By Angela Tao
The disproportionate ratio between females and males when it comes to autism spectrum disorder (ASD) has been recognized since 1940, with males being 4 times more likely to have been diagnosed with ASD than females [1]. One possible cause of this is x-linked mutations. Males have one x-chromosome, so they only need one mutation on their x-chromosomes to have x-linked conditions. In contrast, females have two x-chromosomes, which means they need to have two mutations in their x-chromosomes to have x-linked conditions [3]. It would appear that the excess in males with ASD is directly linked to x-linked mutations, but several studies have shown that x-linked intellectual disabilities occur too infrequently to fully account for all the males with intellectual disabilities [2].
A more likely cause for the superabundance in males with ASD is the “female protective effect,” which states that females have to be exposed to more factors that contribute to the development of ASD than males to develop intellectual disabilities [4]. In a study on the mutational burden in females, researchers discovered that females naturally have more neurodevelopmentally harmful mutations than males. Females with intellectual disabilities have an increased burden of copy number variants (CNV) and single-nucleotide variants (SNV), both of which are types of mutations that can disrupt genes in neurodevelopment. In other words, females require more mutations to develop ASD. The mutational burden in females may be due to specific cognitive and behavioral phenotypes that are prone to cause extra mutations [2].
In brief, researchers were able to conclude that male brains do not need as many mutations as female brains do to develop ASD. Whether or not this is the only factor influencing the higher proportion of male ASD cases is still uncertain, but further research can be expected to be conducted in the future.
References:
Fombonne, E. (n.d.). Epidemiology of pervasive developmental disorders. Retrieved March 26, 2021, from https://www.nature.com/articles/pr2009131
Jacquemont, S., Coe, B., Hersch, M., Beckmann, J. S., Rosenfeld, J. A., & Eichler, E. E. (n.d.). A Higher Mutational Burden in Females Supports a “Female Protective Model” in Neurodevelopmental Disorders. Retrieved March 26, 2021, from https://www.cell.com/ajhg/fulltext/S0002-9297(14)00059-7#app2
NCI dictionary of genetics terms. (n.d.). Retrieved March 26, 2021, from https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/x-linked-recessive-inheritance
Taylor, M., Lichtenstein, P., Larsson, H., Anckarsäter, H., Greven, C., & Ronald, A. (2016, April 07). Is there a female protective effect Against Attention-Deficit/Hyperactivity Disorder? Evidence from two REPRESENTATIVE twin samples. Retrieved March 26, 2021, from https://www.sciencedirect.com/science/article/pii/S0890856716301046#:~:text=The%20%E2%80%9Cfemale%20protective%20effect%E2%80%9D%20posits,will%20display%20more%20ADHD%20behaviors.