1例3p部分三体综合征患儿的临床表型与遗传学分析

目的 明确1例体格发育异常合并多发畸形患儿染色体拷贝数变异的性质和来源，并分析基因与表型相关性。方法 采用G显带染色体核型分析及单核甘酸多态性微阵列芯片（SNP-array）技术对患儿进行检测，并用荧光原位杂交（FISH）进行验证。患儿父母外周血样本进行染色体核型分析及其母亲外周血样本进行荧光原位杂交（FISH）分析。结果 G显带染色体核型结果为：46,XY,der(2)t(2;3)(p25.3;p24.1),SNP-array分析结果显示患儿染色体3p26.3p24.1存在30.4Mb重复，2p25.3存在1.39Mb缺失。结论 患儿3p26.3p24.1重复与3p部分三体综合征（partialtrisomy3p syndrome）相关，该重复是导致患儿多发畸形及发育异常的主要遗传学病因。3p部分三体综合征临床表型差异较大，患儿临床特征与基因型有一定关联，临床诊断时应结合临床表型及遗传学检测技术进行综合诊断。     

5p缺失综合征胎儿1例的产前诊断

目的对1例超声影像提示左足足内翻的胎儿进行遗传学分析, 探讨其染色体拷贝数变异与临床表型的相关性。方法选取2020年10月14日于台州医院就诊的1例5p缺失综合征胎儿为研究对象。采集胎儿的羊水及其父母的外周血样, 进行G显带核型分析, 应用拷贝数变异测序(CNV-seq)检测胎儿染色体的微缺失与微重复, 进一步用荧光原位杂交(FISH)技术进行家系验证。结果胎儿及其父母的G显带核型分析均未见明显异常, CNV-seq发现胎儿5号染色体存在23.12 Mb的拷贝数缺失, 7号染色体存在21.46 Mb的拷贝数重复, FISH进一步验证胎儿母亲为隐匿性t(5;7)(p14.3;q33)携带者, 胎儿的拷贝数变异遗传自母亲。结论 CNV-seq联合FISH技术能有效诊断出隐匿性5p缺失综合征, 避免患儿的出生, 为产前遗传咨询提供理论依据。     

罕见的8p部分缺失伴重复患儿1例的临床及遗传学分析

目的明确1例智力低下、语言发育迟缓及自闭症患儿的遗传学病因。方法选取2019年6月30日于泉州市妇幼保健院就诊的1例罕见8p部分缺失伴重复患儿为研究对象。采集患儿及其父母的外周血样, 进行G显带染色体核型分析以及单核苷酸多态性微阵列(SNP-array)检测。结果患儿核型为46, XX, dup(8p?), 其父母均未见明显异常。SNP-array检测显示患儿染色体8p23.3p23.1区存在6.8 Mb的片段缺失, 8p23.1p12区存在21.8 Mb的片段重复, 上述拷贝数变异均为新发, 并判断为致病变异。结论患儿的临床表型与染色体8p部分缺失重复相关, SNP-array检测对智力低下的患儿的诊断具有一定的价值。     

1例父源性46,XX,der(18)t(8;18)(q23.3;q21.3)染色体非平衡易位的遗传学分析

目的 对1例唇腭裂、先天性心脏病伴手足畸形的新生儿进行遗传学诊断。方法 联合应用常规G显带核型分析技术及CNV-seq测序技术对新生儿进行遗传学检测，并对双亲进行外周血染色体核型分析以明确患儿染色体异常的来源。结果 患儿染色体初步定为46,XX,?add(18)(q22)。CNV-seq结果提示患儿8q23.3-8q24.3存在32.1 Mb重复，18q21.32-q23存在19.6 Mb缺失。患儿母亲染色体正常，父亲染色体为46,XY,t(8;18)(q23.3;q21.3)。患儿核型结果最终确定为46,XX,der(18)t(8;18)(q23.3;q21.3)pat。结论 患儿携带有8q部分三体和18q部分单体，可能导致严重的临床表型；明确患儿的遗传学病因，指导家庭再次生育。     

一例22q12.1-q13.3重复患儿的遗传学分析

目的对1例先天性心脏病合并腭裂等畸形的新生儿进行遗传学分析。方法应用常规G带对患儿及其父母外周血染色体进行核型分析,用低深度全基因组高通量测序技术(low-coverage massively parallel copy number variation sequencing,CNV-seq)对患儿及其父母进行拷贝数变异(copy number variants,CNVs)分析。结果患儿核型为46,X,add(Y)(q11.23),Y染色体长臂存在不明来源的染色体片段,CNV-seq结果为seq[hg19]22q12.1q13.3(29520001~51180000)×3。父母核型及CNV-seq结果均正常。结论患儿Y染色体上的不明来源染色体片段为22q12.1-q13.3重复区域,属新发变异,患儿异常表型为其所导致。CNV-Seq与核型分析技术相互补充,明确诊断,为遗传咨询提供精准指导。     

6p25.3杂合缺失伴15q部分三体患者1例的临床表型与遗传学分析

目的探讨1例6p25.3杂合缺失伴15q部分三体患者的临床表型及遗传学特征。方法选取2021年5月14日就诊于郑州大学第一附属医院遗传与产前诊断中心的1例发育异常患者为研究对象。收集患者临床资料, 应用染色体G显带核型分析和拷贝数变异测序(CNV-seq)技术对其进行遗传学分析。结果患者主要临床特征为完全性子宫纵隔、阴道纵隔、左眼球萎缩、手指和脚趾异常以及精神发育迟滞。患者核型分析结果为46, XX, der(6)t(6;15)(p25.3;q26.1)。CNV-seq结果提示其染色体6p25.3区和15q26.1q26.3区分别存在1.20 Mb的杂合缺失和10.20 Mb的重复, 其中杂合缺失片段包含FOXQ1基因, 可能与患者左眼发育异常相关, 重复片段与15q26过度生长综合征96.16%的区域重叠(包括IGF1R基因), 可能与患者苗勒氏管发育异常、手指和脚趾异常、精神发育迟滞相关。结论染色体6p25.3区杂合缺失和15q26.1q26.3区重复可能是导致患者异常临床表型的遗传学病因。     

一例不典型新生儿猫叫综合征的遗传学分析CSCD

目的对1例仅表现为哭声无力,声音嘶哑,无特殊面容,不伴有先天性心脏病等其他症状或体征的不典型新生儿猫叫综合征患儿的临床及遗传学特点进行分析。方法对患儿及其父母外周血淋巴细胞G显带染色体核型分析,对患儿用应荧光原位杂交技术（fluorescence in situ hybridization, FISH）进行验证,之后用染色体微阵列法（chromosome microarray analysis, CMA）进一步精确遗传学分析。结果患儿染色体核型分析结果为46,XX,del（5）（p14p15）,其父母外周血染色体核型分析未见异常。FISH结果证实了此缺失的存在。染色体微阵列检测结果显示患儿chr5p15．33p14．1区域存在25．7Mb片段缺失。结论猫叫综合征患者个体表型可存在较大差异,尤其是对于新生儿易导致漏诊、误诊。应用细胞遗传学与分子遗传学技术相结合的综合分析有利于弥补单一方法的不足,更加精确地对缺失片段进行定位。     

一例1q部分三体4q部分单体导致Pierre Robin序列征的遗传学分析

目的对1例临床诊断为Pierre Robin序列征的患儿进行细胞及分子遗传学分析,寻找遗传学病因。方法应用外周血染色体核型分析、核苷酸多态性微阵列检测和荧光原位杂交技术,分别对1例表型为下颌小、舌后坠、上呼吸道阻塞、上颚裂开、颈短的患儿及其正常表型的父母进行检测。结果患儿核型为46,XY,der(4)add(4)(q34);母亲核型为46,XX,t(1;4)(q43;q34);父亲核型为46,XY。患儿芯片检测结果为arr[hg19]1q42.2q44(232527958-249202755)×3,4q34.3q35.2(168236901-190880409)×1;父母芯片检测结果正常。母亲荧光原位杂交检测结果为ish t(1;4)(q42;34)。母亲为平衡易位携带者;患儿的4号衍生染色体来源于母亲其中一条结构重排的4号染色体,导致1q42.2q44片段三体、4q34.3q35.2片段单体。结论患儿的1号染色体片段重复及4号染色体片段缺失可能导致其Pierre Robin序列征相关表型。     

一例21号染色体三体嵌合型孤独症谱系障碍患儿的遗传学分析

目的对1例孤独症谱系障碍(autism spectrum disorder,ASD)伴有先天性心脏病的患儿进行细胞遗传学和分子遗传学分析,寻找其病因。方法取患儿及其父母的外周血进行常规染色体G显带核型分析,对患儿外周血提取的基因组DNA进行基于高通量测序的全外显子测序(whole exome sequencing,WES)和低覆盖度全基因组拷贝数变异测序(low-coverage massively parallel copy number variation sequencing,CNV-seq)检测分析,并利用染色体微阵列分析(chromosomal microarray analysis,CMA)进行验证。结果常规染色体G显带核型分析结果显示患儿及其父母染色体核型正常,患儿WES未检测到异常变异,而CNV-seq检测结果为47,XY,+21[10%]/46,XY[90%],提示存在低比例的21号染色体三体嵌合,CMA验证结果与CNV-seq结果一致。结论低比例的21号染色体三体嵌合除与唐氏综合征表型有关外,还可能与ASD的发生密切相关。基于高通量测序的WES及CNV-seq方法可为原因不明的ASD提供准确的遗传学诊断。     

一例3p26．3-pter缺失及7q31．33-qter重复患儿的临床表型与遗传学分析CSCD

目的明确1例发育落后合并多发畸形患儿染色体拷贝数变异（copy numbervariants,CNVs）的性质及来源,并分析其与表型的相关性。方法应用常规G显带分析患儿及其父母的外周血染色体核型,应用二代测序（next generation sequencing,NGS）技术对患儿进行检测。结果G显带分析显示患儿的3号染色体存在结构异常,其父亲的染色体核型为46,XY,t（3;7）（p26;q31）,其母亲核型未见异常。NGS检测显示患儿染色体3p26．3-pter区存在约2．16Mb的微缺失,7q31．33-qter区存在约34．24Mb的重复。结论患儿3号染色体的结构异常源自其父亲的t（3;7）平衡易位,其核型为46,XY,der（3）t（3;7）（p26．3;q31．33）pat。3p26．3-pter区微缺失和7q31．33-qter区重复是导致患儿异常表型的原因。     

A de novo subterminal trisomy 10p and monosomy 18q in a girl with MCA/MR: case report and review

We report on a 3-year-old girl with psychomotor retardation, cardiopathy, strabismus, umbilical hernia, and facial dysmorphism in whom a de novo unbalanced submicroscopic translocation (10p;18q) was found by MLPA (Multiplex Ligation dependent Probe Amplification) and FISH analyses. Additional FISH studies with locus specific RP11 BAC probes and analyses with microsatellites revealed that the translocation resulted in a deletion estimated between 6 and 9 Mb on the maternal chromosome 18 and a subtelomeric 10p duplication of approximately 6.9 Mb. The proband's karyotype is 46,XX.ish der(18) t(10;18)(18pter-->18q23:10p15 --> 10pter). A subterminal duplication of 10p, as well as a subterminal deletion of 18q have been rarely reported so far. The clinical phenotype of this patient is reviewed and discussed.     

Partial 3p trisomy and different rearrangements involving chromosome 3 in the proposita's family

A case of partial 3p trisomy is reported here. A review of published cases (8 ♂, 2 ♀, 7 families) shows a characteristic pattern of anomalies, constituting one more syndrome of multiple congenital anomaly and mental retardation (MCA/MR) characterized by microcephaly, brachycephaly, frontal bossing, temporal indentation, square face, hypertelorism or telecanthus, epicanthus, short nose with a large tip, prominent cheeks, long and protruding philtrum, large and downturned mouth, protruding mid-upper lip, micro- or retrognathia, short neck, congenital heart defects, gastrointestinal malformation, penile hypoplasia, neuromotor or mental retardation, and predominance of whorls on digits. The proposita had a 46,XX,der(11),t(3;11)(p21;q25) karyotype. The mother was a carrier of a de novo 3;11 balanced translocation. Chromosome mosaicism was detected in a female sibling of the proposita: 46% of her cells were 46,XX and 54% had a 46,XX,t(3;20)(p21;q13) karyotype - ie, a de novo 3;20 balanced translocation. We discuss the origin of this mosaicism and the possible meaning of the breaks involving the same region of chromosome 3 (region 3p21) in the members of the proposita's family.     

Mosaic dup (9p) diagnosed by fluorescence in situ hybridization (FISH)

We describe a girl with some manifestations of the dup (9p) syndrome. High-resolution Giemsa-banded karyotype of her lymphocytes documented that she was mosaic with 80% of cells being 46,XX, and 20% 46,XX,-20, + der(20;?) (p13;?). The additional material on 20p could not be defined clearly by high-resolution Giemsa banding, as the banding pattern appeared consistent with either distal 9p or distal 13q. In order to make a definitive cytogenetic diagnosis, we used fluorescence in situ hybridization (FISH) with a chromosome 9 specific DNA library to establish that the origin of the additional chromosomal material on chromosome 20 was from 9p. FISH used in this situation enabled us to counsel the family specifically regarding the prognosis and manifestations of distal 9p duplication. © 1993 Wiley-Liss, Inc.     

Inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) with manifestations of partial duplication 4p and Wolf-Hirschhorn syndrome

An 8-year-old girl with a combination of clinical manifestations of partial duplication 4p and the Wolf-Hirschhorn syndrome was studied. Chromosomal G-banding and FISH analyses showed a 33.2-Mb segment of inverted duplication at 4p14-p16.3 and a 2.8-Mb segment of deletion at 4p16.3-pter (including the Wolf-Hirschhorn syndrome critical region). The chromosomes of the parents were normal. Her karyotype was thus 46,XX, inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) de novo. The inverted duplication deletion was assumed to have arisen through chromatid breakage at 4p16.3, U-type reunion at the breakpoints to produce a dicentric intermediate, breakage of the dicentric to result in a monocentric, and telomere capture/healing of the broken end. Olfactory receptor gene clusters at 4p16.3 were ruled out as an intermediary of the duplication deletion process.     

Characterization of an unbalanced de novo rearrangement by microsatellite polymorphism typing and by fluorescent in situ hybridization

Unbalanced de novo rearrangements, difficult to characterize by conventional cytogenetic techniques, may be elucidated by molecular approaches. By dinucleotide repeat polymorphism typing and fluorescence in situ hybridization (FISH), we have denned the composition of an unbalanced de novo translocation (46,XX,15p+) in a child with multiple congenital anomalies. Use of a microsatellite repeat D5S208 (localized to 5pl5) and polymerase chain reaction (PCR) analysis confirmed that the extra segment originated from the short arm of chromosome 5. Amplification of the patient's DNA with primers for dinucleotide repeats D5S350 and D5S118 showed that the entire 5p (from Spter to 5q11) was present in 3 copies. FISH confirmed the trisomic status of 5p, and further revealed the presence of centromeres of both chromosomes 5 and 15 on the rearranged chromosome thus delineating its dicentric nature. This information allowed us to redefine the de novo rearrangement in this patient as 46,XX,dic der(15)t(5;15)(q11;p11). © 1995 Wiley-Liss, Inc.     

A patient with an interstitial duplication of chromosome 5p11-p13.3 further confirming a critical region for 5p duplication syndrome

Partial or complete trisomy 5p has been associated with characteristic facial features, developmental delay, seizures, congenital heart defects, and respiratory compromise. We present a child with developmental delay, seizures, and congenital cardiac anomalies found to have a previously unreported de novo interstitial duplication of chromosome 5p, 46,XX,dup(5) (p11p13.3). The breakpoints of the duplication were further confirmed by fluorescence in situ hybridization analysis using bacterial artificial chromosome probes specific for the affected region. Comparison with previously reported cases of patients with duplications of 5p suggests loci of interest for both congenital heart anomalies and seizures.     

Structural abnormalities of chromosome 8 and fetoplacental discrepancy: A second case report and review of fetal phenotype of 8p inverted duplication deletion syndrome

We described a new second case of fetoplacental discrepancy involving first trimester prenatal detection of mosaic isochromosome i (8) (q10). A 32-year-old woman underwent chorionic villous sampling because of increased fetal nuchal translucency. Analysis of direct chromosome preparations was performed by R-banding and FISH using subtelomeric, centromeric and whole chromosome painting probes for chromosome 8 showing the presence of an isochromosome 8q with a complex, female mosaic karyotype: mos 46,XX,i (8) (q10)[13]/46,XX,del (8) (p23)[10]. Cytogenetic analysis of cultured CVS showed an interstitial duplication with concomitant terminal deletion of the short arm of chromosome 8: 46,XX,der (8)del (8) (p23)dup (8) (p?)[18]. Array-CGH analysis from cultured trophoblasts and fetal tissues revealed a 6.69 Mb terminal deletion in 8p23.3p23.1 associated with a 31.49 Mb duplication in 8p23.1p11.1. FISH analysis confirmed the 8p inverted duplication deletion syndrome. Moreover, polymorphic DNA marker analysis demonstrated that the derivative chromosome 8 was of maternal origin. FISH analysis of cultured peripheral blood lymphocytes showed that the mother also carried a cryptic paracentric inversion inv (8) (p23). Our report contributes to expand the fetal phenotype of 8p inverted duplication deletion syndrome and also provides further insight into the underlying mechanism of this rare genomic disorder.     

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.     

15号环状染色体患者的细胞分子遗传学研究

目的明确1例生长发育迟缓患者的遗传学病因。方法收集患者的症状、体征等临床资料,常规应用G和C显带分析患者及父母外周血染色体,然后采用单核苷酸微阵列(single nucleotide polymorphisms array,SNP-array)技术进一步确诊,并采用荧光定量PCR(fluorescence quantitative polymerase chain reaction,qPCR)验证。结果患者染色体核型为46,XX,r(15)(p11.2q26.3)[92]/45,XX,-15[9]/46,XX,dic r(15)(p11.2q26.3;p11.2q26.3)[4];SNP-array提示arr[hy19]15q26.3(98957555-102429040)×1,考虑染色体15q26.3区存在约3.4 Mb的杂合性缺失,缺失片段中包含致病性明确的IGF1R等7个Morbid基因;qPCR验证结果为15号染色体IGF1R基因第3、10和20外显子引物扩增区存在缺失,考虑系包含了IGF1R基因的片段杂合性缺失所致。患者父母核型正常。结论15q26.3区域的微缺失导致IGF1R等基因单倍剂量不足以及环状染色体的不稳定,这可能与患者生长发育迟缓等临床特征相关,细胞分子水平的检查为病因学诊断提供了依据。     

Identification and characterization of a de novo partial trisomy 10p by comparative genomic hybridization (CGH)

We report the characterization of a de novo unbalanced chromosome rearrangement by comparative genomic hybridization (CGH) in a 15-day-old child with hypotonia and dysmorphia. We describe the combined use of CGH and fluorescence in situ hybridization (FISH) to identify the origin of the additional chromosomal material on the short arm of chromosome 6. Investigation with FISH revealed that the excess material was not derived from chromosome 6. Identification of unknown unbalanced aberrations that could not be identified by traditional cytogenetics procedures is possible by CGH analysis. Visual analysis of digital images from CGH-metaphase spreads revealed a predominantly green signal on the telomeric region of chromosome 10p. After quantitative digital ratio imaging of 10 CGH-metaphase spreads, a region of gain was found in the chromosome band 10p14-pter. The CGH finding was confirmed by FISH analysis, using a whole chromosome 10 paint probe. These results show the usefulness of CGH for a rapid characterization of de novo unbalanced translocation, unidentifiable by karyotype alone.