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Investigating Sex Differences in the Behavioral Phenotypes of Phelan-McDermid Syndrome, Tuberous Sclerosis Complex, and PTEN Hamartoma Tumor Syndrome

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
The Developmental Synaptopathies Consortium investigates 3 related rare genetic syndromes associated with autism spectrum disorder (ASD) and intellectual disability (ID): Phelan-McDermid syndrome (PMS), Tuberous Sclerosis Complex (TSC), and PTEN Hamartoma Tumor syndrome (PHTS). In addition to chronic physical health conditions, these syndromes are characterized by developmental delay, neuropsychiatric symptoms, and challenging behaviors. Research has shown that the prevalence of certain neuropsychiatric disorders and behavioral characteristics differs based on sex. For example, males present more frequently with hyperactivity, impulsivity, and aggression, whereas mood and anxiety disorders are more prevalent in females. Previous clinical studies have shown some sex-based differences in neuropsychiatric disorders associated with TSC, but few clinical studies have focused on behavioral sex-based differences, especially in PMS and PHTS. This study aims to further characterize the behavioral phenotypes of these rare genetic syndromes, specifically by investigating differences in males and females.

Methods:
Caregivers of 171 participants with PMS (69 male; 16.9±9.7 years), 158 with TSC (67 male; 17.6±10.7 years), and 123 with PHTS (85 male; 15.9±12.3 years) across 11 sites within the Developmental Synaptopathies Consortium completed the Aberrant Behavior Checklist-Community (ABC-C; Aman & Singh, 1994) rating scale. The ABC-C is a caregiver rating instrument developed to assess the behaviors of individuals 5 years and older with intellectual disability. The ABC-C includes 5 subscales: Irritability, Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech. Multiple linear regressions assessed the relationship between sex and ABC-C domain scores, controlling for age by adding it as a covariate in the model. P-values less than 0.05 were considered statistically significant.

Results:
Females with PMS had lower Social Withdrawal (β1=-2.86; t=-2.54; p=.012; 95% CI [-5.07, -.65]), Stereotyped Behavior (β1=-1.82; t=-2.72; p=.007; 95% CI [-3.13, -.51]), Hyperactivity (β1=-6.52; t=-3.89; p=.0001; 95% CI [-9.80, -3.24]), and Inappropriate Speech (β1=-1.10; t=-2.56; p=.011; 95% CI [-1.95, -.26]) scores compared to males, while controlling for age. There were no significant differences in Irritability scores. Males and females with TSC did not differ significantly in any of the 5 aberrant behavior domains. In PHTS, females had lower Hyperactivity (β1=-3.19; t=-2.15; p=-.034; 95% CI [-6.10, -.28]) and Inappropriate Speech scores (β1=-1.51; t=-3.46; p=-.001; 95% CI [-2.37, -.66]) compared to males, across ages. There were no significant differences based on sex in PHTS in the other ABC-C subscales.

Conclusion:
Across these 3 indications, aberrant behaviors in individuals with PMS seem to differ more based on sex than in TSC and PHTS. Results indicate that males with PMS may be more likely to exhibit aberrant behaviors related to social withdrawal, stereotyped behaviors, hyperactivity, and inappropriate speech than females. In TSC, males and females appear to have similar presentations of aberrant behaviors. Meanwhile, males with PHTS may express more inappropriate speech. Overall, the relatively low adjusted R2 values suggest that there are many other variables that affect aberrant behaviors in these individuals. These variables might include medication use, access to resources, and level of cognitive, language, and motor impairment. Future research should aim to investigate the impacts of these factors on the behavioral phenotypes of these syndromes.

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