Optical genome mapping enables constitutional chromosomal aberration detection
Optical genome mapping enables constitutional chromosomal aberration detection
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DOI：
10.1016/j.ajhg.2021.05.012
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发表时间：
2021-08-05
影响因子：
9.8
通讯作者：
El Khattabi, Laila
中科院分区：
文献类型：
--
作者：
Mantere, Tuomo;Neveling, Kornelia;El Khattabi, Laila
染色体畸变包括结构变异（SV）是人类遗传性疾病的主要原因。在临床常规中，它们的检测仍然依赖于标准细胞遗传学。这些测试的缺点是分辨率非常低（核型分析）并且不能检测平衡的SV或指示重复片段或插入的基因组定位和方向（拷贝数变异[CNV]微阵列）。在这里，我们调查的能力，光学基因组图谱（OGM）检测已知的宪法染色体畸变。从85个血液或培养细胞中分离超高分子量DNA，并通过OGM进行处理。进行从头基因组组装，然后进行结构变异和CNV调用和注释，并将结果与来自标准护理测试（核型、FISH和/或CNV微阵列）的已知畸变进行比较。总共，我们分析了99个染色体畸变，包括7个非整倍性，19个缺失，20个重复，34个易位，6个倒位，2个插入，6个等染色体，1个环状染色体和4个复杂的重排。这些变异中的几个包含重复介导的微缺失/微重复综合征所涉及的人类基因组的复杂区域。高分辨率OGM达到100%的一致性相比，所有畸变与非着丝粒断点的标准测定。这项原理验证研究证明了OGM检测几乎所有类型染色体畸变的能力。我们还建议合适的过滤策略，优先考虑临床相关的畸变，并讨论未来的改进。这些结果强调了OGM提供一种具有成本效益和易于使用的替代方案的潜力，该方案将允许全面检测染色体畸变和结构变异，这可能会带来“下一代细胞遗传学”的时代。''
Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard cytogenetics. Drawbacks of these tests are a very low resolution (karyotyping) and the inability to detect balanced SVs or indicate the genomic localization and orientation of duplicated segments or insertions (copy number variant [CNV] microarrays). Here, we investigated the ability of optical genome mapping (OGM) to detect known constitutional chromosomal aberrations. Ultra-high-molecular-weight DNA was isolated from 85 blood or cultured cells and processed via OGM. A de novo genome assembly was performed followed by structural variant and CNV calling and annotation, and results were compared to known aberrations from standard-of-care tests (karyotype, FISH, and/or CNV microarray). In total, we analyzed 99 chromosomal aberrations, including seven aneuploidies, 19 deletions, 20 duplications, 34 translocations, six inversions, two insertions, six isochromosomes, one ring chromosome, and four complex rearrangements. Several of these variants encompass complex regions of the human genome involved in repeat-mediated microdeletion/microduplication syndromes. High-resolution OGM reached 100% concordance compared to standard assays for all aberrations with non-centromeric breakpoints. This proof-of-principle study demonstrates the ability of OGM to detect nearly all types of chromosomal aberrations. We also suggest suited filtering strategies to prioritize clinically relevant aberrations and discuss future improvements. These results highlight the potential for OGM to provide a cost-effective and easy-to-use alternative that would allow comprehensive detection of chromosomal aberrations and structural variants, which could give rise to an era of "next-generation cytogenetics.''