Genome-wide detection of tandem DNA repeats that are expanded in autism

Brett Trost, Worrawat Engchuan, Charlotte M. Nguyen, Bhooma Thiruvahindrapuram, Egor Dolzhenko, Ian Backstrom, Mila Mirceta, Bahareh A. Mojarad, Yue Yin, Alona Dov, Induja Chandrakumar, Tanya Prasolava, Natalie Shum, Omar Hamdan, Giovanna Pellecchia, Jennifer L. Howe, Joseph Whitney, Eric W. Klee, Saurabh Baheti, David G. Amaral, Evdokia Anagnostou, Mayada Elsabbagh, Bridget A. Fernandez, Ny Hoang, M. E. Suzanne Lewis, Xudong Liu, Calvin Sjaarda, Isabel M. Smith, Peter Szatmari, Lonnie Zwaigenbaum, David Glazer, Dean Hartley, A. Keith Stewart, Michael A. Eberle, Nozomu Sato, Christopher E. Pearson, Stephen W. Scherer and Ryan K. C. Yuen ()
Additional contact information
Brett Trost: The Hospital for Sick Children
Worrawat Engchuan: The Hospital for Sick Children
Charlotte M. Nguyen: The Hospital for Sick Children
Bhooma Thiruvahindrapuram: The Hospital for Sick Children
Egor Dolzhenko: Illumina
Ian Backstrom: The Hospital for Sick Children
Mila Mirceta: The Hospital for Sick Children
Bahareh A. Mojarad: The Hospital for Sick Children
Yue Yin: The Hospital for Sick Children
Alona Dov: The Hospital for Sick Children
Induja Chandrakumar: The Hospital for Sick Children
Tanya Prasolava: The Hospital for Sick Children
Natalie Shum: The Hospital for Sick Children
Omar Hamdan: The Hospital for Sick Children
Giovanna Pellecchia: The Hospital for Sick Children
Jennifer L. Howe: The Hospital for Sick Children
Joseph Whitney: The Hospital for Sick Children
Eric W. Klee: Mayo Clinic
Saurabh Baheti: Mayo Clinic
David G. Amaral: University of California Davis School of Medicine
Evdokia Anagnostou: University of Toronto
Mayada Elsabbagh: McGill University
Bridget A. Fernandez: Memorial University of Newfoundland
Ny Hoang: The Hospital for Sick Children
M. E. Suzanne Lewis: University of British Columbia (UBC)
Xudong Liu: Queen’s University
Calvin Sjaarda: Queen’s University
Isabel M. Smith: Dalhousie University
Peter Szatmari: University of Toronto
Lonnie Zwaigenbaum: University of Alberta
David Glazer: Verily Life Sciences
Dean Hartley: Autism Speaks
A. Keith Stewart: Center for Individualized Medicine, Mayo Clinic
Michael A. Eberle: Illumina
Nozomu Sato: The Hospital for Sick Children
Christopher E. Pearson: The Hospital for Sick Children
Stephen W. Scherer: The Hospital for Sick Children
Ryan K. C. Yuen: The Hospital for Sick Children

Nature, 2020, vol. 586, issue 7827, 80-86

Abstract: Abstract Tandem DNA repeats vary in the size and sequence of each unit (motif). When expanded, these tandem DNA repeats have been associated with more than 40 monogenic disorders1. Their involvement in disorders with complex genetics is largely unknown, as is the extent of their heterogeneity. Here we investigated the genome-wide characteristics of tandem repeats that had motifs with a length of 2–20 base pairs in 17,231 genomes of families containing individuals with autism spectrum disorder (ASD)2,3 and population control individuals4. We found extensive polymorphism in the size and sequence of motifs. Many of the tandem repeat loci that we detected correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated expansions of tandem repeats that were rare among population control individuals were significantly more prevalent among individuals with ASD than their siblings without ASD, particularly in exons and near splice junctions, and in genes related to the development of the nervous system and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in children with ASD compared with 20.7% in children without ASD, which suggests that tandem repeat expansions make a collective contribution to the risk of ASD of 2.6%. These rare tandem repeat expansions included previously undescribed ASD-linked expansions in DMPK and FXN, which are associated with neuromuscular conditions, and in previously unknown loci such as FGF14 and CACNB1. Rare tandem repeat expansions were associated with lower IQ and adaptive ability. Our results show that tandem DNA repeat expansions contribute strongly to the genetic aetiology and phenotypic complexity of ASD.

Date: 2020
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DOI: 10.1038/s41586-020-2579-z

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