Genome testing for siblings of individuals may aid in a diagnosis before symptoms appear

10-year study is first to quantify the predictive value of genomic testing for autism

From the SickKids Canada and University of Alberta press department:

One of the key priorities of interventions for autism spectrum disorder (ASD) is starting early, with some evidence showing infants as young as seven months old could benefit. Yet, most children in North America aren’t diagnosed with ASD until they’re over four years of age. New research led by The Hospital for Sick Children (SickKids) and the University of Alberta published on December 5, 2019 in Nature Communications has found testing the DNA of siblings of individuals with ASD may be predictive of a future diagnosis even if symptoms aren’t yet apparent.

ASD refers to a group of neurodevelopmental conditions resulting in challenges related to communication, social understanding and behaviour. Studies show families who have a child with ASD have a 6.9 to 19.5 per cent chance of another child having ASD and a 30 to 40 per cent chance of another child having atypical development.

Genomic factors linked to ASD-related traits

According to Dr. Stephen Scherer, Senior Scientist and Director of the Centre for Applied Genomics (TCAG) at SickKids, Director of the McLaughlin Centre at the University of Toronto and principal investigator of the study: “Genetic factors are the most likely reason we see a clustering of ASD related traits in families. We wanted to investigate the possible benefits of genetic testing for infants whose older sibling had already been diagnosed with ASD. If we can identify those children early, we may be able to enrol them earlier in therapies.”

The researchers looked for the presence of genetic alterations that have been linked to ASD called copy number variations (CNVs) in over 288 infant siblings from 253 families. By age 3, 157 siblings were either diagnosed with ASD or developing atypically. DNA testing revealed CNVs in genes relevant to ASD in 11 (7 per cent) of the 157 siblings who were eventually diagnosed.

The study found that the presence of an ASD-relevant CNV in a sibling had a high likelihood of predicting a future diagnosis of ASD or atypical development. This marks the first time that scientists have been able to quantify the predictive value of CNVs in determining these diagnoses.

Early identification could lead to earlier intervention

“These findings add to a growing body of evidence that biomarkers might be helpful in identifying pre-symptomatic infants who are likely to develop ASD or other developmental challenges,” says Dr. Lonnie Zwaigenbaum, Professor of Pediatrics, Stollery Children’s Hospital Foundation Chair in Autism and Stollery Science Lab Distinguished Researcher at the University of Alberta.

“At this point, we can’t fully determine the anticipated severity of a child’s future symptoms. What we can say is that it’s important to closely monitor their development and start therapeutic interventions early to support their skill development and address emerging functional impairments related to ASD.”

The research team has confirmed similar findings in a separate group of 2,110 families having one child with, and a second child without ASD. Their next step will be to look beyond CNVs and determine how newer technologies – like whole genome sequencing – might increase the early genetic detection rate.


The families who participated in the primary study are from the Baby Sibling Research Consortium (BSRC). Additional families that participated in replication testing are from the Simons Simplex Collection. This work was supported by Autism Speaks, Autism Speaks Canada, the Simons Foundation Autism Research Initiative, National Institutes of Health (NIH), National Institute of Mental Health (NIMH), Canadian Institutes of Health Research (CIHR), Canada Foundation for Innovation (CFI), Genome Canada, Ontario Genomics, Kids Brain Health Network, Canadian Institutes for Advanced Research (CIFAR), Stollery Children’s Hospital Foundation through the Women and Children’s Health Research Institute at the University of Alberta, Ontario Brain Institute, the Government of Ontario, the McLaughlin Centre at the University of Toronto, and SickKids Foundation.

About The Hospital for Sick Children (SickKids)

The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is a founding member of Kids Health Alliance, a network of partners working to create a high quality, consistent and coordinated approach to paediatric health care that is centred around children, youth and their families. SickKids is proud of its vision for Healthier Children. A Better World.

About the University of Alberta Faculty of Medicine & Dentistry

The Faculty of Medicine & Dentistry at the University of Alberta is a leader in educating and training exceptional practitioners and researchers of the highest international standards. The faculty’s mission is to advance health through excellence in teaching, research and patient care. It is home to one of the top 100 ranked medical schools in the world. For more information, please visit

Media contacts:

Jessamine Luck 
Communications Advisor 

The Hospital for Sick Children (SickKids)

416-813-7654 ext. 201436

Ross Neitz                                                                  

Communications Associate                                                    

University of Alberta                              

This week’s ASF podcast is a special treat – Dr. Daniel Geschwind from UCLA provides an understanding of the brains of people with autism, focusing on those with a mutation in chromosome 15.  He goes over how they are similar and different (teaser: they are more similar) and answers questions from families about how this research is important for helping improve the lives of people across the spectrum. Listen to the podcast here.

This week’s podcast includes a summary of the new study, this time in an animal model, looking at microbiome transplantation.  Because this was more of an experimental model, the researchers could be more rigorous in their design and look at things like behavior, brain activity, and specific biological pathways.  While a mouse does not have autism, transplantation of the autism microbiome resulted in autistic-like behaviors.   Second, a hopeful message of the value of participating in research on outcomes – those infants that were tracked prospectively showed improved outcomes later on, suggesting that all of the extra attention they get leads to a reduction in symptoms and an improvement in adaptive behavior.  Even if you do not have a family history of autism – participate in research.  It’s good for your child, and it’s good for other people’s children. Listen to the podcast here.

The Smithsonian Magazine reported on the story of the Bak family and the Autism Sisters Project, an ASF scientific initiative determined to understand the disparity of autism diagnoses between boys and girls and the potential female protective effect. Through the study of the unaffected sisters of people with autism, the goal is to build a large genetic database that researchers can use to explore this phenomenon and discover how the protective factor can be harnessed to help people with autism of both sexes. Additionally, the project aims to study and understand the differences across the lifespan between males and females with autism and their family members. Read the article here and learn more about the Autism Sisters Project here.

On this week’s podcast, a special episode highlighting recent research focusing on fathers. This includes genetics, parental stress and quality of life, and broader autism phenotype features. Of note, two new studies that look at antidepressant exposure in father and probability of having a child with autism – a variation on studying maternal exposures.

On this week’s podcast, three genetics papers featuring three ASF fellows! All three deal with using whole genome sequencing (WGS) to study non-coding regulatory regions that may be associated with autism. These regions of DNA do not code for proteins but regulate the regions that do. Mutations in the non-coding regulatory regions that regulate the genes associated with autism appear to be passed down from the father. However, the statistics around these findings need to be carefully considered because, for autism risk, the contribution of non-coding mutations seems to be more modest than that of coding mutations.

Read the work by…
Dr. William Brandler of UC San Diego, ASF Fellow ’15 here.
Dr. Joon Yong An of UCSF, ASF Fellow ’18 here.
Dr. Donna Werling of UCSF, ASF Fellow ’16 here.

SETD5 is a master regulator of gene activity that controls the activity of potentially thousands of other downstream genes in the same cell. Researchers, supported in part by ASF, found that this gene is associated with a subtype of autism that is seen mostly in males and includes intellectual disability and facial dysmorphology. This is further support of different genes and gene combinations contributing to different features of autism, rather than the entire spectrum. The UC San Diego investigators, including Dr. Isabella Rodrigues Fernandes, ASF Grantee ’17, in this study will continue to investigate this gene and how it affects brain development, which may lead to therapeutic interventions for those who carry this mutation. Read the study here.

The Autism Science Foundation (ASF) announced the launch of three new multi-year research grants to expand the Autism Sisters Project at the University of California at San Francisco (UCSF) and the Broad Institute in Cambridge, MA. The Autism Sisters Project is an ASF initiative that explores the Female Protective Effect by studying autism families with an undiagnosed sister. Multiple lines of scientific evidence now show that females with an autistic sibling may have protective or resilience factors to autism.


Somer Bishop, PhD (UCSF)

For years, scientists have reported higher autism prevalence in males, but the reason for this gender discrepancy isn’t fully understood. One potential explanation is the presence of protective factors in females that may be genetic, epigenetic, environmental, or a combination of these.  Research has shown that some females carry genetic deletions or duplications that are known causes of autism, yet these girls do not exhibit clinical symptoms of autism. Other studies have pointed to the presence of a higher genetic “load” for females to reach the autism threshold, compared to males.  As a group, girls with autism tend to exhibit more severe symptoms and tend to be diagnosed later. These initial findings warrant a focused study of unaffected sisters of individuals with autism to try to identify this potential protective effect.


Stephan Sanders, BMBS, PhD (UCSF)

The three new research efforts funded by ASF will utilize data collected from families where a sister in the family does not have a diagnosis of ASD. Scientists will analyze thousands of families to understand the association between sex, phenotype and genetic mutation in all family members. Lead researchers will be Dr. Somer Bishop, associate professor at UCSF, Dr. Stephan Sanders, assistant professor at UCSF, and Dr. Elise Robinson, assistant professor at the Harvard T.H. Chan School of Public Health and an associate member of the Broad Institute of MIT and Harvard.


Elise Robinson, ScD (Harvard)

“We are excited to support this important work, which will help scientists understand not only risk factors, but also resilience factors in autism behaviors, as well as autism features in females,” says Alycia Halladay, chief science officer of the Autism Science Foundation. “These researchers will work with data already collected, even as work continues at Mount Sinai School of Medicine to recruit more families to add to these datasets.”

Funding for Drs. Bishop, Sanders and Robinson will allow them to analyze previously collected genetic and behavioral data to study the female protective effect in autism, specifically the genetic and behavioral features of sisters of individuals with ASD.  The unprecedented combination of datasets includes information from thousands of families contained in the Autism Sequencing Consortium as well as datasets such as the Autism Genetic Resource Exchange and the Baby Siblings Research Consortium.

The Autism Sisters Project focuses on three areas:

  • Data on unaffected sisters will be gathered from existing databases with rigorous behavioral phenotyping data on all family members, this funding will start in August.
  • New families with a member who has autism and a female sibling without an ASD diagnosis will be recruited to the Icahn School of Medicine at Mount Sinai to donate saliva samples and participate in a full screening. A full DNA exome scan, among other analyses, will be performed on the entire family. This was funded in 2016 and the study is ongoing.
  • In the future, funds will be provided to autism research sites so that sequencing and phenotyping can be expanded to include an unaffected sister in families where samples from parents and the individual diagnosed with autism have already been collected.
The Autism Science Foundation is also providing financial support to the Seaver Autism Center at Mount Sinai School of Medicine to collect information on families that have not previously participated in a genetic research study.  Interested participants should contact the Seaver Autism Center at 212-241-0961 or
The Hilibrand Foundation provides major financial support for the Autism Sisters Project.
Lots of people tend to think of the genetics of disorders/disease as being one mutation/genetic variation inherited from the mother/father that causes a trait directly. Unfortunately, the genetics of autism isn’t that simple or scientists would have found “the gene” by now. In fact, there are different types of genetic influences in autism. A new study in Nature Genetics led by Elise Robinson shows how common variation influences autism risk, as well as intellectual function in autism, compared to de novo mutations. There is a short primer at the beginning of the podcast about old-school genetic thinking and why it doesn’t apply to ASD.

Podcast Logo_03132017On Monday, the much anticipated MSSNG study which analyzed the entire DNA sequence of over 5000 people with autism was published. The press release can be found here. In it, the researchers found even more genes of interest to autism. Also, those with more of a specific type of mutation, copy number variations, had worse autism symptoms. But of course, the story gets more complicated than just more mutations – worse behavior. An analysis from a different group of individuals reinforced the role of copy number variations in symptoms, but when they matched the groups according to IQ, the autism symptom profiles were different. This shows that adaptive behavior and IQ are important to consider when considering how genetics influence autism symptoms. Finally, another study shows how important measuring genetics is to understanding environmental factors associated with autism.  Michela Traglia reports that increases in PBDEs in moms of kids affected with autism can be explained by mutations in the gene that breaks down these chemicals. It’s important to study genetics of autism, but also crucial to know the genetics of the entire family as well.

Click here to listen to this week’s podcast with Dr. Alycia Halladay.

Podcast Logo_01302017With hundreds of genes, thousands of environmental factors, and now sex being variables in determining risk for autism, where should science start? Over the decades researchers have been able to start narrowing down the combinations based on specific behaviors of interest, genes, and mechanisms which may narrow down which gene, which environmental factor and which sex. Dr. Sara Schaafsma and Dr. Donald Pfaff from Rockefeller University combined the three, and found that epigenetic changes in an autism risk gene called contact in associated protein like 2 contributed to elevation of risk for autism behaviors following maternal infection. In other words, being male and having the mutation produced small changes, increased by the environmental factor. In another separate study, Dr. Keith Dunaway and Dr. Janine LaSalle at UC Davis used brain tissue to look at a rare variant for autism on chromosome 15. Typically, mutations of this area of the genome are thought to cause autism.  However, the effects of these mutations are also increased when environmental factors are present, leading to more de novo mutations. These are all examples of scientific breakthroughs that are helping better understand what causes autism. Even when it looks like one thing, it’s multiple things.

Click here to listen to this week’s podcast with Dr. Alycia Halladay, ASF’s Chief Science Officer.