TY - JOUR
T1 - Genome-wide detection of tandem DNA repeats that are expanded in autism
AU - Trost, Brett
AU - Engchuan, Worrawat
AU - Nguyen, Charlotte M.
AU - Thiruvahindrapuram, Bhooma
AU - Dolzhenko, Egor
AU - Backstrom, Ian
AU - Mirceta, Mila
AU - Mojarad, Bahareh A.
AU - Yin, Yue
AU - Dov, Alona
AU - Chandrakumar, Induja
AU - Prasolava, Tanya
AU - Shum, Natalie
AU - Hamdan, Omar
AU - Pellecchia, Giovanna
AU - Howe, Jennifer L.
AU - Whitney, Joseph
AU - Klee, Eric W.
AU - Baheti, Saurabh
AU - Amaral, David G.
AU - Anagnostou, Evdokia
AU - Elsabbagh, Mayada
AU - Fernandez, Bridget A.
AU - Hoang, Ny
AU - Lewis, M. E.Suzanne
AU - Liu, Xudong
AU - Sjaarda, Calvin
AU - Smith, Isabel M.
AU - Szatmari, Peter
AU - Zwaigenbaum, Lonnie
AU - Glazer, David
AU - Hartley, Dean
AU - Stewart, A. Keith
AU - Eberle, Michael A.
AU - Sato, Nozomu
AU - Pearson, Christopher E.
AU - Scherer, Stephen W.
AU - Yuen, Ryan K.C.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-020-2579-z
DO - 10.1038/s41586-020-2579-z
M3 - Article
C2 - 32717741
AN - SCOPUS:85088553949
SN - 0028-0836
VL - 586
SP - 80
EP - 86
JO - Nature
JF - Nature
IS - 7827
ER -