嘉兴地区无创产前检测性染色体非整倍体病例的妊娠选择及妊娠结局分析

目的评估无创产前检测(non-invasive prenatal testing,NIPT)筛查性染色体非整倍体(sex chromosomal aneuploidy,SCA)的阳性预测值(positive predictive value,PPV),并调研家庭对于SCA胎儿的妊娠选择及妊娠结局分析。方法选择2015年2月至2019年2月在嘉兴市妇幼保健院产前诊断中心行NIPT的单胎孕妇,对NIPT发现的胎儿SCA孕妇的年龄、NIPT检测指征、介入性产前诊断、检测结果、妊娠选择及妊娠结局进行回顾性分析。结果共检测28 033例NIPT样本。共发现SCA病例102例,筛查阳性率为0.36%。经过遗传咨询,除28例拒绝外,74例胎儿SCA孕妇行介入性产前诊断,确诊胎儿SCA病例38例(PPV为51.35%),其中性染色体三体23例(47,XXX 8例,47,XYY4例,47,XXY11例),性染色体单体45,X0 9例和嵌合体4例(XXX[12]/46,XX[8]、mos,46,X,+mar[9]/45、X[6]mos45、X[16]/46,XN[19]mos45、X[8]/46,XX[22]各1例以及2例性染色体的微小缺失/微小重复。经过遗传咨询,28例拒绝介入性产前诊断孕妇中,24例选择继续妊娠,4例终止妊娠;确诊胎儿SCA的38例孕妇中,19例终止妊娠、19例选择继续妊娠,2组合计继续妊娠率为65.15%;排除胎儿SCA的36例孕妇均继续妊娠,经随访妊娠结局未见异常,没有假阴性。结论 NIPT作为一种安全、快速的产前筛查手段,能够在常染色体非整倍体筛查的同时完成部SCA的筛查;家庭可以根据自身情况选择继续妊娠还是终止妊娠,检测前及检测后的遗传咨询还需详细告知NIPT的局限性。     

莆田市28 307例孕中期产前筛查及产前诊断结果分析

目的分析莆田市孕妇孕中期产前筛查及产前诊断情况。方法对2015年8月~2016年7月莆田市地区参加产前筛查的单胎孕妇纳入研究,产前血清学三联筛查检测孕周为14-20+6w,无创产前DNA检测孕周为12-26+6w,对筛查高风险者及其他具有产前诊断指征的孕妇进行胎儿染色体核型分析并随访至胎儿出生。结果参与产前血清学三联筛查孕妇共27 882例,筛查高风险1101例,总阳性率为3.95%;参与无创产前DNA检测共1010例,筛查高风险10例,其中21/18/13高风险6例,4号染色体q12-q13.1重复4.6Mb 1例,性染色体异常3例,总阳性率0.99%,其中7例知情同意行介入性产前诊断,3例染色体核型分析结果为47,XN,+21,1例为47,XN,+18,余3例染色体核型分析结果均为正常;经遗传咨询后行介入性产前诊断孕妇共661例,胎儿染色体核型异常共45例,异常检出率为6.81%,占总筛查人数0.16%,无创产前DNA检测高风险与血清学三联筛查高风险染色体异常检测率比较差异有统计学意义。结论孕中期行产前筛查对莆田地区预测胎儿异常、降低缺陷儿的出生、提高人口素质发挥重要作用,但产前筛查存在一定的局限性,需要与有创性产前诊断相辅相成。     

额外小染色体与原发闭经(附4例报告)

我们发现4例原发闭经伴额外小染色体病例,其核型分别为;46,XX/47,XX mar;46,X,del(X)/47,X,del(X) mar;47,XX, mar;45,X/46,X, mar/46,X r.作者讨论了mar的发生率、起源、诊断、临床表现及产前诊断等问题.     

4611例血清学筛查胎儿高风险染色体核型及妊娠结局分析与无创基因检测应用探讨

目的探讨血清学筛查胎儿染色体非整倍体的效能、异常核型分布特点,为高风险孕妇进行无创产前基因检测(Non-invasive prenatal testing,NIPT)提供指导。方法统计我院2010年1月至2016年12月期间以血清学筛查高风险为指征(或指征之一)行产前诊断的异常核型,计算阳性预测值(positive predictive value,PPV)、异常核型构成比及妊娠结局。结果血清学筛查高风险行产前诊断的孕妇共4611例,检出异常核型282例,异常率为6.1%(282/4611);其中21三体(trisomy 21,T21)高风险最常见,共4448例占96.5%,检出138例T21(T21的PPV为3.1%)、68例结构异常、26例性染色体非整倍体、2例T13、1例T18和4例其他异常;T18高风险88例占1.9%,检出13例T18(PPV为14.7%)和4例结构异常;T21高风险伴T18高风险75例占1.6%,检出7例T21(PPV为9.3%)、17例T18(PPV为22.7%)、1例47,XXY和1例45,XN-13。低龄孕妇共3195例检出76例T21,T21的PPV为2.38%(76/3195),高龄孕妇共1416例检出69例T21,T21的PPV为4.87%(69/1416)。异常核型的构成比依次为:T21占51.4%、结构异常(非平衡性结构异常6例)占25.2%、T18占11.0%、性染色体非整倍体占9.6%、其他异常占1.8%、T13占0.7%;常见非整倍体T21/T18/T13/X/Y共205例占异常核型的72.7%(205/282),197例常见非整倍体、2例其它异常和1例46,XN,del(5)(p14)终止妊娠,其余均继续妊娠至分娩。结论血清学筛查高风险孕妇直接行产前诊断的阳性预测值较低,而且胎儿异常核型以常见非整倍体为主,非平衡性结构异常所占比例较小,高风险孕妇适宜NIPT二次筛查,从而显著减少介入性产前诊断。     

母源性染色体内插入致18q21.2-q22.3重复和缺失后代家系的遗传学分析

目的为1例具有全面发育障碍患儿生育史的孕妇提供产前诊断、家系分析和遗传咨询。方法选取2021年8月在西南医科大学附属医院接受产前诊断的孕妇作为研究对象, 采集先证者、孕妇及其丈夫的外周血样以及胎儿的羊水样本, 对其进行G显带染色体核型分析以及基因组拷贝数变异测序(CNV-seq), 根据美国医学遗传学与基因组学学会(ACMG)相关指南判读变异的致病性, 通过家系分析对变异进行溯源, 并评估其再发风险。结果孕妇、胎儿、先证者的染色体核型依次为46, XX, ins(18)(p11.2q21q22)、46, X?, rec(18)dup(18)(q21q22)ins(18)(p11.2q21q22)mat和46, XY, rec(18)del(18)(q21q22)ins(18)(p11.2q21q22)mat, 孕妇丈夫染色体核型未见异常。CNV-seq检测提示胎儿18q21.2-q22.3区存在19.73 Mb重复, 先证者18q21.2-q22.3区存在19.77 Mb缺失。重复和缺失片段均与孕妇染色体的插入片段相同。根据ACMG指南, 均评估为致病性变异。结论孕妇携带的18q21....     

45,X/46,X,i(Xq)伴4号染色体长臂部分缺失一例及文献复习

目的探讨45,X,del(4)(pter→q33:)/46,X,i(Xq),del(4)(pter→q33:)的产生、主要表现及特征,阐述产前筛查实验的重要性。方法与结果在孕早、中期利用超声检查和母亲血清生化指标进行产前筛查实验,对有异常指标的胎儿可利用孕早期绒毛培养及孕中期羊水细胞培养和脐静脉穿刺等方法检测胎儿染色体核型,可提高染色体异常的检出率。结论产前诊断可以有效预防染色体缺陷的患儿出生,减少家庭和社会的巨大压力。     

高通量测序在胎儿性染色体非整倍体异常检测中的临床应用

目的探讨高通量基因测序技术在诊断胎儿性染色体异常中价值。方法选择2015年01月01日至2016年12月31日于盐城市妇幼保健院产前诊断中心行无创胎儿DNA检测8645例,对提示性染色体异常孕妇行侵入性产前诊断。结果 8645例NIPT孕妇,提示性染色体异常48例,筛查阳性率0.56%。其中42例行侵入性产前诊断,17例与筛查结果一致,其中(45,XO)4例,(47,XXX)5例,(47,XXY)4例,(47,XYY)4例,羊水培养失败1例,NIPT检测准确率41.46%(17/41)。结论 NIPT进行胎儿性染色体非整倍体异常的检测是可行的,但仍需侵入性诊断进一步确诊,NIPT对性染色体三体的准确性高于性染色体单体。     

75例孕中期性染色体异常的细胞遗传学分析

目的通过分析孕中期不同的高危指征与胎儿性染色体异常之间的联系,探讨性染色体异常的产前诊断指征。方法统计分析2009年1月至2014年4月,来我院遗传门诊行羊膜腔穿刺的15 920例患者,制备染色体和核型分析。结果 15 920例羊水产前诊断标本,共检测出75例性染色体异常,其中以17例45,X;10例46,X,inv(Y);9例45,X(m)/46,XX(n);9例47,XXY等为主。结论孕妇在孕中期具有唐氏血清学筛查高危、高龄妊娠或B超检查软指标异常或父母地贫携带者等,这类孕妇具有生育出携带性染色体数目异常或结构构异常胎儿的风险。做好产前诊断是减少出生缺陷儿的重要举措。     

孕妇外周血胎儿游离DNA产前筛查胎儿染色体非整倍体疾病结果分析

目的分析孕妇外周血胎儿游离DNA产前筛查胎儿染色体非整倍体疾病结果。方法随机选取2015年5月至2017年5月我院收治的接受外周血胎儿游离DNA检测孕妇500例,检测游离胎儿DNA、染色体核型,然后对外周血游离胎儿DNA检测结果、外周血游离胎儿DNA检测结果和核型分析结果进行分析。结果 500例孕妇中,染色体非整倍体异常7例,达到了1.4%的阳性率,在孕妇类型方面,3例为唐筛高风险孕妇,2例为高龄孕妇,1例为超声胎儿异常孕妇,1例为其他异常孕妇;在异常类型方面,4例21-三体异常,1例13-三体异常,1例18-三体异常,1例性染色体异常。均愿意接受介入性产前诊断,确诊6例染色体非整倍体异常,其中21-三体异常3例,13-三体异常1例,18-三体异常1例,性染色体异常1例,达到了85.7%的符合率、100.0%的检出率。在核型方面,45,X(28)/46,XX(22)1例,达到了100.0%的诊断符合率。结论孕妇外周血胎儿游离DNA产前筛查胎儿染色体非整倍体疾病结果令人满意。     

无创DNA检测技术在产前筛查中的临床应用

目的探讨无创DNA产前检查(NIPT)在胎儿染色体非整倍体疾病诊断中的临床应用价值及意义。方法对2015年3月到2016年12月在嘉兴市妇幼保健院产前诊断中心就诊的11 654例孕妇,进行外周血游离胎儿DNA检测。孕周介于12-26~(+6)w,指征包括血清学筛查临界风险的孕妇;部分血清学筛查高风险孕妇、高龄或其他原因强烈要求进行该项检测的孕妇。采集孕妇外周血10ml,分离血浆,利用新一代高通量测序分析,对高风险结果进行介入性产前诊断验证,所有病例进行电话随访。结果共检测11 654例,检出各类异常92例,37例21-三体,18例18-三体,3例13-三体,34例性染色体异常,共有84例进行了介入性产前诊断。37例21-三体阳性者中,33例与介入性诊断结果一致,2例假阳性结果,2例由于死胎未做进一步诊断。18例18-三体阳性者中,11例与介入性诊断结果一致,5例假阳性结果,2例死胎未做进一步诊断。3例13-三体阳性结果的孕妇,1例介入性诊断确诊为13-三体,另有2例为假阳性结果。34例性染色体异常者中,有29例进行了介入性产前诊断,14例确诊为性染色体异常,15例假阳性结果。结论无创DNA产前检测技术对21-三体检测有较高的敏感性和特异性,可大幅减少介入性产前诊断,为临床诊断唐氏综合征提供依据;其高准确性、无创伤性的优点将使其成为未来产前筛查的主要手段。     

大连地区78例Turner综合征的临床特征与染色体核型分析

目的探讨Turner综合征（TS）不同核型的遗传学特征、临床特点及其所占比例。方法成人外周血染色体核型分析,高危孕妇羊水染色体核型分析。结果成人外周血检测发现TS 75例,羊水检测发现TS 3例。78例患者中,45,XO 32例（41%）,45,XO/46,XX嵌合型10例（12.8%）,45,XO/46,XX/47,XXX嵌合型2例（2.6%）,45,XO/47,XXX嵌合型4例（5.1%）,46,X,i（X）4例（5.1%）,45,XO/46,X,i（X）嵌合型9例（11.5%）,46,X,del（Xp-）7例（9.0%）,46,X,del（Xq-）7例（9.0%）,45,XO/46,X,del（Xp11）嵌合型2例（2.6%）,45,XO/46,X,del（Xq21）嵌合型1例（1.3%）。结论 TS核型主要包括X单体型,X单体嵌合型和结构畸变型及其嵌合型三种,45,XO的X单体型为本综合症的主要类型;不同核型患者临床表现可存在差异;对有相关临床表现的女孩争取做到早诊断,早治疗;对部分具有一定生育能力的TS患者做好产前诊断,做到优生优育。     

Chromosome mosaicism in 6,000 amniocenteses

Multiple cell-multiple flask mosaicism was found in 0.20% of 6,000 amniocenteses, and multiple cell-single flask mosaicism was found in 0.92%. Multiple cell-multiple flask mosaicism usually was found in fetal or infant tissues at delivery or elective abortion. Most multiple cell-multiple flask mosaicism involved sex chromosomes and was either 45, X/46, XY or 45, X/46, XX. Except for one fetus with 45, X/46, XX and an aortic coarctation, phenotypic abnormalities associated with sex chromosome mosaicism were not found in these patients. One normal boy has continued to show 45,X mosaicism during the first 4 years of life. Autosome abnormalities found in multiple cell-multiple flask mosaicism included del(18q) associated with fetal anomalies. Apparently normal phenotypes were associated with prenatal trisomy 17, two de novo supernumerary marker chromosomes, and monosomy 21. Since an aberrant cell line present in only one primary amniotic fluid cell culture was occasionally identified from another amniocentesis or at birth, multiple cell-single flask mosaicism involving a sex chromosome or a viable autosome abnormality cannot be assumed to be an in vitro event. Maternal cell contamination, which was found in 0.49% of amniocenteses, could have resulted in an erroneous diagnosis of fetal sex in two cases if cells from independent culture vessels were not examined.     

Confirmatory testing illustrates additional risks for structural sex chromosome abnormalities in fetuses with a non‐invasive prenatal screen positive for monosomy X

More and more women rely on non‐invasive prenatal screening (NIPS) to detect fetal sex and risk for aneuploidy. The testing applies massively parallel sequencing or single nucleotide polymorphism (SNP) microarray to circulating cell‐free DNA to determine relative copy number. In addition to trisomies 13, 18, and 21, some labs offer screening for sex chromosome abnormalities as part of their test. In this study, an index neonate screened positive for monosomy X and had discordant postnatal chromosomes indicating an X;autosome translocation. This patient prompted a retrospective chart review for similar cases at a large NIPS testing center. The review found 28 patients with an abnormal NIPS for monosomy X who were eventually diagnosed with additional discrepant structural sex chromosome abnormalities including translocations, isochromosomes, deletions, rings, markers, and uniparental disomy. The majority of these were mosaic with monosomy X, but in seven cases, there was no evidence of mosaicism on confirmatory testing. The identification of multiple sex chromosome aneuploidies in these cases supports the need for additional genetic counseling prior to NIPS testing and following abnormal NIPS results that are positive for monosomy X. This finding broadens our knowledge about the variable outcomes of positive monosomy X NIPS results and emphasizes the importance of confirmatory testing and clinical follow up for these patients.     

Pregnancy outcome and prenatal diagnosis of sex chromosome abnormalities in Hawaii, 1986-1999

Sex chromosome abnormalities such as Turner syndrome, Klinefelter syndrome, triple X syndrome, and 47,XYY can be prenatally diagnosed and electively terminated. This investigation examined the pattern of pregnancy outcome of prenatally and postnatally diagnosed sex chromosome abnormalities in Hawaii during 1986-1999 and calculated prenatal diagnosis and subsequent elective termination rates for various factors. Data were obtained from a statewide population-based birth defects registry. The study included 205 detected sex chromosome abnormality cases of which 93 (45%) were live births, 18 (9%) late fetal deaths, 37 (18%) early fetal deaths, and 57 (28%) elective terminations. Pregnancy outcome distribution varied by type of sex chromosome abnormality. Prenatal diagnosis was reported for 132 (64%) of the cases, of which 46 (35%) were subsequently electively terminated. Eleven cases were elective terminations where the sex chromosome abnormality was diagnosed after delivery. Elective termination rates subsequent to prenatal diagnosis differed by sex chromosome abnormality, being highest for 45,X (54%), followed by 47,XXY (46%), 47,XYY (29%), and 47,XXX (17%). Although prenatal diagnosis rates increased significantly over the time period (P = 0.006), the subsequent elective termination rate declined slightly, albeit the trend was not statistically significant (P = 0.440). The prenatal diagnosis rate was highest for the 35-39-year maternal age group, although this age group did not have subsequent elective termination rates higher than other maternal age groups. Pregnancy outcome distribution and prenatal diagnosis and subsequent elective termination of sex chromosome abnormalities appeared to depend on the type of sex chromosome abnormality, year of delivery, and maternal age.     

Significance of a prenatally diagnosed del(10)(q23)

Structural chromosome mosaicism is rare. We report a case of prenatal mosaicism for a deletion of chromosome 10(q23). To our knowledge, there are only three reports of prenatally diagnosed cases of del(10)(q23). Two of these cases were due to an inherited fragile site. In the present case amniocentesis revealed 46,XY,del(10)(q23)[9]/46,XY[45]. Follow‐up chromosome analysis of peripheral blood and placental tissue from a phenotypically normal liveborn male revealed the del(10)(q23) in only 3/100 blood cells grown in low‐folate medium. It appears that prenatally diagnosed deleted (10q) mosaicism represents culture artifact and is not clinically significant. © 2002 Wiley‐Liss, Inc.     

Significance of a prenatally diagnosed del(10)(q23).

Structural chromosome mosaicism is rare. We report a case of prenatal mosaicism for a deletion of chromosome 10(q23). To our knowledge, there are only three reports of prenatally diagnosed cases of del(10)(q23). Two of these cases were due to an inherited fragile site. In the present case amniocentesis revealed 46,XY,del(10)(q23)[9]/46,XY[45]. Follow-up chromosome analysis of peripheral blood and placental tissue from a phenotypically normal liveborn male revealed the del(10)(q23) in only 3/100 blood cells grown in low-folate medium. It appears that prenatally diagnosed deleted (10q) mosaicism represents culture artifact and is not clinically significant.     

Familial deletion 11q14.3-q22.1 without apparent phenotypic consequences: a haplosufficient 8.5 Mb region

We present the prenatal diagnosis of a chromosome 11q14.3-q22.1 deletion identified in three generations without apparent phenotypic consequences. A 25-year-old G2, P1 woman underwent amniocentesis at 15 weeks' gestation because of a positive result for Down syndrome maternal serum-screening test (1/70). The fetal karyotype revealed an interstitial deletion of the long arm of chromosome 11 confirmed by CGH and FISH: 46,XX,del(11)(q14.3q22.1). The mother and grandfather of the fetus presented the same interstitial deletion with a little if any phenotype effect. The pregnancy was carried to term and resulted in the birth of a normal girl. To our knowledge, only one case of a chromosome 11q14.3-q21 deletion without phenotypic anomalies has been reported. Our study allows the initially described haplosufficient region to be extended from 3.6 Mb to at least 8.5 Mb. This large deletion was compatible with fertility and apparently normal phenotype. Identification of such chromosomal regions is important for prenatal diagnosis and genetic counseling.     

Abnormal chromosome 9 in a neonate program. Report of three cases

We describe three cases with abnormal chromosome 9. Patient 1 shows translocation in a homologous chromosome, with a karyotype of 46,XX,t(9;9)(9pter----cen----9pter; 9qter----cen::9q13----9qter), 1qh+. This case has a variety of anomalies, including brain anomalies. Patient 2 shows a partial trisomy 9p with a karyotype of 47,XY,+del(9)(pter----q11:). The patient has the typical clinical features of 9p trisomy syndrome. Patient 3 is unique because of partial 9p tetrasomy mosaicism without phenotypic abnormalities; the karyotype is mos 46,XY/47,XY,+dic(9)(pter----cen----q21::q21----cen----pter).     

Confirmation of prenatal diagnosis of sex chromosome mosaicism

Prenatal diagnosis of mosaicism causes problems in interpretation and in genetic counselling. Part of the difficulty with any prenatal diagnosis of mosaicism is interpretation of results without knowing the exact origin, embryonic or extraembryonic, of the abnormal cell line. To confuse the issue in cases of prenatal diagnosis of 45,X/46,XY mosaicism is the recent demonstration that a diagnosis of 45,X/46,XY made prenatally is not necessarily associated with the same phenotype as when diagnosed postnatally. We present two cases of prenatal diagnosis of sex chromosome mosaicism (45,X/46,XY and 45,X/47,XYY). Posttermination examination of the phenotypically normal male fetuses and their placentas established that the placenta was the most likely source of the 45,X cell line. An approach to confirming the prenatal diagnosis of sex chromosome mosaicism and establishing its origin utilizing detailed cytogenetic examination of both fetus and placenta is suggested.     

荧光原位杂交技术在遗传病诊断中的应用

目的探讨荧光原位杂交(fluorescenceinsituhybridization,FISH)技术在遗传病和产前诊断中的应用价值。方法应用着丝粒探针、特异性序列探针及染色体涂染探针等对36例常规核型分析疑有染色体异常患者的外周血和45例进行产前诊断的孕妇羊水间期细胞或中期分裂相进行FISH检测。结果检出的染色体异常类型有45,X、45,X/46,XX、45,X/46,Xr(X)、46,X,i(Xq)、47,XXY、46,XX,t(4;7)、47,XYY、47,XXX、47,XXY,inv(7)、46,XY,inv(7)、47,XX, 21,同时产前诊断出两例异常胎儿,分别是47,XX, 18和46,XY,der(15)t(Y;15)。结论FISH技术可以准确、快速地诊断各种染色体异常,是传统细胞遗传学的必要补充,可广泛用于遗传病诊断及产前诊断。