全外显子测序技术在儿童遗传病临床诊断与治疗中的应用

doi:10.6040/j.issn.1671-7554.0.2025.0958

摘要/Abstract

摘要： 目的探讨全外显子组测序技术(whole exome sequencing, WES)在儿童遗传病患者临床诊断与治疗中的价值。方法收集2019年3月至2023年8月于山东第一医科大学第二附属医院就诊的265例疑似儿童遗传病患者的临床资料进行回顾性分析。所有患者均进行WES测序分析,结合患儿临床表型筛选候选变异,用Sanger法进行测序验证,根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics, ACMG)指南完成致病性评估和遗传诊断,通过表型类别、遗传模式、线粒体基因组变异和拷贝数变异来确定WES的总体检出率,分析WES对临床诊疗策略的影响。结果在265例儿童患者中,共检测出98例阳性患儿,总检出率为37.0%(98/265)。检出致病性变异/疑似致病性变异单核苷酸变异(single nucleotide variations, SNVs)102种,拷贝数变异(copy number variations, CNVs)20种,线粒体变异1例,新发变异位点31个。临床表型中神经系统疾病比例最高为55.5%(147/265),61例患儿(62.3%)根据测序结果进行了个体化的精准医疗。结论 WES技术在揭示患儿遗传特征、助力于患儿早期鉴别诊断、提供个性化精准治疗方案方面具有重要意义。

关键词: 全外显子测序技术, 儿童, 遗传病, 诊断, 治疗, 单核苷酸变异, 拷贝数变异

Abstract: Objective To explore the value of whole exome sequencing(WES)in the clinical diagnosis and treatment of children with genetic diseases. Methods The clinical data of 265 children with suspected genetic diseases who visited the The Second Affiliated Hospital of Shandong First Medical University from March 2019 to August 2023 were retrospectively analyzed. All patients underwent WES sequencing analysis. Candidate variants were screened based on the clinical phenotypes of the children, and Sanger sequencing was used for verification. Pathogenicity assessment and genetic diagnosis were completed according to the guidelines of the American College of Medical Genetics and Genomics(ACMG). The overall detection rate of WES was determined based on phenotype categories, inheritance patterns, mitochondrial genome variations, and copy number variations, and the impact of WES on clinical diagnosis and treatment strategies was analyzed. Results Among the 265 children, 98 positive cases were detected, with a total detection rate of 37.0%(98/265). A total of 102 pathogenic or likely pathogenic single nucleotide variations, 20 copy number variations, 1 mitochondrial variation, and 31 de novo mutation sites were detected. In the context of clinical phenotypes, neurological diseases accounted for the highest proportion, reaching 55.5%(147/265). Based on the sequencing results, 61 children(62.3%)received individualized precision medical treatment. Conclusion WES technology is of great significance in revealing the genetic characteristics of children, facilitating early diagnosis, and providing personalized precision treatment plans.

Key words: Whole exome sequencing technology, Children, Genetic diseases, Diagnosis, Treatment, Single nucleotide variations, Copy number variations

中图分类号:

R725.9

武明莉,姜铭迪,李静,宋超,刘晶,李真,周依琳,张红,刘庆华. 全外显子测序技术在儿童遗传病临床诊断与治疗中的应用[J]. 山东大学学报 (医学版), 2026, 64(9): 43-49.

WU Mingli, JIANG Mingdi, LI Jing, SONG Chao, LIU Jing, LI Zhen, ZHOU Yilin, ZHANG Hong, LIU Qinghua. Application of whole exome sequencing technology in the clinical diagnosis and treatment of genetic diseases in children[J]. Journal of Shandong University (Health Sciences), 2026, 64(9): 43-49.

参考文献

[1] Smith L D, Willig L K, Kingsmore S F. Whole-exome sequencing and whole-genome sequencing in critically ill neonates suspected to have single-gene disorders[J]. Cold Spring Harb Perspect Med, 2015, 6(2): a023168. DOI:10.1101/cshperspect.a023168
[2] 左伋, 张学. 医学遗传学[M]. 8版. 北京: 人民卫生出版社, 2024: 8.
[3] 荆梦霞, 余永国. 分子检测技术在儿童罕见遗传病中的临床应用[J]. 检验医学, 2024, 39(2): 103-106. Jing Mengxia, Yu Yongguo. Clinical application of different molecular detection techniques in childrens rare genetic diseases[J]. Laboratory Medicine, 2024, 39(2): 103-106.
[4] Georget M, Pisan E. Next generation sequencing(NGS)for beginners[J]. Rev Mal Respir, 2023, 40(4): 345-358.
[5] 中华儿科杂志编辑委员会. 儿童遗传病遗传检测临床应用专家共识[J]. 中华儿科杂志, 2019, 57(3): 172-176. The Editorial Board, Chinese Journal of Pediatrics. Consensus recommendations for the clinical application of genetic testing for childrens genetic[J]. Chinese Journal of Pediatrics, 2019, 57(3): 172-176.
[6] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424.
[7] Gilissen C, Hehir-Kwa J Y, Thung D T, et al. Genome sequencing identifies major causes of severe intellectual disability[J]. Nature, 2014, 511(7509): 344-347.
[8] Wojcik M H, Lemire G, Berger E, et al. Genome sequencing for diagnosing rare diseases[J]. N Engl J Med, 2024, 390(21): 1985-1997.
[9] Skoczylas S, Poszaj T, Gadzalska K, et al. Mitochon-drial DNA variants revealed by whole exome sequencing: from screening to diagnosis and follow-up[J]. Neurogenetics, 2025, 26(1): 38. DOI:10.1007/s10048-025-00820-z
[10] Sun G G, Huang W, Wang L, et al. Molecular findings in patients for whole exome sequencing and mitochondrial genome assessment[J]. Clin Chim Acta, 2024, 561: 119774. DOI:10.1016/j.cca.2024.119774
[11] Srivastava S, Love-Nichols J A, Dies K A, et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders[J]. Genet Med, 2019, 21(11): 2413-2421.
[12] Lan X P, Tang X J, Weng W H, et al. Diagnostic utility of trio-exome sequencing for children with neurodevelopmental disorders[J]. JAMA Netw Open, 2025, 8(3): e251807. DOI:10.1001/jamanetworkopen.2025.1807
[13] 张丽, 高姚怡, 郁俐, 等. 全外显子组测序技术在成人遗传病中的应用[J]. 中华检验医学杂志, 2024, 47(10): 1192-1196. Zhang Li, Gao Yaoyi, Yu Li, et al. Analysis of whole exome sequencing result in adult genetic diseases[J]. Chinese Journal of Laboratory Medicine, 2024, 47(10): 1192-1196.
[14] Cao L, Huang X J, Wang N, et al. Recommendations for the diagnosis and treatment of paroxysmal kinesigenic dyskinesia: an expert consensus in China[J]. Transl Neurodegener, 2021, 10(1): 7. DOI:10.1186/s40035-021-00231-8
[15] Hannibal L, Jacobsen D W. Intracellular processing of vitamin B12 by MMACHC(CblC)[M] //Vitamin B12. Amsterdam: Elsevier, 2022: 275-298. DOI:10.1016/bs.vh.2022.02.001
[16] Aukema S M, Vandenput K, Scarano E, et al. Growth hormone treatment in patients with KBG syndrome: novel insights, challenges and recommendations from six new patients and literature review[J]. Am J Med Genet A, 2025, 197(12): e64168. DOI:10.1002/ajmg.a.64168
[17] Smith A C, Neveling K, Kanagal-Shamanna R. Optical genome mapping for structural variation analysis in hematologic malignancies[J]. Am J Hematol, 2022, 97(7): 975-982.
[18] 陈奕, 杨莹, 牛雪阳, 等. CASK基因变异相关的癫痫性脑病4例临床表型特点研究[J]. 中国实用儿科杂志, 2021, 36(4): 275-280. Chen Yi, Yang Ying, Niu Xueyang, et al. Clinical features of epileptic encephalopathy caused by CASK gene variants[J]. Chinese Journal of Practical Pediatrics, 2021, 36(4): 275-280.
[19] McKnight D, Morales A, Hatchell K E, et al. Genetic testing to inform epilepsy treatment management from an international study of clinical practice[J]. JAMA Neurol, 2022, 79(12): 1267-1276.
[20] de Grado A, Pisciotta C, Saveri P, et al. Will new investigational drugs change the way we treat Charcot-Marie-Tooth disease?[J]. Expert OpinInvestig Drugs, 2024, 33(7): 653-656.
[21] Inozyme Pharma, Inc. Inozymes INZ-701 receives FDA fast track designation for ABCC6 deficiency[EB/OL].[2024-07-02] (2025-08-13). https://www.rttnews.com/3457736/inozyme-s-inz-701-receives-fda-fast-track-designation-for-abcc6-deficiency.aspx
[22] 李妍, 郝晔. 治疗Rett综合征的首个新药: Daybue[J]. 中国临床药理学杂志, 2024, 40(18): 2743-2746. Li Yan, Hao Ye. Daybue, the first new drug for the treatment of Rett syndrome[J]. The Chinese Journal of Clinical Pharmacology, 2024, 40(18): 2743-2746.
[23] Schambach A, Buchholz C J, Torres-Ruiz R, et al. A new age of precision gene therapy[J]. Lancet, 2024, 403(10426): 568-582.
[24] Azidane S, Gallego X, Durham L, et al. Identification of novel driver risk genes in CNV loci associated with neurodevelopmental disorders[J]. HGG Adv, 2024, 5(3): 100316. DOI:10.1016/j.xhgg.2024.100316
[25] Atli E I, Yalcintepe S, Atli E, et al. Clinical implications of chromosome 16 copy number variation[J]. Mol Syndromol, 2022, 13(3): 184-192.
[26] Arslan A B, Zamani A G, Yıldırım M S. Novel findings, mini-review and dysmorphological characterization of 16p13.11 microduplication syndrome[J]. Int J Dev Neurosci, 2022, 82(4): 289-294.
[27] Allach El Khattabi L, Heide S, Caberg J H, et al. 16p13.11 microduplication in 45 new patients: refined clinical significance and genotype-phenotype correlations[J]. J Med Genet, 2020, 57(5): 301-307.
[28] Wojcik M H, Lemire G, Berger E, et al. Genome sequencing for diagnosing rare diseases[J]. N Engl J Med, 2024, 390(21): 1985-1997.
[29] Ewans L J, Schofield D, Shrestha R, et al. Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders[J]. Genet Med, 2018, 20(12): 1564-1574.
[30] Jalkh N, Corbani S, Haidar Z, et al. The added value of WES reanalysis in the field of genetic diagnosis: lessons learned from 200 exomes in the Lebanese population[J]. BMC Med Genomics, 2019, 12(1): 11. DOI:10.1186/s12920-019-0474-y

相关文章 15

[1]	李波波李道堂刘曙光王兴武. 食管癌患者血清中DKK-1的表达[J]. 山东大学学报(医学版), 2209, 47(6): 58-61.
[2]	徐平于国放李霞. 不同类型甲状腺上动脉PSV对Graves病与桥本氏甲状腺炎鉴别诊断的价值[J]. 山东大学学报(医学版), 2209, 47(6): 62-64.
[3]	王欣，邢春燕，杨艳平. 血清磷酸丙酮酸水合酶检测对诊断侵袭性白念珠菌感染的临床价值[J]. 山东大学学报(医学版), 2209, 47(6): 92-94.
[4]	巩性军，吴树明，张供，李守先，庞昕焱. 无顶冠状静脉窦综合征的诊断和外科治疗[J]. 山东大学学报(医学版), 2209, 47(6): 129-.
[5]	师晓丽,郭瑞祥,赵炎,边天帅,王晓华,牟鸿. 毫米波雷达监测儿童阻塞性睡眠呼吸暂停综合征的诊断价值[J]. 山东大学学报 (医学版), 2026, 64(9): 17-25.
[6]	刘萍,张孝国,计胜伟,张忠法. 发热伴血小板减少综合征相关脑炎治疗药物的研究进展[J]. 山东大学学报 (医学版), 2026, 64(8): 23-28.
[7]	冯建, 杨丽, 王永俊, 刘长青, 田美娜, 周晗, 于连龙. 血清尿酸与儿童青少年代谢综合征的关联:基于山东、河北两省的横断面研究[J]. 山东大学学报 (医学版), 2026, 64(8): 96-106.
[8]	薛宁,魏绪霞,徐俊杰,唐运萍,杨露. 不同年龄组儿童艰难梭菌感染临床特点及预后影响因素[J]. 山东大学学报 (医学版), 2026, 64(7): 55-62.
[9]	惠婷,张广灿. 数字化和人工智能在儿童口腔领域的应用进展[J]. 山东大学学报 (医学版), 2026, 64(7): 118-124.
[10]	山东省医学会心电学分会山东省医学伦理学学会心电学分会. 心电图报告规范化书写专家共识(2026)[J]. 山东大学学报 (医学版), 2026, 64(4): 1-7.
[11]	李东梅,边天帅,王晓华,张静,赵炎,孙素芬,牟鸿,许安廷. 儿童前庭神经炎的前庭诱发肌源性电位结果[J]. 山东大学学报 (医学版), 2026, 64(4): 38-43.
[12]	孙红林,管玉强,于培儒,李磊,杜庆霞,丁浩. 支架植入治疗儿童主动脉缩窄并高血压的可行性及近中期疗效[J]. 山东大学学报 (医学版), 2026, 64(4): 58-62.
[13]	林明霞,刘桂斌,马燕花,连曌昱,任洋洋. ATP酶铜转运蛋白α介导的铜死亡途径及在肿瘤治疗中的价值[J]. 山东大学学报 (医学版), 2026, 64(4): 117-124.
[14]	况利,徐何雁. 从精准评估到整合干预:儿童青少年心理健康问题诊疗范式的革新与展望[J]. 山东大学学报 (医学版), 2026, 64(3): 10-16.
[15]	樊呈敏,宋静雨,于书彦,毛雪琴. 舒肝解郁胶囊治疗青少年抑郁障碍的研究进展[J]. 山东大学学报 (医学版), 2026, 64(3): 17-23.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed