重组8号染色体综合征胎儿1例的临床特征及遗传学分析

目的探讨重组8号染色体(Rec8)综合征胎儿的临床特征和分子遗传学致病机制。方法选取2021年7月20日因"无创产前检测(NIPT)提示胎儿性染色体非整倍体高风险(胎龄为21周)"至山东第一医科大学附属省立医院确诊为Rec8综合征胎儿为研究对象。收集胎儿临床资料, 进行胎儿羊水染色体G显带核型分析及染色体微阵列芯片分析(CMA), 对其父母进行外周血染色体G显带核型分析。结果胎儿胎龄为23周时, 产前胎儿超声提示胎儿眼距宽、唇厚、肾盂分离、肝脏强回声及室间隔缺损。其羊水核型分析结果为46, XX, rec(8)(qter→q22.3::p23.1→qter), CMA检测结果为arr[GRCh37]8p23.3p23.1(158049₆793322)×1, 8q22.3q24.3(101712402₁46295771)×3。胎儿母亲核型为46, XX, inv(8)(p23.1q22.3), 父亲核型正常。结论最终被确诊Rec8综合征胎儿的Rec8变异来源于其母亲的8号染色体臂间倒位。该Rec8综合征断裂点是1个新的断裂点。     

1例携带者筛查意外发现的X染色体长臂部分缺失孕妇的遗传学分析及产前诊断

目的 对携带者筛查意外发现的1例X染色体长臂部分缺失的孕妇进行遗传学分析并为其提供产前诊断。方法 提取孕妇外周全血基因组DNA进行基于毛细管电泳技术的携带者筛查，采用多重连接依赖探针扩增技术（MLPA）和染色体微阵列芯片分析（CMA）进行验证，染色体核型G显带技术分析外周血染色体核型，并提取羊水胎儿脱落细胞DNA进行CMA分析。结果 携带者筛查的结果提示孕妇携带PLP1基因杂合缺失，MLPA结果提示孕妇PLP1基因第2～8号外显子杂合缺失，染色体核型和CMA结果均证实其携带X染色体q13.3q23区段杂合缺失，且胎儿羊水细胞存在同样片段的染色体杂合缺失，最终决定终止妊娠。结论 扩展性携带者筛查发现孕妇X染色体长臂部分缺失，并将其传递给胎儿。     

染色体微阵列产前诊断8q13.3微缺失一例

目的应用染色体微阵列分析(chromosome microarray analysis,CMA)技术对1例超声结构异常胎儿进行全基因组拷贝数变异(copy number variations,CNVs)检测,探讨CMA在超声结构异常胎儿产前诊断中的意义。方法应用常规G显带染色体核型分析胎儿及其父母的染色体核型,应用CMA技术分析胎儿及其父母的CNVs。结果G显带核型分析显示胎儿核型与母亲一致,为46,XN,t(8;11)(q21.2;q13)mat,父亲核型正常;父母CMA检测结果均未见异常;胎儿的检测结果为arr[GRCh37]8q13.3(71314082-73322915)×1,提示一条8号染色体的8q13.3区域发生2.00 Mb缺失。结论超声结构异常胎儿染色体核型分析检出的平衡易位,需借助CMA等技术进一步确定是否存在微缺失微重复。     

核型分析结合单核苷酸多态性微阵列技术在一父源性染色体平衡易位家系中的应用

目的用常规羊水穿刺核型分析方法对胎儿诊断疑似核型不平衡易位的患者,应用单核苷酸多态性微阵列(SNP-array)技术进行进一步检测,并探讨SNP-array技术在产前诊断中的应用价值。方法对1位染色体平衡易位患者的妻子羊水穿刺进行核型分析后,再补充进行SNP-array对胎儿的全基因组进行检测,以排除基因亚微突变胎儿的出生。结果此夫妻第三胎染色体核型46,XY,13q+,芯片结果46,XY,der(13)t(9;13)(p21;q33)。此夫妻第四胎核型结果正常,SNP-array基因检测,结果显示该病例染色体8q23.1位置发现286kb片段缺失,内含OMIM基因TRHR。结论对核型分析诊断不明确的易位,行SNP基因芯片分析有助于检出染色体亚微结构的畸变,具有较好的临床应用价值。     

21号环状染色体嵌合体胎儿2例的临床特征和遗传学分析

目的探讨2例21号环状染色体嵌合体胎儿的围产期临床表型和遗传学特征。方法选取2021年11月在厦门市妇幼保健院接受介入性产前诊断的2例胎儿为研究对象。收集2例胎儿的临床资料, 应用常规G显带核型分析和染色体微阵列分析(CMA)对2例胎儿及其父母进行遗传学检测。结果胎儿1超声提示胎儿鼻骨未显示、室间隔缺损、永存左上腔静脉、三尖瓣轻度返流, 染色体核型结果为46, X?, dic r(21;21)(p12q22;q22p12)[41]/45, X?, -21[9], CMA检测结果提示其染色体21q11.2q22.3区存在30.00 Mb片段的4拷贝, 21q22.3区存在3.00 Mb片段的缺失。胎儿2超声提示鼻骨呈点状回声, 核型为46, X?, r(21)(p12q22)[83]/45, X?, -21[14]/46, X?, dic r(21;21)(p12q22;q22p12)[3], CMA结果提示其染色体21q22.12q22.3区存在5.10 Mb片段的4拷贝, 21q22.3区存在2.30 Mb片段的缺失。结论 2例21号环状染色体嵌合体的围产期表型与靠近染色体缺失断裂位...     

环状染色体综合征孕妇的遗传学分析及产前诊断

目的 对2例智力低下的孕妇进行细胞及分子遗传学检测，寻找致病原因，并对其胎儿进行产前诊断。方法 收集2例孕妇的临床资料，对其进行外周血细胞染色体G显带核型分析和（或）染色体微阵列分析（CMA），并对其胎儿进行相应的产前诊断。结果 病例1：孕妇外周血染色体核型为46,XX,r(6)(p25.3q27)[82]/45,XX,-6[11]/46,XX,dic r(6;6)(p25.3q27;p25.3q27)[6]/46,XX,-6,+mar[1],CMA结果为arr[hg19]6p25.3(156,974-302,273)×1,6q27(166,612,359-170,914,297)×1；其胎儿羊水细胞染色体核型为46,XN,CMA结果为arr[hg19]16p11.2(29,591,326-30,177,240)×3。病例2：孕妇外周血染色体核型为46,XX,r(13)(p12q34)[77]/46,XX,dic r(13;13)(p12q34;p12q34)[13]/45,XX,-13[9]/46,XX[1]，未行CMA检测；其胎儿羊水细胞染色体核型为46,XN,CMA结果正常。结论...     

Xp11.22等臂双着丝粒型Turner综合征2例的产前诊断及遗传学分析

目的探讨Turner综合征(TS)中Xp11.22等臂双着丝粒结构异常的遗传学特征。方法选取分别于2020年10月与2020年6月就诊于成都市妇女儿童中心医院的2例孕妇及其疑似性染色体异常或超声结果提示异常的胎儿为研究对象。收集2例孕妇的羊水样品进行G显带染色体核型分析、染色体微阵列(CMA)及荧光原位杂交(FISH)检测, 并进行遗传学诊断。结果胎儿1的染色体核型均为45, X[47]/46, X, psu idic(X)(p11.2)[53], 胎儿2染色体核型为46, X, psu idic(X)(p11.2)。CMA结果提示2例胎儿均存在Xp22.33p11.22区域缺失及p11.22q28区域重复。FISH结果提示2例胎儿的着丝粒位于1条等臂X染色体上。结论染色体核型分析、FISH和CMA联合检测诊断出2例Turner综合征胎儿, 对染色体复杂结构异常的诊断具有一定辅助作用。高分辨率CMA可以精确定位染色体断裂重排位点, 对断裂重排机制研究可提供依据。     

9p重复伴8p末端缺失胎儿的遗传学分析并文献复习

目的对1例产前异常胎儿及其双亲行细胞遗传学及分子遗传学研究,以明确胎儿异常遗传物质的来源及其发生机制。探讨染色体微阵列分析(Chromosomal Microarray Analysis,CMA)在临床产前诊断中的临床价值。方法对患儿脐血及其双亲外周血进行常规G显带分析,进一步应用CMA对患儿进行全基因组拷贝数分析。结果 G显带核型分析提示胎儿脐血染色体核型结果为46,XX,der(8)(?::p23→qter),其母亲外周血核型结果为46,XX,t(8,9)(p23,p22),父亲核型未见异常。胎儿衍生8号染色体来源于携带平衡易位染色体的母亲。CMA检测提示胎儿存在9p21.3-p24.3区域22.666Mb的重复片段及8p23.2-p23.3末端4.413Mb的缺失片段。胎儿核型最终修正确定为46,XX,der(8)t(8,9)(p23.2,p21.3)mat。结论胎儿染色体9p重复伴8p末端缺失可能造成出生后的严重异常表型,本文对该患胎进行了产前诊断及遗传学分析,为临床产前诊断和遗传咨询提供了有力依据。     

一例染色体复杂易位患儿的细胞-分子遗传学（CNV）研究

目的探讨染色体复杂易位的断裂位点及细胞-分子遗传学特点,提高对染色体复杂易位的诊断能力。方法采集患儿及其父母外周血行淋巴细胞染色体核型分析,通过高通量测序染色体组拷贝数分析(CNV)确诊患儿为罕见的复杂易位。结果患儿外周血染色体核型分析结果为46,XY,t(3;5;5;12)(q23;q15;q31;p13),inv(6)(q13q27),父母染色体核型均正常;CNV检出患儿5q15q21.1(97100001-101920000)缺失4.82Mb,5q23.1q23.2(117200001-123180000)缺失5.98Mb,7q36.1q36.2(152540001-153400000)重复0.86Mb。结论结合多种检测技术可深入研究染色体复杂易位的细胞-分子遗传学特点。     

联合应用多种遗传学方法鉴定1例嵌合型胎儿微小额外标记染色体

目的联合应用染色体微阵列分析(CMA)、荧光原位杂交(FISH)和染色体核型分析对1例嵌合型微小额外标记染色体(sSMC)进行鉴定。方法以2022年深圳市龙华区妇幼保健院无创产前检测(NIPT)提示胎儿染色体4q12-4q13.1区存在8.75 Mb重复的1例孕妇作为研究对象, 采集羊水样本与夫妇双方的外周血样进行染色体G显带核型分析, 用CMA鉴定sSMC的来源和大小, 之后用FISH对羊水中sSMC的嵌合比例进行进一步的确定。结果孕妇外周血G显带染色体核型为46, XX, 其丈夫为46, XY, inv(9)(p12q12), 胎儿为47, XY, inv(9)(p12q12)pat, +mar[75]/46, XY, inv(9)(p12q12)pat[25]。羊水CMA检测结果为arr[hg19]4p11q13.1(48978053₆3145931)×3, 并未显示嵌合。FISH检测经培养的分裂间期的羊水细胞中59%包含3个4号染色体的着丝粒信号, 复抽羊水检查, 有65%的分裂间期羊水细胞包含3个4号染色体着丝粒信号, 证实羊水为三体嵌合体。结论结构异常...     

一例表现为主动脉瓣狭窄的非典型Williams-Beuren综合征患儿的遗传学诊断及分析

目的对1例主动脉瓣狭窄的患儿进行遗传学诊断,分析其发病机制。方法采用常规G显带染色体分析、微阵列比较基因组杂交(array comparative genomic hybridization,aCGH)及多重连接探针扩增(multiplex ligation-dependent probe amplification,MLPA)技术分析患儿及其父母的染色体核型和基因组拷贝数变异。结果患儿及其父母的外周血染色体核型均未见异常。aCGH检测显示患儿7q11.23区存在278 kb杂合缺失,与Williams-Beuren综合征(Williams-Beuren syndrome,WBS)关键区部分重叠,涉及WBS的关键致病基因之一ELN。MLPA检测证实患儿存在上述缺失,患儿父母未发现染色体微重复/微缺失。结论患儿7q11.23区杂合缺失为新发突变。ELN基因单倍剂量不足可能是其发生主动脉瓣狭窄的原因,诊断为非典型WBS。     

一例2q37微缺失综合征患儿的遗传学分析

目的:对1例2q37微缺失综合征患儿进行诊断和精细定位。方法:对患儿进行染色体G显带、多重连接探针扩增(multiplex ligation-dependent probe amplification,MLPA)、单核苷酸多态性微阵列(single nucleotide polymorphism array,SNP-a...     

一例22号环状染色体合并22ql3微缺失综合征患儿的临床及遗传学分析

目的探讨1例语言发育滞后患儿的遗传学病因。方法对患儿进行外周血染色体G显带分析以及单核昔酸多态性微阵列芯片(single nucleotide polymorphism microarray,SNP array)检测。结果患儿染色体核型为46,XY,r(22)(pll.2ql3),SNP array检测在22ql3区发现一处1.67 Mb的缺失,具体为arr[Hgl9]22ql3.33(49531302〜51197766)X1O结论患儿同时携带22号环状染色体以及22ql3微缺失,为明确其病因和遗传咨询提供了重要的线索。     

Maternal transmission of interstitial 8p23.1 deletion detected during prenatal diagnosis

We report on the first prenatally diagnosed interstitial 8p23.1 maternally inherited deletion. At 20 weeks of gestation (WG) the fetus was diagnosed with a complete atrioventricular canal. In infancy, the mother underwent a two‐step cardiac surgery for an interrupted aortic arch type A associated to an inlet ventricular septal defect (VSD). A straddling of the tricuspid valve type B was confirmed during surgery. The outcome showed no cardiac failure or conduction anomalies. However, she presented with moderate intellectual disability. Classical and molecular cytogenetic studies on amniotic and maternal lymphocytes cells showed a nearly identical interstitial deletion of the 8p23.1 region encompassing the GATA4 gene locus (Mother: nt 6,913,337–12,580,828, fetus: nt 7,074,449–12,580,828) with no modification of the telomeric region. The relevance of our report is not only the maternal syndromic interstitial 8p23.1 deletion, but also maternal transmission which has never been reported before. The maternal and fetal phenotypes were not identical, however, even though they had the same cellular and molecular background: an alteration of the epithelial mesenchymal transition of the atrioventricular valvulo‐septal complex where GATA4 plays a positive role in the regulation. We reviewed all cases of interstitial 8p23.1 deletions diagnosed either prenatally or postnatally. © 2012 Wiley Periodicals, Inc.     

Molecular characterization of del(8)(p23.1p23.1) in a case of congenital diaphragmatic hernia

A 36-week-old fetus was referred to the medical center because of his cystic mass and fluid in left thoracic cavity, and was delivered by cesarean section to manage neonatal problems at 37 weeks of gestation. Emergent surgical repair of the left diaphragmatic hernia was performed, but severe hypoxia persisted, and he expired on the following day. Chromosome analysis of cultured amniotic fluid cells indicated 46,XY,del(8)(p23.1p23.1). This is the fourth case of 8p23.1 deletion associated with diaphragmatic hernia. Microarray comparative genomic hybridization analysis using DNA of cultured amniotic fluid cells showed that six clones were deleted, which were mapped to the region between two low copy repeats (LCRs) at 8p23.1 previously described. Microsatellite analysis revealed that the deletion was of paternal origin, and his parents did not carry 8p23.1 polymorphic inversion. These data strongly suggested that the 8p23.1 interstitial deletion should have arisen through a different mechanism from that of inv dup del(8p) whose structural abnormality is always of maternal origin and accompanies heterozygous 8p23.1 polymorphic inversion in mother.     

Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1

Ebstein anomaly is an uncommon congenital heart defect (CHD), characterized by downward displacement of the tricuspid valve into the right ventricle. To uncover the genetic associations with Ebstein anomaly, we have searched chromosomal imbalances using standard cytogenetic and array‐CGH analysis, and single gene conditions associated with syndromic Ebstein anomaly (with extracardiac anomalies), and screened GATA4 and NKX2.5 mutations in nonsyndromic patients (without extracardiac anomalies). Between January 1997 and September 2009, 44 consecutive patients with Ebstein anomaly were evaluated in two centers of Pediatric Cardiology. Ebstein anomaly was syndromic in 12 (27%) patients, and nonsyndromic in 32 (73%). A recognizable syndrome or complex was diagnosed by clinical criteria in seven patients. In one syndromic patient an 18q deletion was diagnosed by standard cytogenetic analysis. Array‐CGH analysis performed in 10 of the 12 syndromic patients detected an interstitial deletion of about 4 Mb at 8p23.1 in one patient, and a deletion 1pter > 1p36.32/dup Xpter‐ > Xp22.32 in another patient. In the 28 of 32 nonsyndromic patients who underwent molecular testing, no mutation in GATA4 and NKX2.5 genes were detected. We conclude that Ebstein anomaly is a genetically heterogeneous defect, and that deletion 1p36 and deletion 8p23.1 are the most frequent chromosomal imbalances associated with Ebstein anomaly. Candidate genes include the GATA4 gene (in patients with del 8p23.1), NKX2.5 (based on published patients with isolated Ebstein anomaly) and a hypothetical gene in patients with del 1p36). © 2011 Wiley‐Liss, Inc.     

两例分别由父源性平衡易位和母源性插入易位导致8p部分三体智力低下患儿的临床表型和遗传学分析

目的 明确两例智力低下患儿8号染色体短臂异常性质和来源,分析其染色体改变与表型的相关性.方法 首先应用常规G显带分析2例患儿及父母外周血染色体改变,然后应用比较基因组杂交芯片(array comparative genomic hybridization,array CGH)对其中1例常规核型分析的结果进行精确定位.结果 例1母亲的染色体改变为8p和3q的平衡插入易位,该患儿继承了母亲的1条衍生3号染色体,核型为46,XX,der(3) inv ins (3;8)(q25.3;p23.1p11.2)mat,导致8p部分三体.Array CGH分析显示重复区域为8p11.21-8p22,片段大小为26.9 Mb,该患儿主要表现为智力低下,未见其他8p三体的典型临床特征.例2父亲的核型为8p和11q的平衡易位,该患儿继承了父亲的1条衍生11号染色体,核型为46,XX,der(11)t(8;11)(p11.2;q25)pat,临床表现为智力低下,特殊面容,同时伴有先天性心脏病和骨骼异常,与典型8p三体表型相似,但面容特征不典型.结论 8p部分三体是2例患儿异常表型的主要原因,但与典型的8p三体相比,表型存在异质性;父母染色体分析可以帮助明确易位的性质从而有利于再发风险评估;与传统的细胞遗传学分析方法相比,arrayCGH在染色体异常分析中具有更高的分辨率和准确性.

Abstract：

Objective To determine the origin of aberrant chromosomes involving the short arm of chromosome 8 in two mentally retarded children, and to correlate the karyotype with abnormal phenotype. Methods Routine G-banding was performed to analyze the karyotypes of the two patients and their parents, and array comparative genomic hybridization (array CGH) was used for the first patient for fine mapping of the aberrant region. Results The first patient presented with only mental retardation. The father had normal karyotype. The mother had an apparent insertion translocation involving chromosomes 8 and 3 [46,XX, inv ins (3;8) (q25.3;p23.1p11.2)], the karyotype of the child was ascertained as 46,XX,der(3) inv ins (3;8)(q25.3;p23.1p11.2). Array CGH finely mapped the duplication to 8p11.21-8p22, a 26.9Mb region. The other patient presented with mental retardation, craniofacial defects, congenital heart disease and minor skeletal abnormality. The mother had normal karyotype. The father had an apparently balanced translocation involving chromosome 8p and 11q, the karyotype was 46,XY, t(8;11)(p11.2;q25). The karyotype of the child was then ascertained as 46,XX,der(11)t(8;11)(p11.2;q25). Conclusion These results suggested that partial trisomy 8p was primary cause for the phenotypic abnormalities of the two patients, whereas a mild phenotypic effect was observed in patient 1. Parental karyotype analysis could help define the aberrant type and recurrent risk evaluation. In contract to routine karyotype analysis, aberrant regions could be mapped by array CGH with higher resolution and accuracy.