Uncovering the complexity of structural variants in four individuals with Autism Spectrum Disorder.

IF 2.3 3区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Genome Pub Date : 2024-12-12 DOI:10.1139/gen-2024-0121
Sarah Dada, Katherine Dixon, Vahid Akbari, Cameron J Grisdale, Kristina Calli, Sally Martell, Caralyn Reisle, Amanda Lillico-Ouachour, M E Suzanne Lewis, Steven J M Jones
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Abstract

Autism spectrum disorder (ASD) is an increasingly recognized childhood developmental disorder. Despite extensive study, causal variants and molecular diagnosis remain elusive. There is both heterogeneity of the phenotype, as well as the genetic landscape associated with phenotype, which includes both inherited and de-novo mutations. Currently, diagnosis is complex and behaviourally based, oftentimes occurring years after the ideal 1-2 years age. Structural variants (SVs) are large and sometimes complex genomic variants that are likely underrepresented contributors to ASD due to the limitations of short-read DNA sequencing, such as alignment in repetitive regions and regions with GC bias. Here, we performed long read sequencing (LRS) on four individuals with autism spectrum disorder to delineate SV complexity and determine precise breakpoints for SVs, which was not possible with short read sequencing (SRS). We use LRS to interrogate the methylation pattern associated with the SVs and phase the SV haplotypes to further clarify their contribution to disorder. LRS allows insight into the genome and methylome that allow us to uncover variant complexity and contribution that was previously unseen with SRS. Ultimately, this furthers precision diagnosis and contributes to individualized treatment for affected individuals and their families within the clinic.

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揭示四名自闭症谱系障碍患者结构变异的复杂性。
自闭症谱系障碍(ASD)是一种日益被认可的儿童发育障碍。尽管进行了广泛的研究,但因果变异和分子诊断仍然难以捉摸。自闭症的表型以及与表型相关的遗传情况都存在异质性,其中包括遗传突变和新发突变。目前,诊断很复杂,而且以行为为基础,往往在理想的 1-2 岁年龄之后数年才能确诊。结构变异(SVs)是大的、有时是复杂的基因组变异,由于短读DNA测序的局限性,如重复区域和具有GC偏倚的区域的配准,这些变异很可能是导致ASD的代表性不足的因素。在这里,我们对四名自闭症谱系障碍患者进行了长读数测序(LRS),以划分 SV 的复杂性并确定 SV 的精确断点,而这是短读数测序(SRS)无法实现的。我们利用 LRS 分析与 SV 相关的甲基化模式,并对 SV 单倍型进行分期,以进一步明确它们对自闭症的影响。通过 LRS,我们可以深入了解基因组和甲基组,从而发现 SRS 以前无法发现的变异复杂性和贡献。最终,这将促进精准诊断,并有助于在临床上为受影响的个体及其家庭提供个体化治疗。
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来源期刊
Genome
Genome 生物-生物工程与应用微生物
CiteScore
5.30
自引率
3.20%
发文量
42
审稿时长
6-12 weeks
期刊介绍: Genome is a monthly journal, established in 1959, that publishes original research articles, reviews, mini-reviews, current opinions, and commentaries. Areas of interest include general genetics and genomics, cytogenetics, molecular and evolutionary genetics, developmental genetics, population genetics, phylogenomics, molecular identification, as well as emerging areas such as ecological, comparative, and functional genomics.
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