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Autism Whole Genome Sequencing Reveals 134 Autism-Linked Genes

Published: 2022-11-11
Author: The Hospital for Sick Children | Contact: sickkids.ca
Peer-Reviewed Publication: Yes | DOI: https://dx.doi.org/10.1016/j.cell.2022.10.009
Additional References: Library of Autism Information Publications

Synopsis: Study sequences the entire genomes of more than 11,000 individuals, offering new insights into the genetics that underlie autism spectrum disorder. 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. 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.

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Definition

Autism

Autism, or autism spectrum disorder (ASD), is a lifelong, nonprogressive neurological disorder typically appearing before the age of three years. The word "autism" means a developmental disability is significantly affecting verbal and non-verbal communication and social interaction. People with ASD may behave, communicate, interact, and learn in ways that are different from most others. Often, nothing about how they look sets them apart from other people. The classic form of autism involves a triad of impairments; in social interaction, communication, language use, and limited imagination as reflected in restricted, repetitive, and stereotyped behavior patterns and activities.

Main Digest

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.

Related Publications:

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.

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.

Reference Source(s):

Autism Whole Genome Sequencing Reveals 134 Autism-Linked Genes | The Hospital for Sick Children (sickkids.ca). Disabled World makes no warranties or representations in connection therewith. Content may have been edited for style, clarity or length.

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