董 辰劉姜睿璇楊 琳任蕓蕓周文浩
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COL1A2新突變致胎兒嚴(yán)重成骨不全癥1例報告并表型基因型關(guān)聯(lián)性文獻(xiàn)復(fù)習(xí)
董辰1,4劉姜睿璇1,4楊琳1任蕓蕓2周文浩3
摘要目的總結(jié)1例COL1A2新突變致胎兒嚴(yán)重成骨不全癥(OI)的臨床特征及基因突變的特點,為胎兒產(chǎn)前咨詢提供依據(jù)。方法對產(chǎn)檢B超檢查示OI可能的胎兒流產(chǎn)組織抽提DNA進(jìn)行基因型分析,自行設(shè)計COL1A1和COL1A2所有外顯子及剪接區(qū)域的引物。利用Sanger測序法對胎兒行COL1A1和COL1A2基因外顯子及剪接區(qū)域的測序分析并行父母驗證。依據(jù)人類基因突變數(shù)據(jù)庫(HGMD)專業(yè)版,對COL1A2突變所致疾病臨床表型行文獻(xiàn)復(fù)習(xí)。結(jié)果胎兒的COL1A1和COL1A2基因均檢測出變異位點。COL1A2基因檢測到雜合突變(c.3142G>T,p.Glu1048Cys)在寡核苷酸多態(tài)性數(shù)據(jù)庫、HGMD及Ⅰ型膠原蛋白突變數(shù)據(jù)庫均未見報道,結(jié)合胎兒父母驗證為新發(fā)突變,對比公共數(shù)據(jù)庫及在線預(yù)測軟件預(yù)測該突變類型為致病突變。在HGMD專業(yè)版中搜索COL1A2,共檢索到387個COL1A2致病突變,與21種疾病及其亞型相關(guān)。92%的突變引起OI或其亞型,還可引起Ehlers-Danlos綜合征或其亞型。結(jié)合COL1A2突變所致疾病臨床表型行文獻(xiàn)復(fù)習(xí),本文報告胎兒符合Ⅱ型OI。結(jié)論產(chǎn)前通過超聲影像結(jié)合基因分型診斷胎兒為COL1A2基因新發(fā)突變(c.3142G>T,p.Glu1048Cys)所致Ⅱ型OI; COL1A2基因編碼蛋白長鏈雙螺旋的400~480氨基酸及MLBR 3區(qū)域中甘氨酸被天冬氨酸或谷氨酸替代,多導(dǎo)致嚴(yán)重表型的OI;本文為產(chǎn)前準(zhǔn)確預(yù)測胎兒結(jié)局、指導(dǎo)臨床決策提供依據(jù)。
關(guān)鍵詞COL1A2基因;成骨不全癥;突變;表型基因型相關(guān)性分析
作者單位1復(fù)旦大學(xué)附屬兒科醫(yī)院上海,201102; 2復(fù)旦大學(xué)附屬婦產(chǎn)科醫(yī)院上海,200011; 3上海市出生缺陷防治重點實驗室,復(fù)旦大學(xué)兒童發(fā)育與疾病轉(zhuǎn)化醫(yī)學(xué)研究中心,復(fù)旦大學(xué)附屬兒科醫(yī)院上海,201102; 4共同第一作者
孕婦,G2P0,34歲。第1胎為自然胎停,未行相應(yīng)檢查。胎兒父親39歲,體健。父母家族否認(rèn)疾病家族史及近親結(jié)婚史。孕婦孕早期未見異常,無放射性物質(zhì)接觸史,無藥物服用史。孕24+1周于復(fù)旦大學(xué)附屬婦產(chǎn)科醫(yī)院行產(chǎn)檢B超示:單胎,胎兒頭位,可見胎心胎動;胎頭雙頂徑長58 mm,頭圍204 mm,腹圍173 mm;右側(cè)肱骨長32 mm,左側(cè)肱骨長29 mm;右側(cè)腦室后角3.9 mm;小腦橫徑25 mm;后顱窩池深5.9 mm;可見局部腸管強回聲;左側(cè)股骨長21 mm,見彎曲;可見右側(cè)股骨長30 mm,明顯彎曲、成角畸形(圖1A)。依據(jù)單胎、局部腸管強回聲、股骨及肱骨短小、雙側(cè)股骨成角彎曲,產(chǎn)檢B超提示成骨不全癥(OI)可能。
經(jīng)胎兒產(chǎn)前診斷與咨詢,孕婦選擇行人工流產(chǎn)術(shù)終止妊娠,并同意留取胎兒流產(chǎn)組織行分子診斷,先在上海集愛遺傳與不育診療中心行人類全基因組SNP分型芯片檢測,未見明顯染色體拷貝數(shù)異常。為求得進(jìn)一步診斷來復(fù)旦大學(xué)附屬兒科醫(yī)院(我院)行基因檢測。經(jīng)胎兒家屬同意及我院倫理委員會審核通過,取胎兒流產(chǎn)組織,父、母親外周靜脈血各2mL(EDTA抗凝),抽提DNA(TIANGEN試劑盒抽提胎兒組織DNA,QIAGEN mini blood全血試劑盒抽提父母外周血DNA),行基因分析?;谖墨I(xiàn)復(fù)習(xí),約90%的OI是由常染色體顯性遺傳COL1A1和COL1A2基因突變引起[1],自行設(shè)計COL1A1 (NM_000088)和COL1A2 (NM_ 000089)所有外顯子及剪接區(qū)域的引物72(35和37)對,全部引物由上海捷瑞生物工程有限公司合成。利用Sanger測序法(3500XL Genetic Analyzer,ABI),對該胎兒分別行COL1A1和COL1A2基因外顯子及剪接區(qū)域的測序分析。
胎兒2個基因上均檢測出變異位點,對照寡核苷酸多態(tài)性數(shù)據(jù)庫(dbSNP)、人類基因突變數(shù)據(jù)庫(HGMD)和Ⅰ型膠原蛋白突變數(shù)據(jù)庫(http: / /www.le.ac.uk/genetics/ collagen/)確定變異位點性質(zhì)。圖1B~F顯示患兒及其父母COL1A2突變位點在染色體及蛋白質(zhì)位置,胎兒COL1A1基因中有5個SNP位點和1個剪接區(qū)域的未知突變: c.1156-9G>A,COL1A2基因中有6個SNP位點和1個編碼區(qū)致病性未知的突變: c.3142G>T p.Glu1048Cys。COL1A2基因檢測到的雜合突變(c.3142G>T,p.Glu1048Cys)在dbSNP、HGMD及Ⅰ型膠原蛋白突變數(shù)據(jù)庫均未見報道。胎兒父母驗證此位點無突變,證實為新發(fā)突變(圖1F)。對比公共數(shù)據(jù)庫,ExAC及1000 Genomes phase數(shù)據(jù)庫中均未有該突變,并且在線預(yù)測軟件Mutation Taster(http: / /www.mutationtaster.org/)預(yù)測該突變類型為致病突變。
圖1 胎兒B超圖像和胎兒及其父母COL1A2突變位點在染色體及蛋白質(zhì)位置分析注 A:胎兒B超圖像,所示右側(cè)股骨成角畸形; B: 7號染色體結(jié)構(gòu)示意圖; C: COL1A2基因所編碼蛋白質(zhì)全長及其功能結(jié)構(gòu)域:綠色代表膠原三螺旋重復(fù)區(qū)域,紫紅色代表膠原C端結(jié)構(gòu)域; D: HGMD報道的COL1A2基因編碼區(qū)錯義突變導(dǎo)致不同疾病的突變位點位置示意圖:紅色條柱代表導(dǎo)致嚴(yán)重表型的Ⅱ型和Ⅲ型OI的突變位點,綠色條柱代表導(dǎo)致表型較輕的Ⅰ型和Ⅳ型OI的突變位點,黃色條柱代表除OI外導(dǎo)致其他疾病的突變位點; E:Ⅰ型膠原蛋白的結(jié)構(gòu)示意圖:灰色代表兩條由COL1A1編碼的α1肽鏈,紅色代表由COL1A2編碼的α2肽鏈; F:胎兒及其家系突變位點Sanger驗證峰圖,證實該位點為新發(fā)(de novo)。圖B~F中的紅色柱分別代表該突變位點在染色體、α1肽鏈、HGMD報道的突變位點、Ⅰ型膠原和Sanger測序堿基序列中的位置
截至2016年1月20日,在HGMD專業(yè)版中搜索COL1A2,共檢索到387個HGMD收錄的COL1A2基因致病突變,與21種疾病及其亞型相關(guān)。共包含279個編碼區(qū)錯義突變,11個編碼區(qū)小片段缺失突變,11個編碼區(qū)小片段插入突變,5個編碼區(qū)相鄰位置雙突變,81個非編碼區(qū)突變。
結(jié)合既往文獻(xiàn)報道及在線人類孟德爾遺傳數(shù)據(jù)庫(OMIM),表1總結(jié)了HGMD中報道的COL1A2突變所引起的主要疾病種類及臨床表型。92%的突變引起OI或其亞型,6%的突變引起Ehlers-Danlos綜合征(EDS)或其亞型,1例引起Marfan綜合征(c.2123G>A,p.Arg708Gln)[2],1例引起青年型骨質(zhì)疏松(c.1576G>A,p.Gly526Arg)[3],1例引起骨質(zhì)疏松癥(c.2251G>A,p.Gly751Ser)[4]。除此之外,還有2例非編碼區(qū)突變導(dǎo)致轉(zhuǎn)錄增加[5],1例與顱內(nèi)動脈瘤易感性相關(guān)[6],1例導(dǎo)致輕微結(jié)締組織異常[7]。
表1 COL1A2突變所致疾病臨床表型比較
雖然目前的研究已將OI的分型增加到17種,但是COL1A2基因突變可引起Ⅰ、Ⅱ、Ⅲ、Ⅳ4種OI亞型,且引起的各型數(shù)量較為平均。其中76%是由錯義突變引起,占所有錯義突變引起疾病的98%。約20%的COL1A2基因的非錯義突變(移碼突變、整碼突變和非編碼區(qū)堿基突變)會導(dǎo)致EDS或其亞型,1例錯義突變引起EDS(c.1201G>T,p.Glu1201Term)[8]。EDS根據(jù)產(chǎn)生的原因分為主要的6大類以及其他類型[9]。其中,COL1A2基因突變引起的主要是關(guān)節(jié)松弛型EDS。HGMD有1例為未分型的EDS[10],其余均為關(guān)節(jié)松弛型EDS。
本文胎兒超聲影像初步診斷為OI的患兒進(jìn)行分子診斷,結(jié)合既往文獻(xiàn)、數(shù)據(jù)庫及相關(guān)軟件,診斷為COL1A2基因突變(c.3142G>T,p)所致的Ⅱ型OI。
COL1A2基因位于第7號染色體7q22.1,由52個外顯子組成,編碼骨骼中的Ⅰ型膠原的α2肽鏈。1條α2肽鏈與2條COL1A1基因編碼的α1肽鏈組成異源三聚體,3條肽鏈相互纏繞成繩索樣結(jié)構(gòu),中間的螺旋狀功能域及兩側(cè)N端和C端的球狀前肽鏈構(gòu)成了Ⅰ型前膠原分子。螺旋狀功能域是一個由1 014個氨基酸組成的Gly-Xaa-Yaa三肽重復(fù)的三重螺旋結(jié)構(gòu)。只有最小的甘氨酸分子才能進(jìn)入三重螺旋的內(nèi)部結(jié)構(gòu)。通過對肽鏈特定部位的羥化、折疊,以及分泌后對N端和C端前肽剪除的成熟過程,最終形成成熟Ⅰ型膠原。Ⅰ型膠原是構(gòu)成骨骼、皮膚和肌腱等結(jié)締組織的最主要的細(xì)胞外基質(zhì)蛋白,在生長發(fā)育中起著重要的作用。
在COL1A2基因突變引起的多種疾病中,最多見的為OI。OI又稱脆性骨病或脆骨-藍(lán)鞏膜-耳聾綜合征,是一種罕見的以骨脆性增加和膠原蛋白代謝紊亂為特征的風(fēng)濕性疾?。?1]。1979年,Sillence等根據(jù)臨床癥狀、影像學(xué)表現(xiàn)及分子生物學(xué)信息將OI為4型:Ⅰ型最主要的特點為藍(lán)鞏膜,Ⅳ型鞏膜表現(xiàn)為正常,Ⅱ型為圍生期致死型,Ⅲ型為進(jìn)展型不伴有鞏膜異常[12]。
表1總結(jié)的4種OI分型的臨床表型中,①從骨骼表型看,Ⅰ和Ⅳ型OI的骨骼畸形程度明顯小于Ⅱ和Ⅲ型,顱骨也僅出現(xiàn)縫間骨的改變,而沒有囟門增大或者礦化異常。特別是Ⅰ型OI患兒并未出現(xiàn)身材矮小,四肢長骨的彎曲偶爾出現(xiàn),骨折發(fā)生的時間較晚,頻率也會隨著性成熟而減少,愈合后也不會遺留畸形。雖然Ⅳ型OI的骨折發(fā)生時間較早,但發(fā)生的頻率也會隨著青春期之后而減少,更年期之后再增加。Ⅱ型OI患兒多存活不超過1歲,Ⅲ型OI患兒生后2年內(nèi)即可發(fā)現(xiàn)骨骼畸形,廣泛嚴(yán)重的骨質(zhì)疏松使其出生后即出現(xiàn)多發(fā)骨折,骨折愈合后常遺留肢體畸形。②從生長發(fā)育來看,Ⅳ型OI的身材矮小主要表現(xiàn)為比正常人群的平均身高低5%,Ⅲ型OI成年人的身高在92~108 cm,遠(yuǎn)低于Ⅳ型OI患者。③從不同系統(tǒng)來看,Ⅱ、Ⅲ型常有呼吸、循環(huán)及神經(jīng)系統(tǒng)的嚴(yán)重表型??傊?、Ⅲ型OI表型嚴(yán)重,Ⅰ、Ⅳ型OI表型輕微。
依據(jù)臨床表型的不同,如果能早期通過分子診斷的方法明確疾病的分型,或可盡早干預(yù)或可提示預(yù)后。已有研究表明,COL1A1和COL1A2無義或者移碼突變導(dǎo)致膠原數(shù)量減少而引起的OI,常為臨床表型最輕微的Ⅰ型OI,而導(dǎo)致膠原結(jié)構(gòu)異常的錯義突變則更易導(dǎo)致致死型OI[13]。圖1D總結(jié)了HGMD中COL1A2基因編碼區(qū)所報道的所有錯義突變,并根據(jù)突變位點及其導(dǎo)致的疾病進(jìn)行表型基因型相關(guān)性分析。
在COL1A2基因C端的突變均導(dǎo)致表型輕微的Ⅰ、Ⅳ型OI或者其他綜合征,而N端幾乎沒有突變會出現(xiàn)相關(guān)表型。而長鏈螺旋功能域的突變位點大多數(shù)都能導(dǎo)致疾病,而且表型輕重不一。研究還發(fā)現(xiàn),這些位點的變異均是Gly-Xaa-Yaa三肽重復(fù)中甘氨酸被其他氨基酸替代。從膠原分子的結(jié)構(gòu)中不難推斷,甘氨酸殘基是唯一可以進(jìn)入螺旋內(nèi),調(diào)節(jié)三股螺旋核心空間結(jié)構(gòu)的分子。因此,當(dāng)甘氨酸被其他大分子氨基酸替代時,螺旋折疊結(jié)構(gòu)就會被破壞,三條鏈就會暴露在外,過多的被修飾[14]。
進(jìn)一步研究發(fā)現(xiàn),除了甘氨酸被替代的變異,僅有2個錯義突變會導(dǎo)致表型嚴(yán)重的Ⅱ型OI(分別是p.His182Asp 及p.Arg234Cys)[1,15],其余突變均導(dǎo)致的是輕型OI及其他綜合征。在由丙氨酸或絲氨酸替代甘氨酸的突變中僅有少數(shù)為嚴(yán)重表型,而由半胱氨酸、纈氨酸和精氨酸替代的有近50%突變?yōu)閲?yán)重表型,≥50%由天冬氨酸和谷氨酸替代的突變會表現(xiàn)出嚴(yán)重致死型的表型??赡芘c氨基酸的大小及其酸堿性相關(guān),既往研究也表明相對分子質(zhì)量相對較小的丙氨酸和絲氨酸對膠原結(jié)構(gòu)的影響較小,而酸性氨基酸(天冬氨酸和谷氨酸)則影響較大。特別是那些在同一位點突變?yōu)椴煌被岬耐蛔?,所?dǎo)致的臨床表型不同。如在氨基酸第286位Gly286Ala的患者表現(xiàn)為Ⅳ型OI[16],而Gly286Val的患者就表現(xiàn)為嚴(yán)重的Ⅱ型OI[13]。
另外在長鏈中出現(xiàn)輕重表型交叉,還有可能和轉(zhuǎn)錄后修飾的位置相關(guān),如在氨基酸計數(shù)400~480區(qū)域較集中的出現(xiàn)所致嚴(yán)重表型的突變,就有可能是和第420位、441位及444位氨基酸轉(zhuǎn)錄后需要被羥化有關(guān),在這一區(qū)域突變會使羥化過程受到干擾,從而導(dǎo)致嚴(yán)重表型。
本文患兒所檢測到的突變位于c.3142G>T,p.Glu1048Cys,既往未報道。這一突變位于長鏈螺旋功能域,是Gly-Xaa-Yaa三肽重復(fù)中甘氨酸被半胱氨酸所替代。在氨基酸序列第1 048位前后目前已報道的突變中,均是導(dǎo)致嚴(yán)重表型的突變。本文胎兒在產(chǎn)檢超聲中已顯示股骨彎曲畸形,屬于Ⅱ型OI,符合嚴(yán)重臨床表型,與既往文獻(xiàn)報道相符。并結(jié)合基因突變在線預(yù)測軟件Mutation Taster的結(jié)果,可確定該突變導(dǎo)致患兒Ⅱ型OI。查詢既往文獻(xiàn)該區(qū)域?qū)儆冖裥湍z原的主要配基結(jié)合區(qū)域3(MLBR 3)[17],該區(qū)域?qū)δz原分子間交聯(lián)、核心蛋白聚糖的結(jié)合都有重要作用[18,19],故推測該區(qū)域突變致嚴(yán)重表型的原因與蛋白相互作用的功能相關(guān)。
本文通過產(chǎn)前超聲影像結(jié)合基因分型診斷1例胎兒為COL1A2基因新發(fā)突變(c.3142G>T,p.Glu1048Cys)所致Ⅱ型OI。結(jié)合表型基因型相關(guān)性分析,可初步得出在COL1A2基因編碼蛋白長鏈雙螺旋的400~480氨基酸及MLBR 3區(qū)域中甘氨酸被天冬氨酸或谷氨酸替代,多會導(dǎo)致嚴(yán)重表型的OI。本文同時也為產(chǎn)前準(zhǔn)確預(yù)測胎兒結(jié)局、指導(dǎo)臨床決策提供依據(jù)。
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(本文編輯:張崇凡)
A de novo COL1A2 gene mutation in a fetus with severe osteogenesis imperfect and phenotype-genotype correlation analysis
DONG Cheng1,4,LIUJIANG Rui-xuan1,4,YANG Lin1,REN Yun-yun2,ZHOU Wen-hao3(1 Children's Hospital of Fudan University,Shanghai 201102; 2 Obstertrics and Gynecology Hospital of Fudan University,Shanghai 200011; 3 The Molecular Genetic Diagnosis Center,Shanghai Key Lab of Birth Defect,Translational Medicine Research Center of Children Development and Disease,Pediatrics Research Institute,Children's Hospital of Fudan University,Shanghai 201102,China; 4 Co-first author)
Corresponding Author: ZHOU Wen-hao,E-mail: zwhchfu@126.com; REN Yun-yun,E-mail: renyunyun@ hotmail.com
AbstractObjective To summarize the clinical features and gene mutation characteristics of a de novo COL1A2 gene mutation in a fetus with severe osteogenesis imperfect (OI),and to provide evidence for prenatal counseling.Methods DNA was extracted from the fetal abortion tissues,and primers of the whole exons and splicing sites of COL1A1 and COL1A2 genes were designed.Using Sanger sequencing,the fetal sequences of the whole exons and splicing sites of COL1A1 and COL1A2 genes were analyzed and confirmed with the parents'samples.According to HGMD,literatures on clinical symptoms of the diseases caused by COL1A2 mutation were reviewed.Results The variants on both COL1A1 and COL1A2 gene were detected.On COL1A2 gene a de novo heterozygous mutation (c.3142G>T,p.Glu1048Cys) was detected,which had never been reported in dbSNP,HGMD and osteogenesis imperfecta&Ehlers-Danlos syndrome variant databases.Compared with the common database and online prediction software the mutation was predicted to be a the disease-causing mutation.HGMD professional version was searched with "COL1A2" and 387 disease-causing mutations were found to be related to 21 diseases or their subtypes.Ninety-two percent of the mutations caused OI or its subtypes; others caused Ehlers-Danlos syndrome or its subtype.Combined with the clinical symptoms of the disease caused by COL1A2 gene,the fetus was more consistent with the OI typeⅡ.Conclusion A fetus OI typeⅡcaused by a de novo mutation in COL1A2(c.3142G>T,p.Glu1048Cys) was diagnosed with prenatal ultrasound imaging and genotyping.Glycine in 400 to 480 amino acid and MLBR 3 region of the protein encoded by COL1A2 gene replaced by aspartate acid or glutamic will causebook=43,ebook=46sever OI.This article provides the basis for accurate prediction of fetal outcome and clinical decision-making.
Key wordsCOL1A2 gene; Osteogenesis imperfect; Mutation; Phenotype genotype correlation analysis
(收稿日期:2015-10-30修回日期: 2016-01-27)
通訊作者周文浩,E-mail: zwhchfu@126.com;任蕓蕓,E-mail: renyunyun@ hotmail.com
基金項目上海市科學(xué)技術(shù)委員會: 14411950402;新生兒嚴(yán)重神經(jīng)系統(tǒng)畸形規(guī)范化診治的多中心臨床研究;上海市科學(xué)技術(shù)委員會: 15XD1500800;上海市優(yōu)秀學(xué)術(shù)帶頭人新生兒常見出生缺陷疾病的分子遺傳研究
DOI:10.3969/j.issn.1673-5501.2016.01.011