Investigation and clinical phenotypic analysis of gene copy number variation in 120 children with intellectual disability/developmental delay in Anhui province

doi:10.11852/zgetbjzz2020-1808

Abstract

Abstract: Objective To investigate the detection of pathogenic and likely pathogenic copy number variations (CNVs) in 120 children with intellectual disability (ID)/developmental delay (DD) in Anhui province, and to analyze the clinical phenotype of the children, so as to clarify the genetic etiology of ID/DD children. Methods A total of 120 children with unexplained ID/DD who were treated in the Department of Pediatric Rehabilitation of Anhui Children′s Hospital from May 2019 to June 2020 were selected and tested for the presence of pathogenic and likely pathogenic CNVs by chromosome microarray analysis (CMA).The clinical phenotype and characteristics of pathogenic and likely pathogenic CNVs were analyzed. Results Among 120 children with ID/DD, pathogenic CNVs were detected in 18 cases (15.00%), likely pathogenic CNVs in 2 cases (1.67%), variation of uncertain significance CNVs in 39 cases (32.50%), and likely benign and benign CNVs in 61 cases (50.83%). Among 20 children with pathogenic and likely pathogenic CNVs, 5 had congenital malformations/special faces, and 14 had one or more other diseases. There were 3 cases, 12 cases and 5 cases with mild, moderate and severe mental retardation, respectively. There were 21 pathogenic and likely pathogenic CNVs in 20 children with ID/DD, including 13 microdeletion fragments (61.90%) and 8 microduplication fragments (38.10%) with a ratio of 1.63∶1. The average fragment size was 6.34 Mb. Twenty one pathogenic and possibly pathogenic CNVs were detected most on chromosomes 2 and 22 (3 locations).Among the 20 children with ID/DD, 10 cases (50.00%) had known syndromes, and 10 cases (50.00%) had still undefined syndromes or disease areas in the database. Conclusion For children with unexplained ID/DD, CMA detection can clarify the genetic etiology, which is of great significance for the treatment of children and guidance for their parents to reproduce.

Key words: intellectual disability, developmental delay, chromosome microarray analysis, copy number variation, clinical phenotype

摘要： 目的调查安徽省120例智力障碍(ID)／发育迟缓(DD)儿童致病性与可能致病性拷贝数变异(CNVs)的检出情况,并分析患儿临床表型,明确ID／DD患儿遗传学病因,为患儿的治疗及其父母再生育指导提供依据。方法选取2019年5月—2020年6月在安徽省儿童医院小儿康复科就诊的120例不明原因ID／DD患儿,行染色体微阵列分析(CMA)检测明确存在的致病性与可能致病性CNVs,分析患儿临床表型及致病性与可能致病性CNVs特点。结果 120例ID／DD患儿检出致病性CNVs 18例(15.00%),可能致病性CNVs 2例(1.67%),意义不明的CNVs 39例(32.50%),可能良性和良性CNVs 61例(50.83%)。20例检出致病性与可能致病性CNVs的患儿伴先天畸形／特殊面容5例,伴1种或多种其他疾病14例;轻、中、重度智力低下分别为3、12、5例。20例ID／DD患儿共存在21处致病性或可能致病性CNVs,其中微缺失片段13个(占61.90%),微重复片段8个(占38.10%),比例约为1.63∶1,片段平均大小6.34 Mb。21处致病性与可能致病性CNVs以2号与22号染色体(3处)检出最多。20例ID／DD患儿中,已知综合征10例(50.00%),仍有10例(50.00%)为数据库中暂未定义的综合征或疾病区域。结论对于不明原因ID／DD患儿,应用CMA方法进行检测可明确其遗传学病因,对患儿的治疗及其父母再生育指导意义重大。

关键词: 智力障碍, 发育迟缓, 染色体微阵列分析, 拷贝数变异, 临床表型

CLC Number:

R749.94

CHEN Lu-lu, TONG Guang-lei, ZHOU Tao-cheng, LI Hong, XU Yan-hong, SU Wei, LUO Yuan-yuan, LIANG Dong. Investigation and clinical phenotypic analysis of gene copy number variation in 120 children with intellectual disability/developmental delay in Anhui province[J]. Chinese Journal of Child Health Care, 2021, 29(11): 1172-1175.

陈露露, 童光磊, 周陶成, 李红, 徐艳红, 苏薇, 罗媛媛, 梁栋. 安徽省120例智力障碍/发育迟缓儿童基因拷贝数变异检出情况调查及临床表型分析[J]. 中国儿童保健杂志, 2021, 29(11): 1172-1175.

References

[1] 孙昱,傅启华,余永国.高通量测序技术在智力障碍/全面发育迟缓中的临床应用[J].中华检验医学杂志,2019,42(2):84-88.
[2] 万瑞平,黄小霏,张玲华,等.智力障碍/发育迟缓患儿的染色体核型和基因拷贝数变异分析[J].中国妇幼保健,2019,34(15):3520-3522.
[3] Lee SH, Song WJ. Chromosomal microarray testing in 42 korean patients with unexplained developmental delay, intellectual disability, autism spectrum disorders, and multiple congenital anomalies[J]. Genomics Inform,2017,15(3):82-86.
[4] 张亚南,席惠,贾政军,等.神经发育障碍420例遗传病因学分析[J].中华实用儿科临床杂志,2019,34(24):1862-1866.
[5] de Souza LC, Dos Santos AP, Sgardioli IC, et al. Phenotype comparison among individuals with developmental delay/intellectual disability with or without genomic imbalances[J]. J Intellect Disabil Res,2019,63(11):1379-1389.
[6] 中华医学会儿科学分会神经学组,中国医师协会神经内科分会儿童神经疾病专业委员会.儿童智力障碍或全面发育迟缓病因诊断策略专家共识[J].中华儿科杂志,2018,56(11):806-810.
[7] Riggs ER, Andersen EF, Cherry AM, 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.
[8] 张鑫丽,潘黎明,沈国松.一例重度智力障碍患儿的 LINS1基因变异分析 [J].中华医学遗传学杂志,2020,37(1):57-59.
[9] Arican P, Olgac Dundar N, Ozyilmaz B, et al. Chromosomal microarray analysis in children with unexplained developmental delay/intellectual disability[J].J Pediatr Genet,2019,8(1):1-9.
[10] 戚锋锋,沈学萍,梁友,等.染色体微阵列分析技术诊断不明原因智力低下/发育迟缓儿童遗传学病因[J].预防医学,2019,31(11):1169-1171.
[11] 付春云,范歆,罗仕玉,等.不明原因智力障碍64例全基因组拷贝数变异分析[J].中华实用儿科临床杂志,2017,32(12):924-927.
[12] Kim HJ, Park CI, Lim JW, et al. Phenotypic analysis of korean patients with abnormal chromosomal microarray in patients with unexplained developmental delay/Intellectual disability[J].Yonsei Med J,2018, 59(3):431-437.
[13] Chaves TF,Baretto N, Oliveira LF, et al. Copy number variations in a cohort of 420 individuals with neurodevelopmental disorders from the south of Brazil[J]. Sci Rep,2019,9
(1):17776.
[14] 杨晓,马宁,彭薇,等.60例精神发育迟滞/生长发育迟缓患儿的遗传学分析[J].中国计划生育学杂志,2018,26(9):823-826.
[15] 杨李,王宝田,唐久来,等.神经发育障碍患儿致病性拷贝数变异与临床表型分析[J].中华实用儿科临床杂志,2020,35(6):445-449.
[16] 王荣跃,雷婷缨,符芳,等.染色体微阵列分析技术在489例生长发育迟缓/智力低下患儿中的应用[J].中华医学遗传学杂志,2017,34(4):528-533.
[17] 党颖慧,宋婷婷,万陕宁,等.32例智力低下发育迟缓患儿基因组拷贝数变异的分析[J].医学研究杂志,2019,48(4):29-33.
[18] Lindstrand A, Eisfeldt J, Pettersson M, et al. From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability[J]. Genome Med,2019,11(1):68.
[19] 李红,童光磊,张敏,等.染色体微阵列分析技术在210例发育迟缓/智力低下患儿中的应用[J].安徽医科大学学报,2019,54(6):976-980.