Complex chromosomal rearrangement and multiple spontaneous abortions

Summary We report on a woman with a balanced complex chromosomal rearrangement (CCR) involving chromosomes 7, 10, and 21. She is the third individual with an apparently de novo CCR to be ascertained by repeated fetal wastage. Both familial and de novo CCRs are associated with recurrent spontaneous abortions.     

Micro-array analyses decipher exceptional complex familial chromosomal rearrangement

Recently there has been an increased interest in large-scale genomic variation and clinically in the consequences of haploinsufficiency of genomic segments or disruption of normal gene function by chromosome rearrangements. Here, we present an extraordinary case in which both mother and daughter presented with unexpected chromosomal rearrangement complexity, which we characterized with array-CGH, array painting and multicolor large insert clone hybridizations. We found the same 12 breakpoints involving four chromosomes in both mother and daughter. In addition, the daughter inherited a microdeletion from her father. We mapped all breakpoints to the resolution level of breakpoint spanning clones. Genes were found within 7 of the 12 breakpoint regions, some of which were disrupted by the chromosome rearrangement. One of the rearrangements disrupted a locus, which has been discussed as a quantitative trait locus for fetal hemoglobin expression in adults. Interestingly, both mother and daughter show persistent fetal hemoglobin levels. We detail the most complicated familial complex chromosomal rearrangement reported to date and thus an extreme example of inheritance of chromosomal rearrangements without error in meiotic segregation. Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

A new chromosomal rearrangement in cattle

The karyotype of a heifer with 2n-59 was studied using routine, C- and high-resolution G-banding techniques. A 1/29 translocation was identified. One of X chromosomes was normal. Another X chromosome was absent, but G-positive, partly heterochromatic biarmed element was present in all the cells. It is supposed that deletion of greater part of the q-arm of the second X chromosome and heterochromatinization of the remains took place.     

A complex chromosomal rearrangement detected prenatally and studied by fluorescence in situ hybridization

We report of case of a complex chromosomal rearrangement detected prenatally and studied with traditional banding methods and fluorescence in situ hybridization. The combination of these techniques showed that four chromosomes were involved in the translocation. Nine breakpoints were proposed to explain these results. Some of the findings could only be detected with fluorescence in situ hybridization, demonstrating the usefulness of this technique in characterizing chromosomal abnormalities that would otherwise be difficult to interpret correctly with classical cytogenetics alone.     

A cytogenetic study of repeated spontaneous abortions.

During a cytogenetic study of spontaneous abortions, successive abortions from 40 couples were karyotyped. The chromosome constitutions of the first and second abortions were found to be highly correlated. In each of 21 instances in which the first abortion was chromosomally normal, the subsequent abortion(s) was normal as well. In nine cases, the two abortions were chromosomally abnormal, and in four of these, both abortions were trisomic. Combined with findings from other studies of consecutive spontaneous abortions, the present data indicate that certain couples are at an increased risk for either repeated chromosomally normal abortions or for repeated trisomic conceptions. The increased risk of trisomy does not seem to be restricted to a particular chromosome, and the magnitude of the risk increase appears to be independent of maternal age.     

tSNP-based identification of allelic loss of gene expression in a patient with a balanced chromosomal rearrangement

Identification of genes affected by disease-associated rare chromosomal rearrangements has led to the cloning of several disease genes. Here we have used a simple approach involving allele-specific RT-PCR-based detection of gene expression to identify a gene affected by a balanced autosome;autosome translocation. We identified a transcribed SNP (tSNP), c.68G-->A, present in a novel untranslated exon of the CLDN14 gene in a male patient with mental retardation who had a balanced t(13;21) chromosomal translocation. We determined an allelic loss of expression of the CLDN14 gene isoform at the 21q22.1 chromosomal breakpoint. Although additional work is necessary to explore a possible function of the novel CLDN14 isoform in brain development and function and the potential pathogenic consequences of its disruption in this patient, the result clearly demonstrates the utility of a tSNP-based detection of allelic loss of gene expression in studies involving chromosomal rearrangements.     

Genetic counseling in balanced chromosomal inversions

The genetic counseling given at carriers of equilibrated chromosomal inversions is in relation with the type of the inversion. The risk for carriers of pericentric inversions concerning euchromatic regions depends on many factors, i.e. the length of the inserted segment in relation with the total length of the chromosome involved, the sex of the carrier and the way of assortment. In contrast, the carriers of pericentric inversions concerning the heterochromatic regions, as well as of paracentric inversions, have not a particular risk for their descendance.     

平衡复杂染色体重排携带者的遗传与生育情况分析

为探讨中国人群平衡复杂染色体重排(complex chromosome rearrangements, CCRs)的类型、特征和减数分裂行为及其与生殖异常的关系,采用常规G显带技术对因生育问题就诊的1063对夫妇进行核型分析,并检索中国人群平衡CCR携带者的核型及临床资料进行统计分析。在受检者中检出2例平衡CCR携带者,并从国内外数据库中检索发现的平衡CCR携带者总共124例,3方和4方重排为主要类型,占51.6%,双重相互易位占26.6%,特殊CCR占21.8%。平衡CCR携带者或其配偶自然流产和胚胎停止发育(胎停育)发生率为77.6%,多发性先天畸形(multiple congenital abnormalities, MCA)等不良妊娠发生率为9.7%。三种类型平衡CCR携带者各种妊娠结局发生率的差异具有统计学意义(P<0.05)。对男性CCRs累及的染色体分析发现,累及1号染色体的CCRs多表现为生精障碍,累及8号染色体的CCRs多发生不良妊娠(P≤0.05)。分析CCRs减数分裂染色体分离模式发现,后代的异常核型多来自于邻近-1分离方式(8/12)。发生不对称分离(3:2、4:2和5:3分离)的CCRs中D-G组染色体累及频率相对高(46.2%)。结果表明,平衡CCR携带者不良妊娠风险高,即使正常妊娠也应进行产前诊断。男性平衡CCR携带者生精障碍发生机率高,CCRs累及的染色体对男性携带者生育能力有影响。另外,CCRs携带者减数分裂染色体分离模式也与累及的染色体有关。分析CCRs的类型、累及的染色体和易位片段的大小等因素可针对特定CCR做出更准确的遗传和生育指导。     

A case of prenatal detection of a de novo unbalanced complex chromosomal rearrangement involving four chromosomes

Complex chromosomal rearrangements are rarely observed prenatally. Genetic counceling of CCR carriers is complicated, especially in cases of de novo origin of the rearrangement. Here we present a new case of a de novo CCR involving four chromosomes observed in amniotic fluid cells of the fetus at 17 weeks of gestation. The rearrangement was characterized as an apparently balanced four-way trans-location t(1;11;7;13)(~p21;~q13.5;~q32;~q22)dn by conventional cytogenetic studies. However, array-based comparative genomic hybridization revealed 5 submicroscopic heterozygous interstitial deletions on chromosome 1, 11, 7, 13 with a total loss of 21.1 Mb of genetic material in regions close to those, designated as breakpoints by conventional cytogenetic analysis. The described case clearly illustrates that high-resolution molecular genetic analysis should be combined with conventional cytogenetic techniques to exclude subtle chromosomal abnormalities in CCR cases detected prenatally.     

Chromosome investigation in married couples with repeated spontaneous abortions

Summary The karyotype analysis is performed in 28 married couples who had had two or more spontaneous abortions. In 8 of them minor chromosomal anomalies were found: 3 men had a large Y chromosome, 2 women had satellites on chromosome No. 17, 1 woman had double satellites on one of the chromosomes in group G, 1 man and 1 woman had enlarged short arms in one of the D-group chromosomes.In the control group (20 normal married couples) the only striking feature noticed was the unusually short Y chromosome in one of the men studied.

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Zusammenfassung Bei 28 Ehepaaren, die zwei oder mehr spontane Aborte gehabt hatten, wurde eine Chromosomenanalyse durchgeführt. Bei 8 von ihnen fanden sich kleinere Chromosomenanomalien: 3 Männer hatten ein besonders großes Y-Chromosom, 2 Frauen hatten Satelliten am Chromosom Nr. 17, 1 Frau hatte doppelte Satelliten an einem der Chromosomen der G-Gruppe, und je 1 Mann und 1 Frau zeigten verlängerte kurze Arme an einem der Chromosomen der D-Gruppe. In der Kontrollgruppe (20 normale Ehepaare) fand sich dagegen nur bei einem der Männer ein ungewöhnlich kurzes Y-Chromosom als einziger auffälliger Befund.

     

A highly complex chromosomal rearrangement between five chromosomes in a healthy female diagnosed in preparation for intracytoplasmatic sperm injection.

We report a case of a de novo complex chromosomal rearrangement among five chromosomes found in a clinically healthy woman. The only indication for chromosome analysis was a planned intracytoplasmatic sperm injection. Physical examination, including internal and external genitals, and ovaries and hormone status were normal. Banding cytogenetics showed a rearrangement among chromosomes #3, #4, #7, #9, and #17. Twenty-four-color fluorescence in situ hybridization and multicolor banding were applied to characterize the translocations and breakpoints more precisely. This confirmed the involved chromosomes and revealed two breakpoints in chromosome #4. This six-breakpoint rearrangement [der(3)t(3;4), der(4)t(17;4;7), der(7)t(3;7), der(9)t(4;9), and der(17)t(9;17)] seemed to be balanced on a molecular cytogenetic level, although submicroscopic deletions or duplications close to the breakpoints cannot be excluded.     

De novo complex chromosomal rearrangement in a woman with recurrent spontaneous abortion and one healthy daughter

Summary Although rare, complex chromosomal rearrangements have been reported in the literature. The result is multiple congenital malformations in the offspring and recurrent spontaneous abortion. Chromosome 7 is usually involved, but in our patient chromosome 18 was involved.     

Pilus expression in Neisseria gonorrhoeae involves chromosomal rearrangement

The Neisseria gonorrhoeae pilus protein is one of the major antigenic determinants on the cell's surface. It is comprised of identical subunits of approximately 18 kd and plays a role in the infectivity and virulence of the organism. We have cloned the gene encoding a gonococcal pilus protein into Escherichia coli, and, using one of these clones as a probe in hybridization studies, we have shown that conversion of the pilus positive to pilus negative state in N. gonorrhoeae involves chromosomal rearrangement. Although the pilus protein is produced by E. coli, it does not appear to be assembled on the surface of the cell in native form.     

A test of the chromosomal rearrangement model of speciation in Drosophila pseudoobscura

Recent studies suggest that chromosomal rearrangements play a significant role in speciation by preventing recombination and maintaining species persistence despite interspecies gene flow. Factors conferring adaptation or reproductive isolation are maintained in rearranged regions in the face of hybridization, while such factors are eliminated from collinear regions. As a direct test of this rearrangement model, we evaluated the genetic basis of hybrid male sterility in a sympatric species pair, Drosophila pseudoobscura pseudoobscura and D. persimilis, and an allopatric species pair, D. pseudoobscura bogotana and D. persimilis. Our results are consistent with the proposed model: virtually all of the sterility factors in the former pair are associated with three inverted regions, whereas sterility factors are present in the collinear regions in the latter pair. These findings indicate recombination and selection may have eliminated sterility factors outside the inverted regions between D. p. pseudoobscura and D. persimilis, suggesting chromosomal rearrangements may facilitate species persistence despite hybridization.     

A suitable method for chromosomal preparations from foetal tissue arising from induced abortions

A simple method for human chromosomal preparation was developed for mixed foetal tissues which were artificially aborted. Chromosomal analysis of artificially aborted foetal material assists in discovering the causes of many spontaneous abortions, and could be of great help in decisions about child bearing. It is an efficient method by which the abortion-karyotype can be defined within about 2 days of sampling.     

Oncogene activation by chromosomal rearrangement in chronic myelocytic leukemia

A considerable number of human tumors, especially leukemias and lymphomas is associated with a consistent specific chromosome translocation. At a number of the breakpoint regions of these specific aberrations are c-oncogenes (c-onc) located. The structure and/or expression of some of these c-onc is altered as a result of the specific translocation. In the CML-specific (9;22) translocation the transposition of the c-abl oncogene to the chromosome 22 bcr sequences results in the production of a chimeric bcr/c-abl fusion protein. This result strongly suggests that tumor-specific chromosomal aberrations can lead to the activation of cellular oncogenes.     

Successive spontaneous abortions with diverse chromosomal aberrations in human translocation heterozygote.

A patient who had 3 first-trimester spontaneous abortions (blighted ova) was found to be carrying a balanced 13/14 Robertsonian translocation. In the 2 cases cytogenetically analyzed, different chromosomal aberration were found (trisomy 16 and supernumerary D elements). Histologic examination of the placentas of all 3 abortions revealed hypovascular or avascular villi, hydropic degeneration, and occasional atypical stromal (Hofbauer-like) cells. In 2 cases the decidua was examined by light microscopy and was diffusely inflamed with a plasmolymphocytic infiltrate. The relation of the maternal translocation to the repeated abortions with chromosome anomalies is discussed.