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 disorders 1 . 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 individuals 4 . 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. Genome-wide analysis of tandem DNA repeats in the genomes of individuals with autism spectrum disorder and control participants reveals a strong contribution of tandem repeat expansions to the genetic aetiology and phenotypic complexity of autism spectrum disorder.

中文翻译：

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全基因组检测自闭症中扩展的串联 DNA 重复序列


串联 DNA 重复序列的每个单元（基序）的大小和序列各不相同。扩展后，这些串联 DNA 重复序列与 40 多种单基因疾病相关 1 。他们与复杂遗传学疾病的关系在很大程度上尚不清楚，其异质性程度也是如此。在这里，我们研究了包含自闭症谱系障碍（ASD）个体 2 , 3 和人口对照个体 4 的 17,231 个家庭基因组中串联重复序列的全基因组特征，这些重复序列具有长度为 2-20 个碱基对的基序。我们发现基序的大小和序列存在广泛的多态性。我们检测到的许多串联重复基因座与细胞遗传学脆弱位点相关。在 2,588 个位点上，与基因相关的串联重复扩展在群体对照个体中很少见，但在 ASD 个体中比没有 ASD 的兄弟姐妹中更常见，特别是在外显子和剪接点附近，以及与神经发育相关的基因中。系统和心血管系统或肌肉。罕见串联重复扩增在 ASD 儿童中的患病率为 23.3%，而在非 ASD 儿童中为 20.7%，这表明串联重复扩增对 ASD 风险的总体影响为 2.6%。这些罕见的串联重复扩增包括先前未描述的 DMPK 和 FXN 中与神经肌肉状况相关的 ASD 相关扩增，以及先前未知的基因座（例如 FGF14 和 CACNB1）。罕见的串联重复扩增与较低的智商和适应能力有关。我们的结果表明串联 DNA 重复扩增对 ASD 的遗传病因学和表型复杂性有很大影响。 对自闭症谱系障碍患者和对照参与者基因组中串联 DNA 重复序列的全基因组分析揭示了串联重复序列扩展对自闭症谱系障碍的遗传病因学和表型复杂性的重要贡献。