基因组光学图谱技术在疾病诊断中的应用与研究

doi:10.16288/j.yczz.24-192

遗传 ›› 2025, Vol. 47 ›› Issue (4): 428-436.doi: 10.16288/j.yczz.24-192

基因组光学图谱技术在疾病诊断中的应用与研究

权静¹^,²(), 肖艳群¹, 卢大儒²(), 鲍芸¹()

1.上海市临床检验中心，上海 200126
2.复旦大学生命科学学院，上海 200438

收稿日期:2024-09-27 修回日期:2024-12-06 出版日期:2025-04-20 发布日期:2024-12-25
通讯作者: 鲍芸，博士，副主任技师，研究方向：临床分子生物学。E-mail: baoyun@sccl.org.cn;
卢大儒，博士，教授，研究方向：遗传病，分子检测与基因诊断。E-mail: drlu@fudan.edu.cn
作者简介:权静，硕士，主管技师，研究方向：遗传咨询、临床分子生物学。E-mail: quanjing@sccl.org.cn
基金资助:
国家重点研发专项课题(2023YFC2705602);上海市临床检验中心自选课题(2023ZXKT-02);上海市卫生健康委员会卫生行业临床研究专项(202240271);上海市“医苑新星”青年医学人才培养资助计划(2022-65)

Application and research of genomic optical mapping technology in disease diagnosis

Jing Quan¹^,²(), Yanqun Xiao¹, Daru Lu²(), Yun Bao¹()

1. Shanghai Clinical Laboratory Center, Shanghai 200126, China
2. School of Life Sciences, Fudan University, Shanghai 200438, China

Received:2024-09-27 Revised:2024-12-06 Published:2025-04-20 Online:2024-12-25
Supported by:
National Key Research and Development Project(2023YFC2705602);Shanghai Center for Clinical Laboratory General Fund(2023ZXKT-02);Shanghai Municipal Health Commission Resarch Project(202240271);Shanghai “Rising Stars of Medical Talent” Youth Development Program(2022-65)

摘要/Abstract

摘要：

随着基因组研究的不断深入，越来越多的研究发现结构变异(structural variantions，SVs)在人类进化及疾病发生发展中发挥着重要作用，由此SVs也引起了临床研究的广泛关注。近年来，基因组光学图谱技术(optical genome mapping, OGM)作为一种高分辨率、超长读长、自动化的新型非测序基因检测技术凸显了在SVs研究中的优势。与核型(karotyping)、荧光原位杂交(fluorescence in situ hybridization，FISH)、染色体微阵列分析(chromosomal microarray analysis，CMA)及高通量测序技术相比，OGM可一次性检测全基因组范围内的结构和数目异常，包括染色体非整倍体、插入、缺失、重复、倒位、平衡易位以及复杂结构变异等，且OGM检测分辨率高至500 bp，因其分辨率高和分析片段长度长的检测特性，又被称为下一代细胞遗传学技术，对基因组结构变异检测具有重大应用价值。本文主要对OGM检测方法及其在疾病相关SVs诊断中的应用研究进行了综述，旨在为SVs在疾病诊断领域中的研究提供参考和借鉴。

关键词: 结构变异, 基因组光学图谱, 疾病诊断应用

Abstract:

In the continuous progression of genomic research, an increasing number of investigations have revealed that structural variations (SVs) hold a vital role in human evolution and the pathogenesis of diseases. Consequently, SVs have attracted extensive attention within the realm of clinical research.In recent years, optical genome mapping (OGM), which represents a high-resolution, ultra-long-read, automated, non-sequencing genomic detection technique, has exhibited remarkable advantages in the exploration of structural variations. When compared with karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and high-throughput sequencing technologies, OGM is capable of detecting structural and numerical aberrations throughout the entire genome in a single assay. These encompass aneuploidy, insertions, deletions, duplications, inversions, balanced translocations, and complex structural variations. With a detection resolution reaching as high as 500 bp, OGM is alternatively designated as the next-generation cytogenetic technology due to its high-resolution and long-fragment analysis capabilities. This endows it with substantial practical value in the detection of genomic structural variations. In this review, we comprehensively summarize the application of OGM methods in the detection of disease-related SVs, with the intention of providing valuable references and profound insights for SVs research, especially in the domain of disease diagnosis.

Key words: structural variations, optical genome mapping, diagnosis of disease-related SVs

权静, 肖艳群, 卢大儒, 鲍芸. 基因组光学图谱技术在疾病诊断中的应用与研究[J]. 遗传, 2025, 47(4): 428-436.

Jing Quan, Yanqun Xiao, Daru Lu, Yun Bao. Application and research of genomic optical mapping technology in disease diagnosis[J]. Hereditas(Beijing), 2025, 47(4): 428-436.

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参考文献 35

[1]	Hollox EJ, Zuccherato LW, Tucci S. Genome structural variation in human evolution. Trends Genet, 2022, 38(1): 45-58. pmid: 34284881
[2]	He YS, Zhang W, Yang ZQ. Structural variation in the human genome. Hereditas(Beijing), 2009, 31(8): 771-778.
	何永蜀, 张闻, 杨照青. 人类基因组结构变异. 遗传, 2009, 31(8): 771-778.
[3]	Caspersson T, Zech L, Johansson C. Differential binding of alkylating fluorochromes in human chromosomes. Exp Cell Res, 1970, 60(3): 315-319. pmid: 5422961
[4]	Shaffer LG, Bejjani BA. A cytogeneticist’s perspective on genomic microarrays. Hum Reprod Update, 2004, 10(3): 221-226. pmid: 15140869
[5]	Gall JG, Pardue ML. Formation and detection of RNA-DNA hybrid molecules in cytological preparations. Proc Natl Acad Sci USA, 1969, 63(2): 378-383. [DOI]
[6]	Amaldi F, Buongiorno-Nardelli M. Molecular hybridization of chinese hamster 5S, 4S and “pulse-labelled” RNA in cytological preparations. Exp Cell Res, 1971, 65(2): 329-334. pmid: 5554032
[7]	Kirchhoff M, Rose H, Lundsteen C. High resolution comparative genomic hybridisation in clinical cytogenetics. J Med Genet, 2001, 38(11): 740-744. pmid: 11694545
[8]	Kosugi S, Momozawa Y, Liu XX, Terao C, Kubo M, Kamatani Y. Comprehensive evaluation of structural variation detection algorithms for whole genome sequencing. Genome Biol, 2019, 20(1): 117. pmid: 31159850
[9]	Pabinger S, Dander A, Fischer M, Snajder R, Sperk M, Efremova M, Krabichler B, Speicher MR, Zschocke J, Trajanoski Z. A survey of tools for variant analysis of next-generation genome sequencing data. Brief Bioinform, 2014, 15(2): 256-278. pmid: 23341494
[10]	Dremsek P, Schwarz T, Weil B, Malashka A, Laccone F, Neesen J. Optical genome mapping in routine human genetic diagnostics-its advantages and limitations. Genes (Basel), 2021, 12(12): 1958. pmid: 34946907
[11]	Bionano Genomics. Bionano solve theory of operation: structural variant calling. San Diego, CA, USA: Bionano Genomics, Inc, 2021.
[12]	Chen M, Zhang M, Qian YQ, Yang YM, Sun YX, Liu B, Wang LY, Dong MY. Identification of a likely pathogenic structural variation in the LAMA1 gene by bionano optical mapping. NPJ Genom Med, 2020, 5: 31. pmid: 33083009
[13]	Dai Y, Li PD, Wang ZQ, Liang F, Yang F, Fang L, Huang Y, Huang SZ, Zhou JP, Wang DP, Cui LY, Wang K. Single-molecule optical mapping enables quantitative measurement of D4Z4 repeats in facioscapulohumeral muscular dystrophy (FSHD). J Med Genet, 2020, 57(2): 109-120. pmid: 31506324
[14]	Zheng YT, Kong LR, Xu H, Lu YJ, Zhao XC, Yang YX, Yu GL, Li PD, Liang F, Jin HS, Kong XD. Rapid prenatal diagnosis of facioscapulohumeral muscular dystrophy 1 by combined bionano optical mapping and karyomapping. Prenat Diagn, 2020, 40(3): 317-323. pmid: 31711258
[15]	Lestringant V, Duployez N, Penther D, Luquet I, Derrieux C, Lutun A, Preudhomme C, West M, Ouled-Haddou H, Devoldere C, Marolleau JP, Garçon L, Jedraszak G, Ferret Y. Optical genome mapping, a promising alternative to gold standard cytogenetic approaches in a series of acute lymphoblastic leukemias. Genes Chromosomes Cancer, 2021, 60(10): 657-667. pmid: 33982372
[16]	Gupta A, Place M, Goldstein S, Sarkar D, Zhou SG, Potamousis K, Kim J, Flanagan C, Li Y, Newton MA, Callander NS, Hematti P, Bresnick EH, Ma J, Asimakopoulos F, Schwartz DC. Single-molecule analysis reveals widespread structural variation in multiple myeloma. Proc Natl Acad Sci USA, 2015, 112(25): 7689-7694. pmid: 26056298
[17]	Pei ZL, Deng K, Lei CX, Du DF, Yu GL, Sun XX, Xu CJ, Zhang S. Identifying balanced chromosomal translocations in human embryos by oxford nanopore sequencing and breakpoints region analysis. Front Genet, 2022, 12: 810900. [DOI]
[18]	Pastor S, Tran O, Jin A, Carrado D, Silva BA, Uppuluri L, Abid HZ, Young E, Crowley TB, Bailey AG, McGinn DE, McDonald-McGinn DM, Zackai EH, Xie M, Taylor D, Morrow BE, Xiao M, Emanue BS. Optical mapping of the 22q11.2DS region reveals complex repeat structures and preferred locations for non-allelic homologous recombination (NAHR). Sci Rep, 2020, 10(1): 12235. pmid: 32699385
[19]	Guruju NM, Jump V, Lemmers R, Van Der Maarel S, Liu R, Nallamilli BR, Shenoy S, Chaubey A, Koppikar P, Rose R, Khadilkar S, Hegde M. Molecular diagnosis of facioscapulohumeral muscular dystrophy in patients clinically suspected of FSHD using optical genome mapping. Neurol Genet, 2023, 9(6): e200107. pmid: 38021397
[20]	Shieh JT, Penon-Portmann M, Wong KHY, Levy-Sakin M, Verghese M, Slavotinek A, Gallagher RC, Mendelsohn BA, Tenney J, Beleford D, Perry H, Chow SK, Sharo AG, Brenner SE, Qi ZX, Yu JW, Klein OD, Martin D, Kwok PY, Boffelli D. Application of full-genome analysis to diagnose rare monogenic disorders. NPJ Genom Med, 2021, 6(1): 77. pmid: 34556655
[21]	Fadaie Z, Neveling K, Mantere T, Derks R, Haer-Wigman L, den Ouden A, Kwint M, O'Gorman L, Valkenburg D, Hoyng CB, Gilissen C, Vissers LELM, Nelen M, Cremers FPM, Hoischen A, Roosing S. Long-read technologies identify a hidden inverted duplication in a family with choroideremia. HGG Adv, 2021, 2(4): 100046. pmid: 35047838
[22]	Schnause AC, Komlosi K, Herr B, Neesen J, Dremsek P, Schwarz T, Tzschach A, Jägle S, Lausch E, Fischer J, Gläser B. Marfan syndrome caused by disruption of the FBN1 gene due to a reciprocal chromosome translocation. Genes (Basel), 2021, 12(11): 1836. [DOI]
[23]	Zhang Y, Wang T, Wang F, Liu HX. Application of the new generation cytogenetics technology in structural variation of leukemia genome. J Leuk Lymphoma, 2021, 30(4): 197-200.
	张杨, 王彤, 王芳, 刘红星. 新一代细胞遗传学技术在白血病基因组结构变异分析中的应用. 白血病·淋巴瘤, 2021, 30(4): 197-200.
[24]	Smith AC, Neveling K, Kanagal-Shamanna R. Optical genome mapping for structural variation analysis in hematologic malignancies. Am J Hematol, 2022, 97(7): 975-982. pmid: 35560245
[25]	Neveling K, Mantere T, Vermeulen S, Oorsprong M, van Beek R, Kater-Baats E, Pauper M, van der Zande G, Smeets D, Weghuis DO, Stevens-Kroef MJPL, Hoischen A. Next-generation cytogenetics: comprehensive assessment of 52 hematological malignancy genomes by optical genome mapping. Am J Hum Genet, 2021, 108(8): 1423-1435. pmid: 34237281
[26]	Levy B, Baughn LB, Akkari Y, Chartrand S, LaBarge B, Claxton D, Lennon PA, Cujar C, Kolhe R, Kroeger K, Pitel B, Sahajpal N, Sathanoori M, Vlad G, Zhang LJ, Fang M, Kanagal-Shamanna R, Broach JR. Optical genome mapping in acute myeloid leukemia: a multicenter evaluation. Blood Adv, 2023, 7(7): 1297-1307. pmid: 36417763
[27]	Goldrich DY, LaBarge B, Chartrand S, Zhang LJ, Sadowski HB, Zhang Y, Pham K, Way H, Lai CYJ, Pang AWC, Clifford B, Hastie AR, Oldakowski M, Goldenberg D, Broach JR. Identification of somatic structural variants in solid tumors by optical genome mapping. J Pers Med, 2021, 11(2): 142. pmid: 33670576
[28]	Peng YZ, Yuan CZ, Tao XT, Zhao Y, Yao XX, Zhuge LD, Huang JW, Zheng Q, Zhang Y, Hong H, Chen HQ, Sun YH. Integrated analysis of optical mapping and whole-genome sequencing reveals intratumoral genetic heterogeneity in metastatic lung squamous cell carcinoma. Transl Lung Cancer Res, 2020, 9(3): 670-681. pmid: 32676329
[29]	Baelen J, Dewaele B, Debiec-Rychter M, Sciot R, Schöffski P, Hompes D, Sinnaeve F, Wafa H, Vanden Bempt I. Optical genome mapping for comprehensive cytogenetic analysis of soft-tissue and bone tumors for diagnostic purposes. J Mol Diagn, 2024, 26(5): 374-386. pmid: 38395407
[30]	Bai F, Liu C, Fan YJ. Strategies for infertility prevention and control: a brief review. Chin J Public Health, 2018, 34(9): 1303-1305.
	白符, 刘畅, 樊延军. 不孕不育防控策略研究进展. 中国公共卫生, 2018, 34(9): 1303-1305.
[31]	Xie M, Zheng ZJ, Zhou Y, Zhang YX, Li Q, Tian LY, Cao J, Xu YT, Ren J, Yu Q, Wu SS, Fang S, Zhuang DY, Geng J, Chen CS, Li HB. Prospective investigation of optical genome mapping for prenatal genetic diagnosis. Clin Chem, 2024, 70(6): 820-829. pmid: 38517460
[32]	Zhang S, Pei ZL, Lei CX, Zhu SJ, Deng K, Zhou J, Yang JM, Lu DR, Sun XX, Xu CM, Xu CJ. Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping. J Med Genet, 2023, 60(3): 274-284. pmid: 35710108
[33]	Wang H, Jia ZJ, Mao AP, Xu B, Wang SL, Wang L, Liu S, Zhang HM, Zhang XJ, Yu T, Mu T, Xu MN, Cram DS, Yao YQ. Analysis of balanced reciprocal translocations in patients with subfertility using single-molecule optical mapping. J Assist Reprod Genet, 2020, 37(3): 509-516. pmid: 32026199
[34]	Zhang QX, Wang Y, Xu YY, Zhou R, Huang MT, Qiao FC, Meng LL, Liu A, Zhou J, Li L, Ji XQ, Xu ZF, Hu P. Optical genome mapping for detection of chromosomal aberrations in prenatal diagnosis. Acta Obstet Gynecol Scand, 2023, 102(8): 1053-1062. pmid: 37366235
[35]	Hui XY, Yang JM, Zhang J, Sun JQ, Wang XC. Optical genomic mapping identified a heterozygous structural variant in NCF2 related to chronic granulomatous disease. J Clin Immunol, 2022, 42(8): 1614-1617. pmid: 35900637

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类型	OGM	核型分析	FISH	CMA	CNV-seq
覆盖度	全基因组100~1600×	全基因组	单个/两个基因	全基因组，非连续覆盖	全基因组0.1~8.0×
条带数	500,000	300~500	不涉及	不涉及	不涉及
分辨率	500 bp	5~10 Mb	100 kb~1 Mb	30 kb	50 kb
新发SV	可以检出	可以检出	不能检出	不能检出	部分检出
拷贝数变异	可以检出	可以检出	可以检出	可以检出	可以检出
平衡易位	可以检出	可以检出	不能检出	不能检出	不能检出
倒位	可以检出	可以检出	不能检出	不能检出	不能检出
单倍体型区分	可以检出	不能检出	不能检出	可以检出带SNP探针的芯片；不能检出不带SNP探针的芯片	不能检出
嵌合比例	2%	5%	0.50%	30%	25%~70%
细胞培养	不需要	需要	不需要	不需要	不需要
片段化	不需要	不需要	不需要	需要	需要
周期	3~5天	2~3周	2~3天	3~5天	5~7天
总结	分辨率高、兼顾平衡及非平衡变异、低比例嵌合体检测，操作简单，检测周期短	金标准；劣势：分辨率低，检测周期长，结果判读主观性强	金标准；劣势：仅检测个别已知位点，实验操作复杂，结果判断主观性强，探针定制周期长	分辨率高、周期短、操作简便劣势：不能检测平衡性易位和倒位，无法定位插入性变异；不能区分串联重复和in-trans插入	分辨率高、周期短劣势：不能检测平衡性易位和倒位，无法检测低比例嵌合

基因组光学图谱技术在疾病诊断中的应用与研究

Application and research of genomic optical mapping technology in disease diagnosis

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[3]	马磊, 张婷婷. 应用嵌合基因实例拓展遗传学染色体畸变的教学[J]. 遗传, 2018, 40(12): 1129-1135.
[4]	何永蜀，张闻，杨照青 . 人类基因组结构变异[J]. 遗传, 2009, 31(8): 771-778.