Abnormal Gaze Linked to Social Cognition in Women With FMR1 Premutation, Study Finds

Atypical gazing when looking at facial expressions is associated with social cognition and language abilities in women with a premutation in the FMR1 gene, a new study has found.

The study, titled “Physiological regulation and social-emotional processing in female carriers of the FMR1 premutation,” was published in the journal Physiology and Behaviour.

Fragile X is caused by having 200 or more CGG repeats in the FMR1 gene, which disrupts production of the fragile X mental retardation protein, or FMRP. (Of note, C stands for cytosine and G for guanine, which are two of the four building blocks of DNA).

Such a high number of repeats is a “full” mutation. People with 55 to 200 CGG repeats are said to have a premutation, which reduces the amount of FMRP produced. This premutation is relatively common in women (as high as 1 in 150) and is associated with a greater likelihood of having a child with fragile X.

A premutation in FMR1 does not lead to the same manifestations as a full mutation, but carriers can exhibit alterations in social cognition and communication, as well as higher rates of autism spectrum disorder (ASD)-related traits.

Autonomic function — the regulation of internal organs and processes such as breathing, digestion, and heartbeat — is associated with social communication and is impaired in people with fragile X. Similar alterations have been reported in FMR1 premutation carriers, as changed nerve activity has been linked with dysregulated arousal responses and social language.

While autonomic regulation is generally measured through skin conductance or cardiac variables, pupillary responses (measuring the pupil of the eye) can help evaluate autonomic dysfunction, while also providing information on cognitive processing.

In the study, researchers measured pupillary responses in 47 women (mean age of 44 years) who carried the FMR1 premutation, and investigated whether autonomic dysregulation correlated with social cognition and social language abilities.

The team also evaluated fixation patterns (maintaining gaze focused on a single spot) while women viewed facial expressions (denoting happy, fear, and calm feelings) and analyzed if these patterns were linked to pupillary responses.

“We predicted that carriers of the FMR1 PM [premutation] would demonstrate atypicalities in both fixation patterns and pupillary response compared to controls, and that these atypicalities would relate to social cognition, social language abilities, and molecular-genetic expression of the FMR1 gene,” the researchers wrote.

Results showed that — compared to 25 controls without a family history of fragile X, ASD, or related disorders — women with the FMR1 premutation exhibited atypical pupillary responses and fixation patterns, after accounting for intelligence quotient (IQ).

In these women, pupillary responses and fixation patterns were linked to social cognition and language abilities, and to FMR1-related variations — namely altered levels of the FMRP protein and number of CGG repeats.

“Interestingly, this atypical fixation pattern in the PM group was associated with better performance on social-cognitive tasks and stronger social language abilities,” the researchers said.

“Findings suggest that autonomic dysregulation may have an impact on important social phenotypes, even in a population that does not exhibit clinical impairment,” the scientists wrote. “These findings lend insight into the FMR1 gene’s potential contributions to complex human traits such as social emotional processing and social language.”