhibited an enlarged brain volume, altered cerebral blood flow, disrupted brain rhythms, among other changes -- pathways strongly associated with autism and other neurodevelopmental disorders, the researchers said.

They found that male-female differences became progressively weaker as mutation severity increased, suggesting that the biological mechanisms underlying sex differences in autism may not be fixed, but instead depend on the intensity of genetic disruption.

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