1例18号环状染色体患儿遗传学分析及文献复习

doi:10.3969/j.issn.1673-8640.2025.02.006

摘要/Abstract

摘要：

目的对1例智力低下、生长发育迟缓的患儿进行遗传学检查，分析其临床表型与遗传学特征的关系。方法收集1例智力低下、生长发育迟缓患儿的临床资料，并进行外周血G显带染色体核型分析和基因组拷贝数变异测序（CNV-seq）。以 “18号环状染色体”和“ring chromosome 18”为关键词，对中国知网、万方数据知识服务平台和PubMed数据库1998年1月—2024年10月收录的文献进行检索。总结18号环状染色体患者的临床表现和染色体核型分析结果。结果患儿具有特殊面容，染色体核型分析结果为46，XY，r（18）（p11.21q23），CNV-seq检测结果为seq[hg19]del（18）（p11.32p11.21）chr18：g.120000_14980000del，提示18p11.32p11.21区域存在14.86 Mb的片段缺失，被确诊为18号环状染色体。患儿父母染色体核型均无异常。共检索到16篇关于18号环状染色体的文献，涉及16例患者。文献复习结果显示，17例患者中，特殊面容占100.00%（17/17），智力低下占93.75%（15/16，1例产前诊断的胎儿除外），语言和行为落后占64.71%（11/17），身材矮小占52.94%（9/17），神经发育异常占41.18%（7/17），小头畸形占17.65%（3/17），心脏异常占23.53%（4/17），内分泌和免疫系统异常占17.65%（3/17），肌张力低下占17.65%（3/17），眼部异常占17.65%（3/17），癫痫占11.76%（2/17），性腺发育异常占11.76%（2/17），皮肤病变占5.88%（1/17）。结论 18号环状染色体患者主要临床表现为生长发育迟缓、智力低下、特殊面容、神经发育异常和心脏结构畸形，其临床表型与染色体缺失部位、缺失的片段大小有关。

关键词: 18号环状染色体, 染色体核型分析, 拷贝数变异测序

Abstract:

Objective To conduct a genetic analysis on a child with mental decline and delayed growth and development，and to analyze the relationship between clinical phenotype and genetic characteristics. Methods The clinical data from the patient with mental decline and delayed growth and development were collected. G-banding karyotype analysis and copy number variation sequencing（CNV-seq） were performed. Using "ring chromosome 18" as the keyword，the papers included in China National Knowledge Infrastructure，Wanfang Data Knowledge Service Platform and PubMed were searched from January 1998 to October 2024. The clinical manifestations and chromosomal karyotype analysis results of patients with ring chromosome 18 were summarized. Results The child had a distinctive facial appearance，and the chromosomal karyotype analysis result was 46，XY，r（18）（p11.21q23）. The CNV-seq result was seq[hg19]del（18）（p11.32p11.21）chr18：g.120000_14980000del，indicating a 14.86 Mb copy number deletion in the 18p11.32p11.21 region，diagnosed with ring chromosome 18. The chromosomal karyotypes of the child's parents were both normal. A total of 16 papers on ring chromosome 18 were searched（16 cases）. Among the 17 patients，distinctive facial appearance accounted for 100.00%（17/17），mental decline accounted for 93.75%（15/16，excluding one prenatally diagnosed fetus），language and behavioral delays accounted for 64.71%（11/17），short stature accounted for 52.94%（9/17），neurodevelopmental abnormalities accounted for 41.18%（7/17），microcephaly accounted for 17.65%（3/17），cardiac anomalies accounted for 23.53%（4/17），endocrine and immune system abnormalities accounted for 17.65%（3/17），hypotonia accounted for 17.65%（3/17），ocular abnormalities accounted for 17.65%（3/17），epilepsy accounted for 11.76%（2/17），gonadal dysgenesis accounted for 11.76%（2/17），and skin lesions accounted for 5.88%（1/17）. Conclusions Children with ring chromosome 18 may present with manifestations such as delayed growth and development，mental decline，distinctive facial appearance，neurodevelopmental abnormalities and cardiac anomalies. Their clinical phenotypes are related to the location of the chromosome deletion and the size of the deleted segment.

Key words: Ring chromosome 18, Chromosomal karyotype analysis, Copy number variation sequencing

中图分类号:

R446.1

黄冰怡, 赵芹, 庾冬兰, 王曼伊, 朱春江. 1例18号环状染色体患儿遗传学分析及文献复习[J]. 检验医学, 2025, 40(2): 135-141.

HUANG Bingyi, ZHAO Qin, YU Donglan, WANG Manyi, ZHU Chunjiang. Genetic analysis of a case of ring chromosome 18 child and literature review[J]. Laboratory Medicine, 2025, 40(2): 135-141.

图/表 5

参考文献 37

[1]	KOSZTOLÁNYI G. The genetics and clinical characteristics of constitutional ring chromosomes[J]. J Assoc Genet Technol, 2009, 35(2):44-48. PMID
[2]	MCGOWAN-JORDAN J, HASTINGS R, MOORE S. ISCN 2020:an international system for human cytogenomic nomenclature(2020)[M]. Basel: Karger, 2020.
[3]	RIGGS E R, ANDERSEN E F, CHERRY A M, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics(ACMG) and the Clinical Genome Resource(ClinGen)[J]. Genet Med, 2020, 22(2):245-257.
[4]	LAMMERT D B, MIEDEMA D, OCHOTORENA J, et al. Central and peripheral dysmyelination in a 3-year-old girl with ring chromosome 18[J]. Clin Case Rep, 2019, 7(11):2087-2091.
[5]	ZLOTINA A, NIKULINA T, YANY N, et al. Ring chromosome 18 in combination with 18q12.1(DTNA)interstitial microdeletion in a patient with multiple congenital defects[J]. Mol Cytogenet, 2016,9:18.
[6]	HEYDARI S, HASSANZADEH F, HASSANZADEH NAZARABADI M. Ring chromosome 18:a case report[J]. Int J Mol Cell Med, 2014, 3(4):287-289.
[7]	ERAS N. A case of ring chromosome 18 with single umbilical artery detected during prenatal period[J]. Mol Syndromol, 2020, 11(4):217-222. DOI PMID
[8]	WANG J, XIAO L, WANG J, et al. Mosaic ring chromosome 18 in a Chinese child with epilepsy:a case report and review of the literature[J]. Neurol Sci, 2021, 42(12):5231-5239.
[9]	BAGHERIZADEH E, BEHJATI F, SABERI S H, et al. Prenatal diagnosis in a mentally retarded woman with mosaic ring chromosome 18[J]. Indian J Hum Genet, 2011, 17(2):111-113. DOI PMID
[10]	张秀玲, 李岩, 张颖. 18号环状染色体一例[J]. 中华医学遗传学杂志, 2006, 23(2):201.
[11]	庄宇, 祁建勤, 杨晓红, 等. 18号环状染色体嵌合体1例[J]. 中国实验诊断学, 2012, 16(1):157-158.
[12]	苏爱, 战玉竹, 王培林. 18号环状染色体综合征1例[J]. 青岛医学院学报, 1998,2:13.
[13]	杨慧, 文珺, 吴量. 18号环状染色体综合征1例[J]. 当代医学, 2019, 25(23):96-98.
[14]	宋银森, 郭振欣, 赵鼎. 18号环状染色体综合征一例[J]. 中国优生与遗传杂志, 2011, 19(12):59.
[15]	柴乐, 杜荷香, 耿丹, 等. 1例18号环状嵌合体的遗传学分析[J]. 中国优生与遗传杂志, 2022, 30(6):1006-1007.
[16]	王辉, 耿茜, 邵聪文, 等. 18号环状染色体患儿的产前回顾及出生后追踪[J]. 广东医学, 2019, 40(11):1665-1667.
[17]	宋婷婷, 黎昱, 郑芸芸, 等. 产前诊断胎儿环状18号染色体并缺失一例[J]. 中华围产医学杂志, 2018, 21(12):817-821.
[18]	YAO H, YANG C, HUANG X, et al. Breakpoints and deleted genes identification of ring chromosome 18 in a Chinese girl by whole-genome low-coverage sequencing:a case report study[J]. BMC Med Genet, 2016, 17(1):49.
[19]	李瑞, 许召杰, 王超杰, 等. 嵌合型18号环状染色体综合征1例[J]. 中华医学遗传学杂志, 2023, 40(5):634-635.
[20]	任慧颖, 张凯, 王芳, 等. 环状染色体综合征孕妇的遗传学分析及产前诊断[J]. 中国优生与遗传杂志, 2023, 31(12):2489-2494.
[21]	PRISTYAZHNYUK I E, MENZOROV A G. Ring chromosomes:from formation to clinical potential[J]. Protoplasma, 2018, 255(2):439-449.
[22]	王安娣, 杨斌. 携带环状染色体患儿9例细胞遗传学诊断及临床特征分析[J]. 山西医科大学学报, 2024, 55(5):650-656.
[23]	FEENSTRA I, VISSERS L E, PENNINGS R J, et al. Disruption of teashirt zinc finger homeobox 1 is associated with congenital aural atresia in humans[J]. Am J Hum Genet, 2011, 89(6):813-819. DOI PMID
[24]	CHEN P C, BHATTACHARYYA B J, HANNA J, et al. Ubiquitin homeostasis is critical for synaptic development and function[J]. J Neurosci, 2011, 31(48):17505-17513.
[25]	TATSI C, SERTEDAKI A, VOUTETAKIS A, et al. Pituitary stalk interruption syndrome and isolated pituitary hypoplasia may be caused by mutations in holoprosencephaly-related genes[J]. J Clin Endocrinol Metab, 2013, 98(4):E779-E784.
[26]	WALLI R, SCHÄFER H, MORYS-WORTMANN C, et al. Identification and biochemical characterization of the human brain galanin receptor[J]. J Mol Endocrinol, 1994, 13(3):347-356. PMID
[27]	VARON R, GOODING R, STEGLICH C, et al. Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase Ⅱ is associated with congenital cataracts facial dysmorphism neuropathy syndrome[J]. Nat Genet, 2003, 35(2):185-189.
[28]	JIN Q, QIANG R, CAI B, et al. The genotype and phenotype of chromosome 18p deletion syndrome:case series[J]. Medicine(Baltimore), 2021, 100(18):e25777.
[29]	EL-JAICK K B, POWERS S E, BARTHOLIN L, et al. Functional analysis of mutations in TGIF associated with holoprosencephaly[J]. Mol Genet Metab, 2007, 90(1):97-111. PMID
[30]	AGUILELLA C, DUBOURG C, ATTIA-SOBOL J, et al. Molecular screening of the TGIF gene in holoprosencephaly:identification of two novel mutations[J]. Hum Genet, 2003, 112(2):131-134.
[31]	KEATON A A, SOLOMON B D, KAUVAR E F, et al. TGIF mutations in human holoprosencephaly:correlation between genotype and phenotype[J]. Mol Syndromol, 2010, 1(5):211-222.
[32]	TANIGUCHI K, ANDERSON A E, SUTHERLAND A E, et al. Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway[J]. PLoS Genet, 2012, 8(2):e1002524.
[33]	丁哲, 梅世月, 章波, 等. 18号环状染色体2例患儿的综合诊断与遗传学分析[J]. 中华医学遗传学杂志, 2024, 41(9):1110-1116.
[34]	WESTER U, BONDESON M L, EDEBY C, et al. Clinical and molecular characterization of individuals with 18p deletion:a genotype-phenotype correlation[J]. Am J Med Genet A, 2006, 140(11):1164-1171.
[35]	TURLEAU C. Monosomy 18p[J]. Orphanet J Rare Dis, 2008,3:4.
[36]	CROSIERS D, BLAUMEISER B, VAN GOETHEM G. Reply to:the spectrum of movement disorders in 18p deletion syndrome[J]. Mov Disord Clin Pract, 2019, 6(8):731-732.
[37]	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. DOI

病例序号	性别	年龄/岁	染色体核型	缺失区域	缺失长度	缺失基因	参考文献
1^①	男	7.0	46，XY，r（18）（p11.21q23）	18p11.32p11.21	14.86 Mb	TGIF1	本例
2	女	3.0	46，XX，r（18）（p11.32q22.2）	18q	9.775 Mb		[4]
3	男	20.0	46，XY，r（18）	18q12.1	442 Kb	DTNA	[5]
4	男	2.5	46，XY，r（18）（p11.32q21.32）	18q21.31 18q21.33			[6]
5	女	1.0	46，XY，r（18）（p11.31q21.31）	18p11.32p11.31 18q21.31q23	6.3 Mb、21.9 Mb	MBP、TGIF1、TSHZ1	[7]
6	女	12.0	46，XY，r（18）				[8]
7	女	22.0	46，XY，r（18）（p11.3q23）[24]/46，XX[36]				[9]
8	男	6.0	46，XY，r（18）（p11q23）				[10]
9	女	4.0	46，XY，r（18）[31]/46，XY，r（18；18）[8]/45，XX，-18[10]				[11]
10	女	8.0	46，XX，18，+18（p11p23）				[12]
11	男	1.6	46，XY，r（18）（p11.3q23）	18p11.32p11.21 18q23	8.8 Mb、918 Kb		[13]
12	男	0.6	46，XY，-18，+r（18q）18p-18q-				[14]
13	女	11.7	46，XX，r（18）（p11.3q23）[70]/46，XX，der（18）r（18）（p11.3q23；p11.3q23）[14]/45，XX，-18[6]	18q22.3q23	7.779 Mb		[15]
14	女	1.9	46，XY，r（18）（p11.32q22.1）	18p11.32 18q22.1q23	360 Kb、14.77 Mb		[16]
15^②	男		46，XY，r（18）（p11.3q21.3）	18p11.32p11.31 18q21.33q23	3.3 Mb、16.9 Mb	TGIF1、TWSG、TYMS、USP14	[17]
16	女	6.0	46，XX，r（18）（p11.31q23）	18p11.31 18q23	3.88 Mb、4.83 Mb	USP14、TGIF1、GALR1、CTDP1	[18]
17	男	3.9	46，XY，r（18）（p11.21q22.1）[40]/46，XY[7]	18p11.21p11.32 18q22.1q23	14.86 Mb、14.02 Mb	TGIF1	[19]

病例序号	性别	年龄/岁	染色体核型	缺失区域	缺失长度	缺失基因	参考文献
1^①	男	7.0	46，XY，r（18）（p11.21q23）	18p11.32p11.21	14.86 Mb	TGIF1	本例
2	女	3.0	46，XX，r（18）（p11.32q22.2）	18q	9.775 Mb		[4]
3	男	20.0	46，XY，r（18）	18q12.1	442 Kb	DTNA	[5]
4	男	2.5	46，XY，r（18）（p11.32q21.32）	18q21.31 18q21.33			[6]
5	女	1.0	46，XY，r（18）（p11.31q21.31）	18p11.32p11.31 18q21.31q23	6.3 Mb、21.9 Mb	MBP、TGIF1、TSHZ1	[7]
6	女	12.0	46，XY，r（18）				[8]
7	女	22.0	46，XY，r（18）（p11.3q23）[24]/46，XX[36]				[9]
8	男	6.0	46，XY，r（18）（p11q23）				[10]
9	女	4.0	46，XY，r（18）[31]/46，XY，r（18；18）[8]/45，XX，-18[10]				[11]
10	女	8.0	46，XX，18，+18（p11p23）				[12]
11	男	1.6	46，XY，r（18）（p11.3q23）	18p11.32p11.21 18q23	8.8 Mb、918 Kb		[13]
12	男	0.6	46，XY，-18，+r（18q）18p-18q-				[14]
13	女	11.7	46，XX，r（18）（p11.3q23）[70]/46，XX，der（18）r（18）（p11.3q23；p11.3q23）[14]/45，XX，-18[6]	18q22.3q23	7.779 Mb		[15]
14	女	1.9	46，XY，r（18）（p11.32q22.1）	18p11.32 18q22.1q23	360 Kb、14.77 Mb		[16]
15^②	男		46，XY，r（18）（p11.3q21.3）	18p11.32p11.31 18q21.33q23	3.3 Mb、16.9 Mb	TGIF1、TWSG、TYMS、USP14	[17]
16	女	6.0	46，XX，r（18）（p11.31q23）	18p11.31 18q23	3.88 Mb、4.83 Mb	USP14、TGIF1、GALR1、CTDP1	[18]
17	男	3.9	46，XY，r（18）（p11.21q22.1）[40]/46，XY[7]	18p11.21p11.32 18q22.1q23	14.86 Mb、14.02 Mb	TGIF1	[19]