Long-read sequencing resolves a complex structural variant in PRKN Parkinson's disease.
Long-read sequencing resolves a complex structural variant in PRKN Parkinson's disease.
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长读长测序解决了 PRKN 帕金森病的复杂结构变异。
DOI：
10.1101/2023.08.14.23293948
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Nishi
中科院分区：
文献类型：
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作者：
Daida,Kensuke;Funayama,Manabu;Billingsley,KimberleyJ;Malik,Laksh;Miano-Burkhardt,Abigail;Leonard,HamptonL;Makarious,MaryB;Iwaki,Hirotaka;Ding,Jinhui;Gibbs,JRaphael;Ishiguro,Mayu;Yoshino,Hiroyo;Ogaki,Kotaro;Oyama,Genko;Nishi
背景Parkin RBR E3泛素蛋白连接酶（PRKN）突变是年轻发病和常染色体隐性遗传帕金森病（PD）的最常见原因。PRKN位于FRA6E，FRA6E是人类基因组中常见的脆弱位点之一，使得该区域容易发生结构变异。然而，诸如PRKN倒位之类的复杂结构变异却很少报道，这表明可能存在未揭示的复杂致病性PRKN结构变异。目的利用长读长测序识别PRKN中的复杂结构变异。方法我们利用靶向测序、全外显子组测序、多重连接探针扩增和长读长测序研究了年轻发病肌张力障碍帕金森症同卵双胞胎的遗传原因。我们使用加速药物合作伙伴帕金森病 (AMP-PD) 和英国 (UK)-Biobank 数据集的全基因组测序数据评估了与 PRKN 重叠的复杂倒位的存在和频率。结果多重连接探针扩增鉴定了 PRKN 中的杂合外显子 3 缺失，长读长测序鉴定了跨度超过 7 Mb 的大型新型倒位，包括 PRKN 编码 DNA 序列的大部分。我们可以诊断受影响的受试者为PRKN复合杂合子携带者。我们分析了 UK-Biobank 的 43,538 名参与者和 AMP-PD 数据集的 4941 名参与者的全基因组测序数据。 UK-Biobank 中的 9 个倒置和 AMP PD 中的 2 个倒置被识别，并被认为具有潜在破坏性并可能影响 PRKN 表达。结论这是第一份描述涉及 PRKN 外部断点的 7 Mb 大型倒置的报告。这项研究强调了在未解决的年轻发病帕金森病病例中使用长读长测序进行结构变异分析的重要性。 © 2023 作者。运动障碍由 Wiley periodicals LLC 代表国际帕金森和运动障碍协会出版。本文由美国政府雇员撰写，他们的作品在美国属于公共领域。
BackgroundParkin RBR E3 ubiquitin‐protein ligase(PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD).PRKNis located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions ofPRKNare seldom reported, suggesting that there are potentially unrevealed complex pathogenicPRKNstructural variants.ObjectivesTo identify complex structural variants inPRKNusing long‐read sequencing.MethodsWe investigated the genetic cause of monozygotic twins presenting with a young onset dystonia‐parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long‐read sequencing. We assessed the presence and frequency of complex inversions overlappingPRKNusing whole‐genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP‐PD) and United Kingdom (UK)‐Biobank datasets.ResultsMultiple ligation probe amplification identified a heterozygous exon three deletion inPRKNand long‐read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence ofPRKN. We could diagnose the affected subjects as compound heterozygous carriers ofPRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK‐Biobank and 4941 participants of the AMP‐PD datasets. Nine inversions in the UK‐Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affectPRKNexpression.ConclusionsThis is the first report describing a large 7 Mb inversion involving breakpoints outside ofPRKN. This study highlights the importance of using long‐read sequencing for structural variant analysis in unresolved young‐onset PD cases. © 2023 The Authors.Movement Disorderspublished by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.