中国循证儿科杂志
中國循證兒科雜誌
중국순증인과잡지
CHINESE JOURNAL OF EVIDENCE-BASED PEDIATRICS
2010年
2期
85-93
,共9页
陈晓丽%郭金%王珺%王立文%丁秀原%张霆%吴柏林
陳曉麗%郭金%王珺%王立文%丁秀原%張霆%吳柏林
진효려%곽금%왕군%왕립문%정수원%장정%오백림
智力低下%发育迟缓%微阵列比较基因组杂交技术%基因组拷贝数变异%微缺失/重复综合征
智力低下%髮育遲緩%微陣列比較基因組雜交技術%基因組拷貝數變異%微缺失/重複綜閤徵
지력저하%발육지완%미진렬비교기인조잡교기술%기인조고패수변이%미결실/중복종합정
Mental retardation%Developmental delay%Array-comparative genomic hybridization%Genomic copy number variations%Microdeletion/duplication syndromes
目的 应用高分辨微阵列比较基因组杂交技术(Array-CGH),对中国人群不明原因的智力低下/发育迟缓(MR/DD)患儿进行全基因组拷贝数变异(CNVs)筛查,获得在这些不明原因MR/DD患儿中CNVs的检出率,并分析其中的罕见CNVs与MR/DD的相关性,以此评估Array-CGH对不明原因MR/DD可能的遗传病因诊断作用.方法 根据特定筛选条件收集在首都儿科研究所临床诊断为不明原因MR/DD患儿,用Oligo 244 K DNA芯片筛查全基因组CNVs.针对所发现的CNVs,首先将其与国际基因组CNVs多态性数据库(database of genomic variants)进行比对,剔除常见多态性CNVs,将获得的罕见CNVs应用美国波士顿儿童医院遗传诊断实验室的临床分子诊断平台,结合基因组异常拷贝数数据库(DECIPHER)进行核查并与既往相关文献比对,以发现罕见CNVs在不明原因MR/DD患儿中的检出率.结果 2004年7月至2008年7月共收集111例不明原因MR/DD患儿,平均年龄为6岁,男女比例为1.775.28例患儿发现36个罕见CNVs,CNVs平均长度为1 326 kb (29～8 760 kb),这些CNVs均无法被常规染色体G带检查所识别.通过评估,19例患儿携带可能与MR/DD相关的CNVs,另1例患儿的CNVs临床意义不明确,Array-CGH在不明原因MR/DD患儿中发现携带与疾病相关的罕见CNVs的诊断率为17.1%(19/111例).22/36个(66.1%)罕见CNVs曾被美国波士顿儿童医院Array-CGH数据库、DECIPHER数据库、既往MR/DD微阵列研究文献所报道.1例患儿在15q11.2-13.1存在2 098 kb的基因组缺失,覆盖Prader-Willi综合征/Angelman综合征关键区的多个候选基因,包括SNRPN、NECDIN、SnRNAs和UBE3A,结合该患儿面部表型、临床检查以及Array-CGH结果 ,诊断为非典型性Prader-Willi综合征.结论 基因组CNVs相关的微缺失/重复是中国人群中不明原因MR/DD患儿的原因之一,高分辨Array-CGH技术可在不明原因MR/DD患儿中发现更多的遗传病因,帮助和提高不明原因MR/DD的分子诊断水平.
目的 應用高分辨微陣列比較基因組雜交技術(Array-CGH),對中國人群不明原因的智力低下/髮育遲緩(MR/DD)患兒進行全基因組拷貝數變異(CNVs)篩查,穫得在這些不明原因MR/DD患兒中CNVs的檢齣率,併分析其中的罕見CNVs與MR/DD的相關性,以此評估Array-CGH對不明原因MR/DD可能的遺傳病因診斷作用.方法 根據特定篩選條件收集在首都兒科研究所臨床診斷為不明原因MR/DD患兒,用Oligo 244 K DNA芯片篩查全基因組CNVs.針對所髮現的CNVs,首先將其與國際基因組CNVs多態性數據庫(database of genomic variants)進行比對,剔除常見多態性CNVs,將穫得的罕見CNVs應用美國波士頓兒童醫院遺傳診斷實驗室的臨床分子診斷平檯,結閤基因組異常拷貝數數據庫(DECIPHER)進行覈查併與既往相關文獻比對,以髮現罕見CNVs在不明原因MR/DD患兒中的檢齣率.結果 2004年7月至2008年7月共收集111例不明原因MR/DD患兒,平均年齡為6歲,男女比例為1.775.28例患兒髮現36箇罕見CNVs,CNVs平均長度為1 326 kb (29～8 760 kb),這些CNVs均無法被常規染色體G帶檢查所識彆.通過評估,19例患兒攜帶可能與MR/DD相關的CNVs,另1例患兒的CNVs臨床意義不明確,Array-CGH在不明原因MR/DD患兒中髮現攜帶與疾病相關的罕見CNVs的診斷率為17.1%(19/111例).22/36箇(66.1%)罕見CNVs曾被美國波士頓兒童醫院Array-CGH數據庫、DECIPHER數據庫、既往MR/DD微陣列研究文獻所報道.1例患兒在15q11.2-13.1存在2 098 kb的基因組缺失,覆蓋Prader-Willi綜閤徵/Angelman綜閤徵關鍵區的多箇候選基因,包括SNRPN、NECDIN、SnRNAs和UBE3A,結閤該患兒麵部錶型、臨床檢查以及Array-CGH結果 ,診斷為非典型性Prader-Willi綜閤徵.結論 基因組CNVs相關的微缺失/重複是中國人群中不明原因MR/DD患兒的原因之一,高分辨Array-CGH技術可在不明原因MR/DD患兒中髮現更多的遺傳病因,幫助和提高不明原因MR/DD的分子診斷水平.
목적 응용고분변미진렬비교기인조잡교기술(Array-CGH),대중국인군불명원인적지력저하/발육지완(MR/DD)환인진행전기인조고패수변이(CNVs)사사,획득재저사불명원인MR/DD환인중CNVs적검출솔,병분석기중적한견CNVs여MR/DD적상관성,이차평고Array-CGH대불명원인MR/DD가능적유전병인진단작용.방법 근거특정사선조건수집재수도인과연구소림상진단위불명원인MR/DD환인,용Oligo 244 K DNA심편사사전기인조CNVs.침대소발현적CNVs,수선장기여국제기인조CNVs다태성수거고(database of genomic variants)진행비대,척제상견다태성CNVs,장획득적한견CNVs응용미국파사돈인동의원유전진단실험실적림상분자진단평태,결합기인조이상고패수수거고(DECIPHER)진행핵사병여기왕상관문헌비대,이발현한견CNVs재불명원인MR/DD환인중적검출솔.결과 2004년7월지2008년7월공수집111례불명원인MR/DD환인,평균년령위6세,남녀비례위1.775.28례환인발현36개한견CNVs,CNVs평균장도위1 326 kb (29～8 760 kb),저사CNVs균무법피상규염색체G대검사소식별.통과평고,19례환인휴대가능여MR/DD상관적CNVs,령1례환인적CNVs림상의의불명학,Array-CGH재불명원인MR/DD환인중발현휴대여질병상관적한견CNVs적진단솔위17.1%(19/111례).22/36개(66.1%)한견CNVs증피미국파사돈인동의원Array-CGH수거고、DECIPHER수거고、기왕MR/DD미진렬연구문헌소보도.1례환인재15q11.2-13.1존재2 098 kb적기인조결실,복개Prader-Willi종합정/Angelman종합정관건구적다개후선기인,포괄SNRPN、NECDIN、SnRNAs화UBE3A,결합해환인면부표형、림상검사이급Array-CGH결과 ,진단위비전형성Prader-Willi종합정.결론 기인조CNVs상관적미결실/중복시중국인군중불명원인MR/DD환인적원인지일,고분변Array-CGH기술가재불명원인MR/DD환인중발현경다적유전병인,방조화제고불명원인MR/DD적분자진단수평.
Objective To screen for genome-wide copy number variations (CNVs) in Chinese children with unexplained mental retardation or developmental delay (MR/DD) using high resolution array-comparative genomic hybridization (Array-CGH), identify rare CNVs (microdeletions/ duplications) which may associate with MR/DD, and evaluate the effectiveness of Array-CGH in clinical molecular diagnosis of children with unexplained MR/DD.Methods Children with unexplained MR/DD were recruited for this study by using a high resolution oligo 244 K array for detection of genomic copy number variations. All identified CNVs were analyzed with the references from database of genomic variants (DGV),database of DECIPHER, and UCSC brower(build 18), as well as an internal Array-CGH database from the Genetics Diagnostic Lab of Children's Hospital Boston, plus a comprehensive literature review, to determine if the rare CNVs found in these children were associated with MR/DD.Results One hundred and eleven children with unexplained MR/DD were collected from July 2004 to July 2008. The average age was 6 years old and the ratio of male to female was 1.775. Among them, 36 rare CNVs were identified in 28 patients. The average size of CNVs was 1 326 kb (29-8 760 kb) which was undetectable by chromosome analysis. Nineteen patients carried CNVs that may be associated with MR/DD but 1 patient had a CNV with uncertain clinical significance. The diagnostic yield of Array-CGH for these MR/DD children is 17.1% (19/111). 22/36 CNVs (61.1%) found by this study was also reported at least in one of the database and/or literature reviews. A 2 098 kb deletion at 15q11.2-13.1 overlapping with PWS/AS critical region was found in a patient who had global developmental delay, feeding difficulty, tricuspid incompetence, hypotonia, cryptorchidism and foot deformity. His dysmorphism included flat face, sparse hair, hypertelorism, down-slanting eyes and small hands. The MRI showed prominent bilateral frontal and temporal lobe sulcus, enlarged lateral ventricles. Atypical PWS was diagnosed according to his clinic information and Array-CGH finding. The deletion included SNRPN,NECDIN,SnRNAs,UBE3A genes.Conclusions CNV associated with microdeletions/duplications found in Chinese patients was one of the causes for unexplained mental retardation and developmental delay. Array-CGH could detect disease associated rare CNVs effectively which should be applied to clinical molecular diagnostics as a useful evaluation to help differential diagnosis of children with unexplained MR/DD and other ambiguous medical conditions.
