Long-read DNA sequencing fully characterized chromothripsis in a patient with Langer-Giedion syndrome and Cornelia de Lange syndrome-4
Long-read DNA sequencing fully characterized chromothripsis in a patient with Langer-Giedion syndrome and Cornelia de Lange syndrome-4
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长读长 DNA 测序完全表征了 Langer-Giedion 综合征和 Cornelia de Lange 综合征患者的染色体碎裂 - 4
DOI：
10.1038/s10038-020-0754-6
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发表时间：
2020-04-15
影响因子：
3.5
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
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作者：
Lei, Ming;Liang, Desheng;Matsumoto, Naomichi
染色体断裂是由染色体断裂和修复过程引起的一种复杂的基因组重排。已知当染色体碎裂症发生在生殖细胞中时会导致罕见的先天性疾病，然而，当前的基因组分析技术难以检测和破译染色体碎裂症。这种复杂的基因重排可能在遗传诊断尚未解决的罕见疾病患者中被忽视。我们将长读纳米孔测序和我们最近开发的分析管道应用于由于两条染色体之间的染色体碎裂而具有相互染色体易位t（8;18）（q22;q21）的患者，并充分表征易位位点处的复杂重排。病人的基因组显然被粉碎成19个片段，并以随机的顺序和方向重新连接成衍生染色体。重建的患者基因组指示五个基因组区域的丢失，其全部与微阵列检测到的拷贝数丢失重叠。我们发现，两个疾病相关基因RAD 21和EXT 1被chromothripsis丢失。这两个基因可以完全解释具有面部畸形和骨骼异常的疾病表型，这可能是一种相邻基因综合征，科尔内利亚德兰格综合征IV型（CdLs-4）和非典型朗格-吉二氏综合征（LGS），也称为毛发鼻指综合征II型（TRPSII）。这提供了证据，证明我们基于长读段测序的方法可以完全表征患者基因组中的染色体断裂，这对于理解由复杂基因组重排引起的疾病的表型很重要。
Chromothripsis is a type of chaotic complex genomic rearrangement caused by a single event of chromosomal shattering and repair processes. Chromothripsis is known to cause rare congenital diseases when it occurs in germline cells, however, current genome analysis technologies have difficulty in detecting and deciphering chromothripsis. It is possible that this type of complex rearrangement may be overlooked in rare-disease patients whose genetic diagnosis is unsolved. We applied long read nanopore sequencing and our recently developed analysis pipeline dnarrange to a patient who has a reciprocal chromosomal translocation t(8;18)(q22;q21) as a result of chromothripsis between the two chromosomes, and fully characterize the complex rearrangements at the translocation site. The patient genome was evidently shattered into 19 fragments, and rejoined into derivative chromosomes in a random order and orientation. The reconstructed patient genome indicates loss of five genomic regions, which all overlap with microarray-detected copy number losses. We found that two disease-related genes RAD21 and EXT1 were lost by chromothripsis. These two genes could fully explain the disease phenotype with facial dysmorphisms and bone abnormality, which is likely a contiguous gene syndrome, Cornelia de Lange syndrome type IV (CdLs-4) and atypical Langer-Giedion syndrome (LGS), also known as trichorhinophalangeal syndrome type II (TRPSII). This provides evidence that our approach based on long read sequencing can fully characterize chromothripsis in a patient's genome, which is important for understanding the phenotype of disease caused by complex genomic rearrangement.