Whole Genome Sequencing Identifies 134 Autism Genes
Author: The Hospital for Sick Children
Published: 2022/11/11 - Updated: 2026/02/23
Publication Details: Peer-Reviewed, Research, Study, Analysis
Category Topic: Autism - Related Publications
Contents: Synopsis - Introduction - Main - Insights, Updates
Synopsis: This research is a peer-reviewed study published in Cell that presents findings from the largest whole genome sequencing analysis of autism spectrum disorder conducted to date. Led by researchers at The Hospital for Sick Children (SickKids) and drawing primarily from the Autism Speaks MSSNG database, the study sequenced the entire genomes of over 7,000 individuals with autism along with 13,000 family members, identifying 134 genes linked to ASD and detecting rare variants in roughly 14 percent of participants. The analysis uncovered genetic changes that previous methods could not detect, including complex DNA rearrangements and tandem repeat expansions, and revealed important differences in the genetic architecture of autism between single-affected families and multiplex families. This work is of significant value to autistic individuals, their families, disability advocates, and clinical geneticists because it advances the understanding of how varied genetic factors contribute to autism and lays groundwork for more individualized approaches to diagnosis and support - Disabled World (DW).
- Topic Definition: Whole Genome Sequencing (WGS)
Whole genome sequencing (WGS) is a laboratory process that determines the complete DNA sequence of an organism's genome in a single analysis, capturing all genetic information contained across every chromosome. Unlike targeted approaches that examine only specific genes or regions of interest, WGS reads the entire genetic code, making it possible to detect a full range of variation types including single-nucleotide changes, insertions, deletions, copy number variations, structural rearrangements, and repeat expansions. In autism research, WGS has become an increasingly important tool because autism spectrum disorder is influenced by many different types of genetic changes spread across the genome, and older sequencing methods miss a substantial portion of these variants. The technology allows researchers and clinicians to identify both common and rare genetic contributors to complex conditions, supporting more precise diagnosis and a deeper understanding of how inherited and spontaneous mutations interact to influence developmental outcomes.
Introduction
Autism Whole Genome Sequencing Reveals 134 Autism-Linked Genes
Researchers from The Hospital for Sick Children (SickKids) have uncovered new genes and genetic changes associated with autism spectrum disorder (ASD) in the largest autism whole genome sequencing analysis to date, providing a better understanding of the 'genomic architecture' that underlies this disorder.
The study, published in Cell, used whole genome sequencing (WGS) to examine the genomes of over 7,000 individuals with autism and an additional 13,000 siblings and family members. The team found 134 genes linked with ASD and discovered a range of genetic changes, most notably gene copy number variations (CNVs), likely to be associated with autism, including ASD-associated rare variants in about 14 percent of participants with autism.
Main Content
The majority of data was drawn from the Autism Speaks MSSNG database, the world's largest autism whole genome dataset, which provides autism researchers with free, open access to thousands of sequenced genomes.
"By sequencing the entire genome of all participants, and with deep involvement from the participating families in MSSNG on forming our research priorities, we maximize the potential for discovery and allow analysis that encompasses all types of variants, from the smallest DNA changes to those that affect entire chromosomes," says Dr. Stephen Scherer, Senior Scientist, Genetics & Genome Biology and Chief of Research at SickKids and Director of the McLaughlin Centre at the University of Toronto.
Dr. Brett Trost, lead author of the paper and a Research Associate in the Genetics & Genome Biology program at SickKids, notes that using WGS allowed researchers to uncover variant types that would not otherwise be detectable. These variant types include complex rearrangements of DNA and tandem repeat expansions, a finding supported by recent SickKids research on the link between autism and DNA segments that are repeated many times. The role of the maternally inherited mitochondrial DNA was also examined in the study and found to account for two percent of autism.
The paper also points to important nuances in autism genetics in families with only one individual with autism compared with families with multiple individuals with autism, known as multiplex families. Surprising to the team was that the "polygenic score" - an estimation of the likelihood of an individual having autism, calculated by aggregating the effects of thousands of common variants throughout the genome - was not higher among multiplex families.
"This suggests that autism in multiplex families may be more likely to be linked to rare, highly impactful variants inherited from a parent. Because both the genetics and clinical traits associated with autism are so complex and varied, large data sets like the ones we used are critical to providing researchers with a clearer understanding of the genetic architecture of autism," says Trost.
The research team says the study data can help expand inquiries into the range of variants that might be linked to ASD, as well as efforts to understand better contributors to the 85 percent of autistic individuals for which the genetic cause remains unresolved. In a linked study of 325 families with ASD from Newfoundland published this month in Nature Communications, Dr. Scherer's team found that combinations of spontaneous, rare-inherited, and polygenic genetic factors combined in the same individual can potentially lead to different sub-types of autism.
Dr. Suzanne Lewis, a geneticist, and investigator at the BC Children's Hospital Research Institute who diagnosed many of the families enrolled in the study said:
"Collectively, these latest findings represent a massive step forward in better understanding the complex genetic and biological circuitry linked with ASD. This rich data set also allows one to examine other factors that may determine an individual's chance of developing this complex condition to help individualize future treatment approaches."
Funding for this study was provided by the University of Toronto McLaughlin Centre, Genome Canada/Ontario Genomics, Genome BC, Government of Ontario, Canadian Institutes of Health Research, Canada Foundation for Innovation, Autism Speaks, Autism Speaks Canada, Brain Child, Kids Brain Health Network, Qatar National Research Fund, Ontario Brain Institute, SFARI and SickKids Foundation.
Insights, Analysis, and Developments
Editorial Note: What makes this study particularly significant is not just its scale but the depth of insight that whole genome sequencing provides compared to older methods that examined only portions of the genetic code. By capturing everything from the smallest single-nucleotide changes to large chromosomal rearrangements, the SickKids team was able to build a far more complete picture of how different types of genetic variation contribute to autism - including the surprising finding that multiplex families did not show higher polygenic scores, suggesting their cases may be driven more by rare inherited variants than by the accumulation of common ones. With the genetic cause still unresolved for an estimated 85 percent of autistic individuals, datasets of this magnitude and resolution are essential for closing that gap and moving toward a future where genetic information can meaningfully inform clinical care and personalized support for people on the spectrum - Disabled World (DW).Attribution/Source(s): This peer reviewed publication was selected for publishing by the editors of Disabled World (DW) due to its relevance to the disability community. Originally authored by The Hospital for Sick Children and published on 2022/11/11, this content may have been edited for style, clarity, or brevity.