Date of Submission
Campus Only Senior Thesis
Bachelor of Arts
2022 Lauren L Richards
The presentation of autism spectrum disorder (ASD) in individuals is male-biased, with a 4:1 distribution between affected males and affected females. Multiple theories including the extreme male brain (EMB) theory, the gender incoherence (GI) theory, and the female protective effect (FPE) theory have sought to explain the sex-biased penetrance of the disorder. While the EMB theory and GI theory have lost credibility over the years, the FPE theory has gained the most attention for playing a large part in the gender bias seen in ASD. Even though several genes associated with the development of autism have been identified, it would be helpful to understand the biological processes behind the sex-biased presentation of ASD. With that, a list of de-novo mutations (DNMs) and risk genes in patients with ASD were identified from previously published data and genes with DNMs shared in both male and female patients, male-specific genes, and female-specific genes were compiled. These genes were run through a protein analysis classification system. The gene ontology biological processes showed that females with autism are mostly affected in processes such as mesodermal cell specification and differentiation, metabolic processes, metabolite transport, chromatin packing and regulation, and apoptosis processes that result in more severe, however, more internalized symptoms compared to males. Male autism-associated genes were identified to be enriched in biological processes like amino acid metabolism, reproductive gland development, and exocrine development. These processes tend to result in physical and/or behavioral symptoms. The differences between symptoms for males and females with autism most likely lead to a difference in diagnosis, as males possess more externalized symptoms that are easier to notice for providers. Autism presentation in females was identified to be associated with several critical genes on the X chromosome. One example is DDX3X (Dead-Box Helicase 3 X-Linked), a protein-coding gene that regulates nearly all stages of RNA metabolism and is responsible for many intellectual developmental disorders. Due to males being hemizygous for this gene, as well as many other genes analyzed in this study, the dose-dependent impact of mutation in this gene is more fatal, most likely resulting in the death of preterm infants or more severe phenotypes on the individual. However, for females who are heterozygous for this mutation, they are able to tolerate the fatality, but the mutation presents in contributing to the autism phenotype. Most females possess more internalized symptoms which makes it difficult for providers and parents to notice the disorder. Following the female protective effect and becoming more knowledgeable about the difference in symptoms between males and females could help decrease the ratio bias seen in autism spectrum disorder. This study gives insight into the inherent bias in autism screening, as male-specific symptoms are used more in diagnosis of the disorder, than female-specific symptoms.
Richards, Lauren, "Analyzing the genetic mechanisms for the sex-biased penetrance of autism spectrum disorder" (2022). CMC Senior Theses. 2806.
This thesis is restricted to the Claremont Colleges current faculty, students, and staff.