Daida Kensuke, Funayama Manabu, Billingsley Kimberley J, Malik Laksh, Miano-Burkhardt Abigail, Leonard Hampton L, Makarious Mary B, Iwaki Hirotaka, Ding Jinhui, Gibbs J Raphael, Ishiguro Mayu, Yoshino Hiroyo, Ogaki Kotaro, Oyama Genko, Nishioka Kenya, Nonaka Risa, Akamatsu Wado, Blauwendraat Cornelis, Hattori Nobutaka
Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
medRxiv. 2023 Aug 21:2023.08.14.23293948. doi: 10.1101/2023.08.14.23293948.
mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). is 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 of are seldom reported, suggesting that there are potentially unrevealed complex pathogenic structural variants.
To identify complex structural variants in using long-read sequencing.
We 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. We assessed the presence and frequency of complex inversions overlapping using whole-genome sequencing data of AMP-PD and UK-Biobank datasets.
Multiple ligation probe amplification identified a heterozygous exon 3 deletion in and long-read sequencing identified a large novel inversion spanning over 7Mb, including a large part of the coding DNA sequence of . We could diagnose the affected subjects as compound heterozygous carriers of . We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4,941 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 affect isoforms.
This is the first report describing a large 7Mb inversion involving breakpoints outside of . This study highlights the importance of using long-read whole genome sequencing for structural variant analysis in unresolved young-onset PD cases.
突变是早发型和常染色体隐性帕金森病（PD）最常见的病因。 位于FRA6E，这是人类基因组中常见的脆性位点之一，使得该区域易于出现结构变异。然而，诸如 的倒位等复杂结构变异很少被报道，这表明可能存在未被揭示的复杂致病结构变异。
使用长读长测序鉴定 中的复杂结构变异。
我们使用靶向测序、全外显子组测序、多重连接探针扩增和长读长测序，研究了一对患有早发性肌张力障碍-帕金森综合征的同卵双胞胎的遗传病因。我们使用AMP-PD和英国生物银行数据集的全基因组测序数据评估了与 重叠的复杂倒位的存在和频率。
多重连接探针扩增在 中鉴定出一个杂合的外显子3缺失，长读长测序鉴定出一个跨越超过7Mb的大型新型倒位，包括 的大部分编码DNA序列。我们可以将受影响的受试者诊断为 的复合杂合携带者。我们分析了英国生物银行43538名参与者和AMP-PD数据集4941名参与者的全基因组测序数据。在英国生物银行中鉴定出9个倒位，在AMP-PD中鉴定出2个倒位，这些倒位被认为具有潜在损害性，可能会影响 异构体。
这是第一份描述涉及 以外断点的7Mb大型倒位的报告。本研究强调了在未解决的早发性PD病例中使用长读长全基因组测序进行结构变异分析的重要性。
