Cell and two other articles reported on the largest autism study to date, discovering hundreds of new genes

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects how a person communicates and interacts with others, as well as how they perceive and respond to the world
around them.
Symptoms of autism spectrum disorder range from mild to severe and include difficulty with social interaction, difficulty communicating verbally and nonverbally, repetitive behaviors, and other unique challenges
.

Researchers at Sick Children's Hospital (SickKids) have revealed new genes and genetic changes associated with autism spectrum disorder (ASD) in the most comprehensive whole-genome sequencing analysis of autism to date, improving our understanding of
the genomic basis of ASD.

The study, published in the journal Cell, used whole genome sequencing to analyze the whole genomes
of more than 7,000 people with autism and another 13,000 siblings and family members.
The study identified 134 autism-related genes and identified a range of genetic changes that may be associated with autism, particularly gene copy number variants, including rare autism-related variants
present in about 14 percent of people with autism.

Much of the data comes from the Autism Voice MSSNG database, the world's largest autism-wide genome dataset, which provides autism researchers with
free, open access to thousands of sequenced genomes.

"By sequencing the entire genome of all participants and forming our research focus with the deep involvement of MSSNG participating families, we maximize the potential of the discovery and allow analysis to cover all types of variations, from the smallest DNA changes to those affecting the entire chromosome," said Dr.
Stephen Scherer, senior scientist, research director 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 SickKids Genetic and Genomic Biology Project, noted that the use of WGS allows researchers to discover types
of variants that would otherwise be undetectable.
These variant types include complex DNA rearrangements, as well as tandem repeat amplification, a finding
supported by recent SickKids' research on the link between autism and repeated DNA fragments.
The study also examined the role of mitochondrial DNA inherited by the mother and found that it accounted for 2%
of autism.

The paper also points out important nuances in autism genetics between families with only one autistic person and families with multiple autistic people (i.
e
.
, multiple families).
To the team's surprise, the "polygenic score" — an estimate of an individual's likelihood of developing autism that is calculated by pooling the effects of thousands of common variants in the genome — was not high
in polygenic families.

"This suggests that in multiple families, autism may be more likely to be associated with
rare, highly influential variants inherited from parents.
" Because the genetics and clinical traits associated with autism are so complex and diverse, large datasets like the one we use are critical to providing researchers with a clearer understanding of the genetic structure of autism," Trost said
.

The team said the data from this study could help expand the investigation of the range of variants that may be linked to autism spectrum disorder, as well as better understand factors
in the 85 percent of people with autism whose genetic causes remain unaddressed.
In a related study of 325 families with ASD in Newfoundland, published in Nature Communications, Dr.
Scherer's team found that a combination of spontaneous, rare, and polygenic genetic factors in the same person may lead to different subtypes
of autism.

These latest findings represent a major step
forward in better understanding the complex genetic and biological circuits associated with ASD.
This rich dataset also provides an opportunity to delve deeper into other factors that may determine an individual's odds of developing this complex disease to help develop personalized future treatments
.

1.
“Genomic architecture of autism from comprehensive whole-genome sequence annotation” by Brett Trost, Bhooma Thiruvahindrapuram, Ada J.
S.
Chan, Worrawat Engchuan, Edward J.
Higginbotham, Jennifer L.
Howe, Livia O.
Loureiro, Miriam S.
Reuter, Delnaz Roshandel, Joe Whitney, Mehdi Zarrei, Matthew Bookman, Cherith Somerville, Rulan Shaath, Mona Abdi, Elbay Aliyev, Rohan V.
Patel, Thomas Nalpathamkalam, Giovanna Pellecchia, Omar Hamdan, Gaganjot Kaur, Zhuozhi Wang, Jeffrey R.
MacDonald, John Wei, Wilson W.
L.
Sung, Sylvia Lamoureux, Ny Hoang, Thanuja Selvanayagam, Nicole Deflaux, Melissa Geng, Siavash Ghaffari, John Bates, Edwin J.
Young, Qiliang Ding, Carole Shum, Lia D’Abate, Clarrisa A.
Bradley, Annabel Rutherford, Vernie Aguda, Beverly Apresto, Nan Chen, Sachin Desai, Xiaoyan Du, Matthew L.
Y.
Fong, Sanjeev Pullenayegum, Kozue Samler, Ting Wang, Karen Ho, Tara Paton, Sergio L.
Pereira, Jo-Anne Herbrick, Richard F.
Wintle, Jonathan Fuerth, Juti Noppornpitak, Heather Ward, Patrick Magee, Ayman Al Baz, Usanthan Kajendirarajah, Sharvari Kapadia, Jim Vlasblom, Monica Valluri, Joseph Green, Vicki Seifer, Morgan Quirbach, Olivia Rennie, Elizabeth Kelley, Nina Masjedi, Catherine Lord, Michael J.
Szego, Ma’n H.
Zawati, Michael Lang, Lisa J.
Strug, Christian R.
Marshall, Gregory Costain, Kristina Calli, Alana Iaboni, Afiqah Yusuf, Patricia Ambrozewicz, Louise Gallagher, David G.
Amaral, Jessica Brian, Mayada Elsabbagh, Stelios Georgiades, Daniel S.
Messinger, Sally Ozonoff, Jonathan Sebat, Calvin Sjaarda, Isabel M.
Smith, Peter Szatmari, Lonnie Zwaigenbaum, Azadeh Kushki, Thomas W.
Frazier, Jacob A.
S.
Vorstman, Khalid A.
Fakhro, Bridget A.
Fernandez, M.
E.
Suzanne Lewis, Rosanna Weksberg, Marc Fiume, Ryan K.
C.
Yuen, Evdokia Anagnostou, Neal Sondheimer, David Glazer, Dean M.
Hartley and Stephen W.
Scherer, 10 November 2022, Cell.

2.
“Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder” by Ada J.
S.
Chan, Worrawat Engchuan, Miriam S.
Reuter, Zhuozhi Wang, Bhooma Thiruvahindrapuram, Brett Trost, Thomas Nalpathamkalam, Carol Negrijn, Sylvia Lamoureux, Giovanna Pellecchia, Rohan V.
Patel, Wilson W.
L.
Sung, Jeffrey R.
MacDonald, Jennifer L.
Howe, Jacob Vorstman, Neal Sondheimer, Nicole Takahashi, Judith H.
Miles, Evdokia Anagnostou, Kristiina Tammimies, Mehdi Zarrei, Daniele Merico, Dimitri J.
Stavropoulos, Ryan K.
C.
Yuen, Bridget A.
Fernandez and Stephen W.
Scherer, 29 October 2022, Nature Communications.