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World’s largest autism whole-genome sequencing study reveals 134 autism-linked genes

Summary: The researchers identified 134 genes associated with autism and a range of genetic alterations associated with ASDs. Notably, the study identified changes in copy number variations with likely associations with ASDs, including autism-associated variants in 14% of people on the autism spectrum.

Source: Hospital for sick children

Researchers at the Hospital for Sick Children (SickKids) have discovered new genes and genetic changes associated with autism spectrum disorders (ASD) in the largest whole genome sequencing analysis of autism to date, providing better understanding of the “genomic architecture” that underlies this disorder.

The study, published today in Cell, used whole genome sequencing (WGS) to examine the whole genomes of more than 7,000 people with autism as well as 13,000 additional siblings and family members.

The team found 134 genes linked to ASD and discovered a range of genetic changes, including gene copy number (CNV) variations, that may be associated with autism, including rare variants associated with ASD in about 14% of autistic participants.

The majority of the data was drawn from the Autism Speaks MSSNG database, the world’s largest whole-genome autism dataset, which provides autism researchers with free and open access to thousands of sequenced genomes.

“By sequencing the whole genome of all participants and with deep involvement of participating families in MSSNG on shaping our research priorities, we maximize the potential for discovery and enable 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 and Genome Biology and Head of Research at SickKids and Director of the McLaughlin Center at the University of Toronto.

Dr. Brett Trost, lead author of the paper and a research associate in the Genetics and Genome Biology program at SickKids, notes that using WGS has allowed researchers to discover types of variants that would not have been detectable. other.

These types of variants include complex rearrangements of DNA, as well as tandem repeat expansions, a finding supported by recent research from SickKids on the link between autism and DNA segments that repeat multiple times.

The role of mitochondrial DNA inherited from the mother was also examined in the study and found to be responsible for 2% of autism.

The article also highlights important nuances in the genetics of autism in families with only one autistic person versus families that have multiple autistic people, called multiplex families.

The team was surprised to find that the “polygenic score” – an estimate of the likelihood that an individual has 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 and highly impactful variants inherited from one parent. Because the genetics and clinical traits associated with autism are so complex and varied , large datasets like the ones we used are essential to provide researchers with a better understanding of the genetic architecture of autism,” says Trost.

It shows a strand of DNA
The research team says the study data can help expand investigations into the range of variants that could be linked to ASD, as well as efforts to better understand contributors to the 85% of autistic individuals for whom the genetic cause remains unresolved. Image is in public domain

The research team says the study data can help expand investigations into the range of variants that might be linked to ASDs, as well as efforts to better understand contributors to the 85% of autistic individuals for whom the genetic cause remains unresolved.

In a related study of 325 families with ASD from Newfoundland published that same month in Nature CommunicationDr. Scherer’s team found that combinations of spontaneous, rare hereditary and polygenic genetic factors brought together in the same individual can potentially lead to different subtypes of autism.

Dr Suzanne Lewis, a geneticist and researcher at 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 genetic and biological circuits TSA-related complexes.

“This rich dataset also offers the opportunity to further examine other factors that may determine an individual’s chance of developing this complex disease to help individualize future treatment approaches.”

Funding: Funding for this study was provided by the McLaughlin Center at the University of Toronto, Genome Canada/Ontario Genomics, Genome BC, the Government of Ontario, the Canadian Institutes of Health Research, the Canadian 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.

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About this genetics and autism research news

Author: Jelena Djurkic
Source: Hospital for sick children
Contact: Jelena Djurkic – Hospital for Sick Children
Image: Image is in public domain

Original research: Access closed.
“Genomic Architecture of Autism from Comprehensive Whole Genome Sequence Annotation” by Stephen Scherer, et al. Cell


Autism genomic architecture from comprehensive whole genome sequence annotation

Strong points

  • New version of MSSNG contains WGS of 11,312 people from families with ASD
  • Extensive variant data available, including SNV/indels, SV, tandem repeats and PRS
  • Annotation reveals 134 ASD-associated genes, plus undetectable SVs without WGS
  • A rare and dominant variation plays a prominent role in multiplex ASDs


Fully understanding the genetics of autism spectrum disorders (ASD) requires whole genome sequencing (WGS). We present the latest version of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 people with ASD and 6,212 non-ASD parents and siblings (total n=11,312).

By screening a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n=9205), we identified rare variants associated with ASDs in 718/5100 individuals with MSSNG ASD (14.1%) and 350/2419 AUC (14.5%).

Considering genomic architecture, 52% were variants at the nuclear sequence level, 46% were nuclear structural variants (including copy number variants, inversions, large insertions, uniparental isodisomies and expansions repeated in tandem) and 2% were mitochondrial variants.

Our study provides a guide to explore genotype-phenotype correlations in families carrying rare ASD-associated variants and serves as an entry point for expanded studies needed to dissect etiology in the remaining ∼85% of the ASD population. idiopathic.

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