CHD8基因新發(fā)突變的孤獨癥譜系障礙1例報道并文獻復習

鄭清文 詹國棟 唐 春 畢 欣 趙薇薇 鄒小兵

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·論著·

CHD8基因新發(fā)突變的孤獨癥譜系障礙1例報道并文獻復習

鄭清文1詹國棟1唐 春1畢 欣2趙薇薇2鄒小兵1

目的 提高對孤獨癥譜系障礙(ASD)CHD8基因突變患兒臨床表型和基因型的認識。方法回顧性分析1例存在CHD8基因突變的ASD患兒的臨床資料，并文獻復習。結果①男，3歲3月齡，頭圍55.0 cm(>4s)，身高107.0 cm(>2s)，體重23.5 kg(>2s)。有典型的ASD表現(xiàn)，運動明顯落后，有慢性便秘史。②提取患兒及其父母靜脈血DNA，以二代高通量測序技術對4 813個臨床相關基因的外顯子區(qū)進行測序，共檢測到變異8 982個，經篩選流程篩選ASD相關的EHMT1、PCDH9、NLGN4X的錯義突變，CHD8的無義突變(c.307C>T, p.Gln103*)有致病可能。Sanger測序顯示患兒EHMT1、PCDH9的突變來源于父親，NLGN4X的突變來源于母親，患兒父母未發(fā)現(xiàn)CHD8的突變。③目前國外共報道了CHD8基因與神經發(fā)育障礙有關的15個重要突變；CHD8基因突變患者的臨床表型包括ASD表現(xiàn)(87%)、身材高大(86%)、大頭畸形(80%)、慢性便秘或間歇性腹瀉(80%)、運動落后(67%)和睡眠異常(67%)等，本文病例臨床表型與文獻報道較為一致。結論CHD8基因是ASD重要的易感基因；ASD患兒合并大頭畸形、生長過快，且有慢性便秘或間歇性腹瀉時應考慮CHD8基因突變可能，可行基因檢測協(xié)助診斷。

孤獨癥譜系障礙；CHD8基因； 大頭畸形； 生長過快； 二代測序技術

1 病例資料

母親孕早期出現(xiàn)陰道流血，服中藥及臥床休息后流血停止；定期產檢，未見異常，無妊娠期發(fā)熱，否認貓、狗、放射線等不良接觸史。否認家族中有神經精神發(fā)育異常者。

查體：身高107.0 cm(>2s)，體重23.5 kg(>2s)，頭圍55.0 cm(>4s)。前額寬且突出。心音有力，律齊，未聞及病理性雜音；腹軟，未捫及包塊，未見臍疝、腹股溝疝；脊柱、指/趾端未見畸形；手掌皮紋未見異常。

實驗室檢查：肝功能、血脂、甲狀腺功能、血漿皮質醇(上午8時)、胰島素樣生長因子-1未見異常；左手X線正位片示：過度生長，骨齡發(fā)育正常(圖1)。睡眠腦電圖、頭顱MRI、聽力檢查、腹部和心臟超聲未見異常。FMR1基因CGG重復次數(shù)正常；染色體基因芯片分析(CytoScan HD芯片，Affymetrix，USA)未發(fā)現(xiàn)致病性拷貝數(shù)變異(CNVs)。

圖1 患兒左手X線正位片

Fig 1 Anterioposterior radiograph of the patient′s left hand

Notes Overgrowth but normal bone age

孤獨癥診斷會談問卷(ADI-R)：社會互動異常15分(截止分10分)，溝通異常17分(截止分8分)，局限、重復、刻板的行為模式3分(截止分3分)，36月齡前發(fā)展異常的跡象3分(截止分1分)。孤獨癥診斷觀察量表(ADOS)：溝通7分[孤獨癥截止分4分，孤獨癥譜系障礙(ASD)截止分2分]，相互性社會互動7分(孤獨癥截止分7分，ASD截止分4分)，游戲1分，刻板行為和局限興趣2分。Gesell發(fā)育評估：粗動作發(fā)育齡30月齡，發(fā)育商76；細動作發(fā)育齡22.5月齡，發(fā)育商57；應物能發(fā)育齡25月齡，發(fā)育商64；言語能23月齡，發(fā)育商59；應人能30月齡，發(fā)育商76。診斷為ASD。

經患兒家長同意和我院倫理委員會審核，采用EDTA抗凝管抽取患兒及其父母靜脈血各2 mL，并抽提基因組DNA(QIAamp DNA提取試劑盒，QIAGEN公司)。提取的DNA用DNA酶片段化后用磁珠法純化，隨后進行PCR擴增并連接上接頭序列，經TruSight One Sequencing Panel(llumina Inc，美國)2次捕獲及純化，再經PCR擴增和純化，獲得的最終文庫在MiSeq測序儀(illumina Inc，USA)上進行測序。其中TruSight One Sequencing Panel根據人類基因突變數(shù)據庫(HGMD Professional)、在線人類孟德爾遺傳數(shù)據庫(OMIM)、GeneTests網站 (www.genetests.org)、Illumina等公司的其他商業(yè)化試劑盒的信息，納入了4 813個與已知臨床表型相關的基因，其中包含102個ASD相關基因(http://www.illumina.com/products/trusight-one-sequencing-panel.ilmn)。

實驗產生1.0 Gb數(shù)據，平均測序深度為114.8×，10×以上的捕獲區(qū)覆蓋率達98.10%，平均插入片段大小237 bp，共檢測到變異8 982個。經篩選流程篩選(圖2)，并結合患兒臨床資料和生物信息學軟件預測結果，對各個基因的功能、變異情況以及遺傳模式進行分析發(fā)現(xiàn)，ASD相關的EHMT1、PCDH9、NLGN4X的錯義突變、CHD8的無義突變(c.307C>T, p.Gln103*)有致病可能(表1)。圖3為二代高通量測序發(fā)現(xiàn)患兒CHD8基因存在突變。

圖2 高通量數(shù)據篩選流程圖

Fig 2 The filtering process of high-throughput sequencing data in this study

Notes Internal database of KingMed Center for Clinical Laboratory Co., Ltd.

表1 本文病例ASD相關基因候選變異總結Tab 1 Summary of candidate causative variants in ASD related genes in this patient

Notes 1)1000 Genome Project

圖3 本文病例二代高通量測序發(fā)現(xiàn)CHD8基因存在突變

Fig 3CHD8 mutation was identified via next-generation sequencing

Sanger測序的PCR引物序列及退火溫度如表2所示。該家系Sanger測序結果(圖4)顯示，患兒EHMT1、PCDH9的突變來源于父親，NLGN4X的突變來源于母親。雙親未發(fā)現(xiàn)CHD8的突變，患兒攜帶的可能為新發(fā)突變，不能除外其父母為性腺嵌合體的可能。

表2 本文病例可疑致病基因外顯子編碼區(qū)引物序列及退火溫度Tab 2 PCR primers and Tm used in this study

2 文獻復習

以“((“autistic disorder”[MeSH Terms] OR (“autistic”[All Fields] AND “disorder”[All Fields]) OR “autistic disorder”[All Fields] OR “autism”[All Fields]) OR (“autistic disorder”[MeSH Terms] OR (“autistic”[All Fields] AND “disorder”[All Fields]) OR “autistic disorder”[All Fields] OR “autistic”[All Fields])) AND CHD8[All

圖4 本文病例及其父母可疑致病基因突變位點Sanger測序圖

Fig 4 Sanger sequencing validation of candidate causative variants in this family

Notes A:CHD8，c.307C>T, p.Gln103* was found in proband; B:EHM1, c.2970G>7,9.Gln990His were found in proband and his father; C:PCDH9, c.2886C>G,p.His962Gln were found in proband and his father; D:NLGN4X, c.1486G>A, p.Val496Ile were found in proband and his mother

Fields]”為檢索式檢索PubMed數(shù)據庫，以檢索詞“CHD8”與“孤獨癥”檢索萬方數(shù)據庫和中國知網，檢索時間均為建庫至2015年1月31日，共檢索到英文文獻13篇、中文文獻9篇；排除其中不相關文獻10篇，12篇文獻中關于“CHD8基因突變與ASD”的臨床相關研究3篇。

Bernier等[1]通過對3 730例臨床診斷為發(fā)育遲緩(DD)或ASD的患者進行CHD8基因測序，并結合O′Roak的研究小組前期外顯子測序(209例ASD患者)[2]和靶基因檢測(2 446例ASD患者)[3]的結果，匯總了CHD8已知的與神經發(fā)育障礙有關的15個重要突變(表3)，而在累計近9 000名正常對照中未發(fā)現(xiàn)CHD8基因的截斷突變(包括無義突變、錯義突變、移碼突變、剪接突變、整碼突變等)。本文患兒的CHD8基因無義突變c.307C>T, p.Gln103*是新發(fā)現(xiàn)的突變，為首次報道。對既往Bernier等[1]和O′Roak等[2,3]已報道的15例CHD8基因突變患者的臨床表型進行總結，結果如表4所示。本文患兒大頭畸形、前額突出，生長較同齡兒童快，有典型的ASD表現(xiàn)，語言、運動和智力落后于同齡兒童，且有慢性便秘病史，其臨床表型與表4描述的臨床表型較為一致。

表3 已知與神經發(fā)育障礙有關的CHD8基因重要突變

Tab 3Summary of CHD8 mutations associated with neurodevelopmental disorders (from 5′ to 3′)

ProbandSexMUT3)HGVS4)Inheritance12714.p11)MNsp.Ser62Xdenovo13986.pl1)MFsp.Tyr747XdenovoNij0234862)FFsp.Val984XInheritedmaternalAPP_109580-1002)MNsp.Glu1114Xdenovo11654.p11)FSpc.3519-2A>Gdenovo13844.p11)MNsp.Gln1238Xdenovo14016.p11)MNsp.Arg1337XdenovoNij07-066462)MMnsp.Arg1797GlnInheritedpaternalTroina26592)MFsp.Glu1932SerfsX3denovo12991.p11)MFsp.Glu2103ArgfsX3denovo12752.p11)FFsp.Leu2120ProfsX6denovoTroina20372)FFsp.Glu2136argfsX6denovoNij0108782)MAap.Lys2287delUnknown14233.p11)MFsp.Asn2371LysfsX2denovo14406.p11)MAap.His2498deldenovoOurcaseMNsp.Gln307Xdenovo

Notes MUT:mutation. 1) Patient′s mutation was previously reported by O′Roak et al[2,3];2) Patient′s mutation was previously reported by Bernier et al[1];3) Ns: nonsense; Fs: Frameshift; Sp: splice; Mns: missense-near-splice site; Aa: single amino-acid deletion;4) HGVS: human genome variant sequence

3 討論

ASD的臨床表型和基因型十分復雜，迄今確切發(fā)病機制尚不清楚，但已明確遺傳因素在其中發(fā)揮重要的作用。

表4 CHD8突變患者的臨床表型[%(n/N)]

Tab 4 Brief description of phenotypic features of patients with CHD8 mutation[%(n/N)]

PhenotypicfeaturesPositiveOurcaseNeurodevelopmentalabnormalityASD87(13/15)+Intellectualdisability60(9/15)+Delayedspeech60(9/15)+Regression47(7/15)-OvergrowthMacrocephaly80(12/15)+Tall86(12/14)+Overweight21(3/14)+DistinctfacesProminentsupraorbitalridge67(6/9)-Broadforehead44(4/9)+Hypertelorism67(6/9)-Down-slantedpalpebralfissures67(6/9)-Pointedchin44(4/9)-Largeears,fleshyearlobes44(4/9)-GastrointestinalproblemsChronicconstipation,intermittentdiar-rhea80(12/15)+SleepproblemsDifficultiesinfallingasleep,frequentnight-timeawakenings67(10/15)-BehavioralabnormalityAttentionalproblems,anxietyproblems73(11/15)+MotordelayGrossmotordelay,impairedfinemotorcoordinationskills67(10/15)+OthersCesareansection33(5/15)+Birthinduction/augmentation40(6/15)-

Notes +: present; -: absent

將異質性明顯的疾病根據某些特征分為不同的亞型，可提高研究對象的同質性，有利于病因的發(fā)現(xiàn)和致病機制的闡述。既往研究發(fā)現(xiàn)，ASD群體中大頭圍(>同年齡同性別P97)的比例為11%～30%[4～6]，高于正常人群，且頭圍與ASD的某些臨床表型如社交障礙的嚴重程度、智力低下等似乎存在聯(lián)系[7, 8]，提示可將大頭圍作為ASD的一種分型標準。

近年來從亞型的角度分析，已發(fā)現(xiàn)某些基因(如PTEN[9, 10]、CHD8[1]、RAB39B[11]等)在伴大頭畸形的ASD患者發(fā)病中起重要作用。本文患兒大頭畸形、生長過快，有明顯的ASD特征，伴隨運動發(fā)育落后和慢性便秘，F(xiàn)MR1基因CGG重復次數(shù)正常，初步排除了脆性X染色體綜合征，染色體基因芯片分析未發(fā)現(xiàn)致病性CNVs的存在。為明確診斷，運用二代高通量測序方法對4 813個臨床相關基因的外顯子區(qū)進行測序，重點關注與ASD有關的基因，發(fā)現(xiàn)患兒EHMT1、PCDH9、NLGN4X、CHD8基因存在突變，其中EHMT1、PCDH9來源于未患病父親，且dbSNP及千人基因組數(shù)據庫有收錄(EHMT1：rs143669310，0.0014；PCDH9：rs192811737，0.0018)，不考慮為患兒的致病原因。NLGN4X的突變來源于母親，該基因突變引起的ASD可認為是X連鎖隱性遺傳，但未見報道過度生長、大頭畸形等表型。結合本文患兒的臨床表型認為NLGN4X的變異可能并不是其致病原因，而根據既往關于CHD8基因的文獻報道[1～3]，CHD8雜合無義突變c.307C>T,p.Gln103*(NM_020920.3)使編碼產物變短而破壞蛋白質原有功能，更有可能是患兒ASD相關的重要遺傳學改變。

CHD8基因位于14q11.2區(qū)，總長約46 kb，由37個外顯子組成；其編碼產物通過結合β-catenin募集組蛋白H1，改變染色質空間結構而發(fā)揮轉錄抑制作用，是Wnt/β-catenin信號通路重要的調節(jié)物[12, 13]，而該通路對神經元增殖和分化、突起生長和突觸形成作用較大[14～18]，與ASD發(fā)病顯著相關[19～21]。O′Roak等于2012年首次對209例ASD患者及其未患病同胞進行外顯子組測序，發(fā)現(xiàn)2例患者存在CHD8基因突變[2]；隨后相關研究已證實，CHD8新發(fā)的截斷突變是ASD發(fā)病的重要危險因素[1, 3, 22]。此外，Talkowski等[23]在攜帶染色體平衡易位的ASD患者中發(fā)現(xiàn)了CHD8的破壞，也提示了該基因對于ASD發(fā)病的重要作用。

Sugathan等[24]在神經前體細胞模擬CHD8基因功能性的雜合缺失發(fā)現(xiàn)，CHD8基因調節(jié)許多功能各異但與ASD相關的基因(SCN2A、DLG2、SHANK3、MBD3等)，以及與突觸形成、神經元分化、細胞黏附等有關的基因(LAMA4、NCAM1、MEGF10等)。突變的CHD8可通過影響上述基因而影響神經系統(tǒng)的正常發(fā)育。chd8基因敲除的斑馬魚模型再現(xiàn)了大頭畸形[1, 24]和胃腸道動力不足[1]的臨床表型。通過神經元特殊染色發(fā)現(xiàn)，前腦和中腦神經元前體細胞的過度增生導致這2個部位體積增大，造成頭部過度生長；而發(fā)育過程中腸道神經叢增殖或是遷移障礙導致腸道神經元減少，影響正常的胃腸道功能。細胞和動物研究結果均說明CHD8破壞會導致神經元發(fā)育的缺陷。

針對CHD8基因異常的ASD患者，除通過特殊教育和訓練提高認知、社交和適應能力外，還應關注患者的胃腸道問題和睡眠狀況。此外，既往研究表明，CHD8與胃腸道、皮膚等部位多種腫瘤密切相關[25～28]；Bernier的研究中1例41歲的CHD8突變患者合并腫瘤，另1例將突變傳給患兒的父親罹患直腸癌[1]，這提示注意腫瘤的早期征象可能是CHD8突變患者日后定期隨訪的又一重點。

總之，CHD8基因是ASD重要的易感基因；ASD患兒合并大頭畸形、生長過快，伴有慢性便秘或間歇性腹瀉時應考慮存在CHD8基因突變可能，可行基因檢測協(xié)助診斷。

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(本文編輯：丁俊杰)

《中國循證兒科雜志》主要欄目及其特點

述評：在高度精練又不失全面地評價某一臨床或基礎研究熱點問題的基礎上，前瞻性地指出研究可能的切入點和方向。

專家對談錄：是國內外或境內外專家共同參與的談話式欄目。選題為最新的基礎或臨床研究問題。

論著：本刊論著文稿的內容應遵循以下類型醫(yī)學研究報告規(guī)范撰寫。

隊列研究、病例對照研究和橫斷面研究以觀察性流行病學研究報告的質量(Strengthening the reporting of observational studies in epidemiology，STROBE) 為標準，STROBE原文見www.strobe-statement.org。STROBE中文解讀見《中國循證兒科雜志》，2010，5(3)：223-227

觀察性研究的Meta 分析(Meta-analysis of observational studies in epidemiology，MOOSE)報告規(guī)范原文見JAMA,2000, 283(15): 2008-2012。隨機對照試驗Meta分析報告質量(the quality of reporting of Meta-analysis of randomized controlled trial, QUORPM)原文見Lancet,1999,354(9193):1896-1900。MOOSE和QUOROM中文解讀見《中國循證兒科雜志》，2010，5(1)：60-63

非劣效性和等效性隨機對照試驗的報告規(guī)范(Consolidated standards of reporting trials,CONSORT)原文見http://www.consort-statement.org。CONSORT中文解讀見《中華流行病學雜志》，2006，12(27)：1086-1088

非隨機對照設計報告規(guī)范(Transparent reporting of evaluations with nonrandomized designs，TREND)原文見Am J Public Health,2004,94(3):361-366。TREND中文解讀見《中華流行病學雜志》，2006，4(27)：408-410

診斷試驗準確性研究的報告規(guī)范(Standards for reporting of diagnostic accuracy,STARD)原文見www.stard-statement.org。STARD中文解讀見《中華流行病學雜志》，2006，10(27)：910-912

隨機對照試驗報告規(guī)范(CONSORT)原文見http://www.consort-statement.org。CONSORT中文解讀見《中國循證兒科雜志》，2010，5(2)：146-150

遺傳關聯(lián)性研究報告規(guī)范(STREGA)原文見http://www.strega-statement.org。STREGA中文解讀見《中國循證兒科雜志》，2010，5(4)：304-307

病例報告：應遵循病例報告的報告規(guī)范(CARE)撰寫，原文見http://www.care-statement.org/index.html。CARE中文解讀見《中國循證兒科雜志》，2014，9(3)：216-219

A novel CHD8 gene mutation in a patient with autism spectrum disorder and literature review

ZHENGQing-wen1,ZHANGuo-dong1,TANGChun1,BIXin2,ZHAOWei-wei2,ZOUXiao-bing1

(1TheThirdAffiliatedHospitalofSunYat-senUniversity,Guangzhou510630; 2KingMedCenterforClinicalLaboratoryCo.,Ltd.,Guangzhou510330,China)

ZOU Xiao-bing，E-mail:zouxb@vip.tom.com; ZHAO Wei-wei，E-mail:lab-zhaoweiwei@kingmed.com.cn

ObjectiveTo draw attention to the phenotype and genotype of patients with autism spectrum disorders (ASD) carryingCHD8 mutation.MethodsThe clinical data of one patient with ASD carryingCHD8 mutation, including clinical manifestations, laboratory findings, genetic testing results and family investigation were summarized and analyzed, and relevant literatures aboutCHD8 mutation were reviewed in this article.Results①The 3-year-and-3-month boy was presented with macrocephaly (head circumference was 55.0 cm,Z>4s), overgrowth (height was 107.0 cm,Z>2s; weight was 23.5 kg,Z>2s) and typical autistic behavior as well as significant motor delay and gastrointestinal(GI) problems (chronic constipation). No additional patient was found in his family. ②Targeting 4 813 genes associated with known clinical phenotypes, a total of 8 982 variances were found in the patient via next-generation high-throughput DNA sequencing. Missense mutations of autism-related genesEHMT1,PCDH9,NLGN4Xand nonsense mutation ofCHD8 [c.307C>T, p.Gln103*(NM_020920.3)] were probably pathogenic after filtering unrelated variances.EHMT1,PCDH9 mutations were identified in his father andNLGN4Xmutation in his mother, butCHD8 mutation was not identified in his parents via Sanger sequencing. ③To date a total of 15 independentCHD8 mutations associated with neurodevelopmental disorders has been reported worldwide. Common phenotypic features of patients withCHD8 disruptions include autism(87%), overgrowth(86%), macrocephaly(80%), GI complaints(80%), motor delay(67%, especially fine motor coordination) and sleep problems(67%).ConclusionThe mutation ofCHD8 is an important risk factor of ASD. ASD patients with macrocephaly, overgrowth and GI problems should be considered as carryingCHD8 mutation and genetic testing is recommended to confirm the diagnosis.

Autism spectrum disorder ;CHD8; Macrocephaly; Overgrowth; Next-generation sequencing

國家重點基礎研究發(fā)展計劃(973計劃)：2012CB517901

1 中山大學附屬第三醫(yī)院 廣州，510630; 2 廣州金域醫(yī)學檢驗中心 廣州,510330

鄒小兵，E-mail:zouxb@vip.tom.com；趙薇薇，E-mail:lab-zhaoweiwei@kingmed.com.cn

10.3969/j.issn.1673-5501.2015.03.012

2015-03-03

2015-05-27)