Patterns of inheritance through the female and male parents of people with autism do not support the hypothesis of a "female protective effect."

Background: The number of males diagnosed with ASD is approximately three times that of females. To account for this disparity, several recent studies have proposed that there is a "female protective effect" that increases the threshold for ASD in females. This means that females would require a greater accumulation of ASD genetic differences to reach a threshold to be diagnosed with ASD, and males would have a lower threshold to be diagnosed with ASD. If such a female protective effect exists, then females who do not have ASD but have family members with ASD may "silently" carry genetic differences that result in increased likelihood of ASD in their male offspring. This would result in a greater recurrence of ASD in the sons of unaffected mothers than unaffected fathers.

Methods & Findings: To test this hypothesis, this study examined transmission of ASD through female and male parents by comparing the prevalence of ASD among offspring with maternal and paternal aunts and uncles with ASD. Using clinical and developmental data linked from Swedish national databases, the researchers identified 13,103 children diagnosed with ASD, 1,744 aunts with ASD, and 1,374 uncles with ASD. The study results revealed that the presence of ASD in both maternal and paternal aunts or uncles was associated with an increased rate of ASD in children. However, the relative risk of ASD between maternal and paternal lineage was similar. That is, children of unaffected mothers who had a sibling with autism had the same probability of ASD diagnosis compared to children of unaffected fathers who had a sibling with autism. For these children, the possibility of developing ASD was no greater than the prevalence rate in the general population. Additionally, the chance of having ASD was similar in both sons and daughters.

Implications: Given these findings, the researchers concluded that a female protective factor is not a primary mechanism for the difference in ASD prevalence between males and females. There may be other explanations for this disparity that could be examined by similar population-level studies. One possibility is that a female protective factor does exist in combination with other factors, such as a factor that lowers the threshold for ASD in males. Importantly, ASD screening in Sweden does not currently include an evaluation of family history, but the results of this study suggest that children with a family history of ASD may benefit from more robust screening methods to confirm a diagnosis and target with early intervention.

A large-scale genetic sequencing study identified 102 autism-related genes involved in early brain development.

Background: A genetic variant (sometimes called a genetic mutation) is a permanent change in the DNA sequence of a gene. Rare and de novo (new) genetic variants significantly contribute to the development of ASD. Despite recent advances in our understanding of the genetic contributions to ASD, there are several unanswered questions about when, where, and in what cell types these genes act to alter neurodevelopment. Studying the sequence of exomes (protein-coding regions of the DNA) can help to answer some of these questions.

Methods & Findings: This paper presents the results of the largest exome sequencing study of ASD to date. In this study, researchers collected 35,583 samples of DNA from 11,986 individuals with ASD, 2,179 unaffected siblings and parents, and 8,809 individuals without ASD. By analyzing the genetic variants in these samples, the researchers identified 102 genes associated with an increased risk of ASD, most of which regulate gene expression in early brain development, including some that affect development broadly and some that are specific to ASD. Of these, 30 genetic variants were considered truly new because they had not been previously implicated in neurodevelopmental disorders. Further characterization of the genetic variants in the 102 ASD risk genes led to new information about how the genes are expressed, the neural processes they affect, and their influence on neurodevelopment.

Implications: When comparing males and females, the researchers found more de novo variants in females with ASD than males with ASD. This finding provides support for the theory of a "female protective effect," which hypothesizes that females require an increased threshold for genetic variants to reach an ASD diagnosis, whereas males require a lower threshold. Additionally, the researchers found that the ASD genes were often expressed in excitatory neurons of the brain. Excitatory neurons promote the transmission of electrical and chemical signals to additional neurons, while inhibitory neurons prevent this transmission. Past research has found that an imbalance in excitatory versus inhibitory neuron activity may contribute to ASD. The findings of this study provide compelling support for both an imbalance in the number and activity of excitatory neurons and inhibitory neurons in the development of ASD.