Clues To Why Autism Strikes More Males
Girls seem to tolerate more genetic mutations than boys do before showing symptoms of disorder
THURSDAY, Feb. 27, 2014 — A new DNA study begins to explain why girls are less likely than boys to have an autism spectrum disorder.
It turns out that girls tend not to develop autism when only mild genetic abnormalities exist, the researchers said. But when they are diagnosed with the disorder, they are more likely to have more extreme genetic mutations than boys who show the same symptoms.
“Girls tolerate neurodevelopmental mutations more than boys do. This is really what the study shows,” said study author Sebastien Jacquemont, an assistant professor of genetic medicine at the University Hospital of Lausanne, in Switzerland.
“To push a girl over the threshold for autism or any of these neurodevelopmental disorders, it takes more of these mutations,” Jacquemont added. “It’s about resilience to genetic insult.”
The dilemma is that the researchers don’t really know why this is so. “It’s more of an observation at a molecular level,” Jacquemont noted.
In the study, the Swiss researchers collaborated with scientists from the University of Washington School of Medicine to analyze about 16,000 DNA samples and sequencing data sets from people with neurodevelopmental disorders, including autism spectrum disorders.
What do the findings mean for parents and patients?
Adesman said there are no immediate benefits, but the knowledge can help direct future research.
Why Does Autism Seem More Common In Males
Being female does appear to protect the brain from many developmental disabilities, not just autism. There is emerging evidence that girls with autism need more extreme genetic mutations than boys to develop autism.
However, there is a growing body of work that indicates that autism just presents differently in girls and therefore often goes unrecognised, especially in verbally fluent girls with normal intelligence. Girls with autism also appear to be better at camouflaging their symptoms in order to fit in.
With the diagnostic criteria for ASD based largely in how autism presents in males, girls can often slip under the radar or get misdiagnosed. Girls with ASD seem to have less restricted and repetitive behaviours than boys, but its also possible that some of these behaviours go unrecognised for example, an obsessive interest in collecting dolls may be misinterpreted as pretend play.
How Girls Differ From Boys With Autism
With all those caveats, however, research is moving forward and providing us with more clues to ASD in girls. Based on recent research, here are a few of the ways in which girls with autism appear to differ from boys with autism:
Also Check: Does Nick Eh 30 Have Autism
Why Arent Girls Being Diagnosed
Hoopers experience of not getting a diagnosis and many people in her life not even considering the possibility is not uncommon for girls and women on the spectrum. The criteria used to diagnose autism favors the way autism presents in boys and men.
Most evaluators will only diagnose girls with autism when they present with a lower IQ because otherwise, girls dont meet enough of the classic male-centric autism symptoms. Boys are more likely to receive an autism diagnosis regardless of their IQ because they fit enough of the other autism symptoms. Parish-Morris said the criteria favors boys because girls are mostly absent from autism research.
Most of the research that was conducted was in boys, Parish-Morris said. Even when studies look at both genders, there are usually far fewer female participants. As a result, autistic girls are compared to autistic boys when they should be compared to typical girls. This change would provide a more accurate picture of the autism spectrum in women.
Gender role socialization also cant be ignored in the context of autism. By age 3, children begin to express their gender identities, which are influenced by the world around them. Girls are generally raised to prioritize social connection and relationships, which may put more emphasis on the importance of social masking for young women. Parish-Morris said research hasnt considered transgender, non-binary or gender non-conforming folks yet.
The Y Chromosome Theory
Since the XYY and XXYY syndromes have an increased incidence of ASC , it is important to consider if the male bias in ASC could also result from the male-limited expression of genes on the Y chromosome. This possibility has attracted very little research attention. Such genes should be located in the non-recombining region of the Y. SRY is expressed in the medial rostral hypothalamus, as well as the frontal and temporal regions of the human brain . In vitro assays suggest that SRY can increase transcription of tyrosine hydroxylase by binding at a promoter site . In addition, the knockdown of SRY expression in the substantia nigra of the rat decreases tyrosine hydroxylase expression . This could implicate SRY in the male bias for disorders involving disregulated catecholamines such as ADHD. SRY may also regulate the monoamine oxidase A gene . Other Y-linked genes known to be expressed in human brain include ZFY and PCDH11Y,.
Evaluation Of The Number Of Co
Developmental human brain RNA-seq data were curated from BrainSpan, which contains expression data spanning different developmental stages, brain regions, gender, and age. Given the recognized importance of the prenatal stage in ASD development previously reported by us and other group,, expression data from fetal development stages between post-conception weeks 8 and 37 and in 15 brain regions were selected in further analysis, including 83 female-brain samples and 120 male-brain samples. We, respectively, calculated the Pearson correlation coefficients between any two candidate genes based on their expression levels in different male and female-brain regions. Gene pairs with |R| >0.80 were regarded as being co-expressed according to our previous study. We counted the number of other candidate genes that were co-expressed with the given gene in different male and female-brain regions. Finally, for each class of candidate gene , we employed pairwise Wilcoxon test to compare the number of co-expressed gene in all 15 male-brain regions and female-brain regions.
Increased Mutation Burden In Female Asd Patients
We collected DNMs from 5748 ASD trios and 1911 control trios from the ASC, SSC, MSSNG, and other published studies. Our analysis revealed that the probands carried significantly more loss-of-function and deleterious missense mutations than the matched controls, with no difference in tolerant missense mutations .
Fig. 1: Mutation load of functional classes of DNMs in the coding region.
a Mutation load per person in ASD versus control group. b Mutation load per person in male ASD subjects versus male controls. c Mutation load per person in female ASD subjects versus female controls. d Mutation load per person in male ASD subjects versus female ASD subjects. Mutation types are displayed by class. p-values were calculated by Fishers exact test. The p.adjust function in R was employed to calculate the corrected p-values for multiple comparisons, *adjusted p<0.05, **adjusted p<0.01, ***adjusted p<0.001, N.S. not significant. The error bars represent 95% confidence intervals for the mean rates.
Don’t Miss: Is There Different Types Of Autism
Presentation Of Asd Symptoms And Related Phenotypes In Males And Females
A recent study from the UK addressed this potential diagnosis gap by characterizing children with high autistic traits who met or fell short of the threshold for ASD diagnosis . A significantly smaller proportion of high-scoring girls met full ASD diagnostic criteria than males whereas ASD-diagnosed girls had a higher mean total problem score and a higher frequency of low IQ than ASD-diagnosed boys. Girls without diagnoses showed increased communication difficulties, but reduced social impairments as compared to non-diagnosed boys. Thus, it may be that relatively higher levels of social ability in females preclude full diagnosis of ASD, particularly for those who are high-functioning. Nevertheless, whether the male-skewed prevalence of ASD is due to biased diagnosis of sex-differential presentations of the disease or to true sex differences in prevalence , sex-specific biology is likely to play a role. For the remainder of this review, we discuss the relationships between ASD and the two major drivers of sex-specific biology: genetics and hormones.
Is Acs An Extreme Expression Of The Male Brain
The Extreme Male Brain theory of autism extends the Empathizing-Systemizing theory of typical sex differences , which proposes that females on average have a stronger drive to empathize , while males on average have a stronger drive to systemize . Whilst sociologists still debate if there are any sex differences at all, and if so whether these are purely the result of cultural conditioning, biologists have long known from animal research that sex differences in behavior exist in primates and are influenced by biology as well as the environment.
On the Empathy Quotient typical females score higher than typical males who score higher than those with ASC . On the Systemizing Quotient , individuals with ASC score higher than typical males who score higher than typical females . Additional psychological evidence shows thatirrespective of the direction of sex differencepeople with autism show an extreme of the male profile. Note that the EMB theory does not state that all psychological sex differences will be exaggerated in ASConly those relating to empathy and systemizing.
Don’t Miss: Is Junie B Jones Autistic
Why More Boys Than Girls Are Autistic
Researchers are a step closer to understanding why autism spectrum disorder affects four times as many boys as girls.
A study led by a team of Toronto scientists has discovered that males who carry specific genetic alterations on their X-chromosome have an elevated risk for developing autism spectrum disorder, or ASD.
The male gender bias in autism has intrigued us for years and now we have an indicator that starts to explain why this may be, said co-principal investigator Stephen Scherer, director of the Centre for Applied Genomics at Torontos Hospital for Sick Children.
The researchers, whose work is published this week in the journal Science Translational Medicine, found that about one per cent of boys with ASD had mutations related to the PTCHD1 gene on the X-chromosome.
Hearing that its in one per cent doesnt get a lot of people excited, conceded Scherer. But it gets geneticists really excited because theres a lot of genes involved .
Boys inherit one X-chromosome from their mother and one Y-chromosome from their father, explained Scherer. If a boys X-chromosome is missing the PTCHD1 gene or other nearby DNA sequences, they will be at high risk of developing ASD or intellectual disability.
Girls are different in that, even if they are missing one PTCHD1 gene, by nature they always carry a second X-chromosome, shielding them from ASD. While these women are protected, autism could appear in future generations of boys in their families.
Evidence Is Lacking On Universal Screening For Autism Panel Says
Autism spectrum disorder is a complex developmental disorder, characterized by repetitive, compulsive behaviors, a lack of interest in social interaction and little or no eye contact. There is no medical test to diagnose autism. Doctors look at the child’s behavior and development to make a diagnosis.
It turns out Haley’s situation is pretty typical for high-functioning girls with autism, whose symptoms can be less noticeable.
Girls appear to have mastered what some call “social camouflaging,” says Amanda Gulsrud, clincial director of the Child and Adult Neurodevelopmental Clinic at University of California, Los Angeles. Gulsrud develops school interventions for children with autism. The interventions are based, in part, on earlier research done by colleagues at UCLA, who did a study looking at how boys and girls with autism interact with their peers on the school playground. The boys clearly stood out as being different, Gulsrud says. They were very isolated from the other boys, who were in a large group playing sports. The boys with autism were the ones “circling the perimeter of the yard, or off by the tree in the back.”
Girls with autism, on the other hand, didn’t stand out as much, she says. They stuck close enough to the other girls to look as if they were socially connected, but in reality they were not really connecting. “They were not having deep, meaningful conversations or exchanges,” Gulsrud says. They were flitting in and out of that social connection.
Recommended Reading: How To Tell If My Child Is Autistic
Why Girls With Autism Are Diagnosed Later Than Boys
A new study looking at gender differences among children with autism spectrum disorders show that girls have different, less obvious symptoms compared to boys, which could be why they are generally diagnosed later.
There are clearly major gender differences in prevalence of autism, with more than four boys being diagnosed for every girl. However, we have little understanding of the roots of these differences, says study author Dr. Paul Lipkin, director of the Interactive Autism Network at the Kennedy Krieger Institute in Baltimore. Are they biological, social, diagnostic, or tied to other factors, such as screening systems?
Lipkin and his colleagues looked at data on people with ASD and their family members using the Institutes online registry of 50,000 people. Almost 10,000 of them had reported how old they were when they were first diagnosed, and about 5,000 had undergone a test to identify their severity of social impairment. The study authors results were presented at the Pediatric Academic Societies annual meeting in San Diego.
These findings suggest that boys behavior are more apparent than the girls, with the potential for girls being more difficult to recognize, says Lipkin. Since the problems experienced by girls are in social cognition and require social opportunities, they are much more likely to be unnoticed until the elementary school years.
Data Collection And Annotation
Data of total 5748 trios and 1911 unaffected controls were collected from recent public trio-based WES/WGS studies,,, on ASD . The patients in these studies were diagnosed with ASD using the gold standard Autism Diagnostic Observation Schedule , the Autism Diagnostic Interview and Autism Diagnostic Interview-Revised . Control samples were composed of unaffected SSC siblings. Only clinical information applied from SFARI base in the SSC was available. Age of the children diagnosed with ASD ranged from 4 to 18 years old, and we estimated the severity of ASD by IQ and restricted repetitive behaviors. Comprehensive annotation of each DNM was performed by ANNOVAR and VarCards with RefSeq as described in our previous studies, including functional implications ; functional predictions for missense mutations; and allele frequencies of different populations from various human genetic variation databases, including gnomAD, ExAC, ESP, and 1000G Genomes Project.
Only coding and splicing-site DNMs were selected for further analysis. In addition, DNMs with a minimum allele frequency>0.1% in the public human genetic variation databases, mentioned above, were excluded. Deleterious missense mutations were predicted by the combination of REVEL and VEST3 due to their best performance in predicting pathogenicity for missense variants. We categorized deleterious missense DNMs and loss-of-functions DNMs as putative functional DNMs.
Read Also: What Kind Of Autism Does Symmetra Have
How Autism Is Different In Girls Vs Boys
Why do boys get diagnosed with autism four times as often as girls?
New research, including some of the latest data from the International Society for Autism Research annual conference last week, addresses this question, one of the biggest mysteries in this field.
A growing consensus is arguing that sex differences exist in genetic susceptibility, brain development and social learning in autismand they are meaningful to our understanding of the disorder and how it will be treated.
Yale University researchers presented results showing that being female appears to provide genetic protection against autism. Meanwhile, scientists at Emory University showed in preliminary work that boys and girls with autism learn social information differently, which leads to divergent success in interactions with other people.The new data, together with previously published studies, suggest that sex should be taken into account in diagnosing and in creating individualized treatment plans, according to experts.
Autism, a developmental disorder characterized by deficits in social skills and repetitive behaviors, affects more than 1 percent of the population. It has long been known to be diagnosed more often in boys.
Why this ratio exists and how much it is skewed by misdiagnosis or under-diagnosis in girls isn’t clear. More and more, however, scientists think the sex distribution is meaningful.
The Cost Of A Missed Diagnosis
Dr. Epstein says undiagnosed autistic girls end up wondering whats wrong with them, which can lead to depression, anxiety and loss of self-esteem. They work so hard to fit in;that it wears them out. Thats the thing;about imitating, she says. You dont necessarily get it so youre just trying to do what people do. If youre just trying to mimic and you dont really understand, it makes it pretty rough.
Dr. Nash says less severe autism in girls is often first flagged because of these social issues, or the depression they generate. In people we call mildly autistic, there are adolescent social problems or theyre seeming hyperfocused on a topic and not participating in school to their potential or abilities, she says. Depression can be more common among high-functioning kids on the spectrum. So theyll come in for something like depression or poor school performance. Then it becomes more clear to me that they have a restricted interest and social communication issues.
Another cost of being overlooked is missing out on early support for skill-building. We talk about early intervention, Dr. Epstein;says. When the girls are identified late, theyve missed out on a lot of social interventions that are much harder later. Thats the danger for anybody who gets a late diagnosis.
You May Like: What To Do During Pregnancy To Avoid Autism