Institute of Human Genetics and Anthropology

Jena, Germany

Institute of Human Genetics and Anthropology

Jena, Germany
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Manolakos E.,Aghia Sophia Childrens Hospital | Manolakos E.,University of Cagliari | Peitsidis P.,Royal Free Hospital | Eleftheriades M.,Aghia Sophia Childrens Hospital | And 5 more authors.
Journal of Obstetrics and Gynaecology Research | Year: 2010

Full monosomy 21 is an extremely rare chromosomal disorder. A 38-year-old woman attended a first trimester scan. Ultrasound (U/S) imaging of the fetus at 12 weeks of gestation showed features of increased nuchal translucency measurement (12 mm). Chorionic villi sampling (CVS) was performed after genetic counseling. At 16 weeks of gestation the fetus showed U/S characteristics of severe intrauterine growth restriction, generalized edema and hydrothorax. Cytogenetic examination was performed using quantitative fluorescent polymerase chain reaction analysis, standard Giesma banding and fluorescent in situ hybridization analysis. Non-mosaic full monosomy 21 was detected and the parents opted to terminate the pregnancy. Microsatellite analysis demonstrated maternal origin of the single chromosome. This case represents one of the few cases of prenatally diagnosed full monosomy 21 confirmed only by CVS, in which the parental origin of the single chromosome was determined. © 2010 Japan Society of Obstetrics and Gynecology.


Pellestor F.,Montpellier University | Pellestor F.,Hospital Arnaud Of Villeneuve | Anahory T.,Hospital Arnaud Of Villeneuve | Lefort G.,Hospital Arnaud Of Villeneuve | And 4 more authors.
Human Reproduction Update | Year: 2011

Background: Complex chromosomal rearrangements (CCRs) describe structural rearrangements, essentially translocations, involving at least three breakpoints on two or more chromosomes. Although they are rare in humans, their clinical identification is important since CCR carriers can display various phenotypes which include phenotypically normal subjects, infertile males and patients with mental retardation and/or congenital abnormalities. The rearrangement can be de novo or familial. The use of fluorescent in situ hybridization assays and molecular techniques for the characterization of CCRs have indicated that the rearrangements could be more complex than initially assumed. Accumulating data have revealed that the mechanisms underlying the genesis of CCRs remain elusive. Methods: We performed a large PubMed search in order to summarize the current knowledge in this field and address important aspects of CCR formation and meiotic behavior, highlighting the complexity of these rearrangements at the chromosomal and genomic level. Results: The review of published data indicates that the complexity of CCRs is becoming increasingly known, thanks to the application of more and more efficient molecular techniques. These approaches have allowed the precise sequence analysis of breakpoints and the identification of insertions, deletions, inversions and recombination events. New models have been proposed for the formation of CCRs, based on replication-based mechanisms and specific sequence elements. Their meiotic behavior has been discussed in the light of these new molecular data. conclusions: Despite the increasing understanding of the mechanisms involved in their genesis, CCRs arise as unique, complex events for which the genetic and reproductive counseling of carriers remains a challenge. © The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Sanjmyatav J.,Jena University Hospital | Steiner T.,Jena University Hospital | Wunderlich H.,Jena University Hospital | Diegmann J.,Institute of Human Genetics and Anthropology | And 2 more authors.
Journal of Urology | Year: 2011

Purpose: The discovery of metastasis markers in clear cell renal cell carcinoma is of critical importance to define individual metastatic risk and select patients for new targeted therapies. We identified potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis. Materials and Methods: We performed transcriptional profiling of 16 primary metastatic and 18 nonmetastatic clear cell renal cell carcinomas with PIQOR™ microarrays. Differentially expressed genes were validated by quantitative real-time polymerase chain reaction. Results: Genes discriminating between metastatic and nonmetastatic tumors were identified at q <0.001 by significance analysis of microarrays. The metastatic signature contained 127 transcripts. In metastatic samples a greater than 4-fold decrease in expression was detected for the genes CD151 and IKBA (t/F statistic p <0.0001) while the genes MMP16, B7-H1, BCL2L2 and FRA2 showed greater than 4-fold increase of expression in metastatic primary tumors (p <0.0001). Quantitative real-time polymerase chain reaction revealed significant differences in expression among all metastatic tumors, including synchronously and metachronously metastasized tumors, and nonmetastatic tumors for FRA2 (p = 0.032) and CD151 (p = 0.005). In addition, the genes B7-H1 (p = 0.040), FRA2 (p = 0.035), CD151 (p = 0.004) and BCL2L2 (p = 0.035) showed significantly higher expression in early metastasized than in nonmetastatic tumor samples. Different B7-H1 (p = 0.002) and BCL2L2 (p = 0.007) expression levels were found in samples with late metastasis compared to those in synchronously metastasized tumors. Conclusions: We determined a metastatic signature of clear cell renal cell carcinoma by microarray analysis. Our data provide the possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even in a localized situation. © 2011 American Urological Association Education and Research, Inc.


Weise A.,Institute of Human Genetics and Anthropology | Timmermann B.,Max Planck Institute for Molecular Genetics | Grabherr M.,Cambridge Broad Institute | Werber M.,Max Planck Institute for Molecular Genetics | And 14 more authors.
European Journal of Human Genetics | Year: 2010

The linkage of disease gene mapping with DNA sequencing is an essential strategy for defining the genetic basis of a disease. New massively parallel sequencing procedures will greatly facilitate this process, although enrichment for the target region before sequencing remains necessary. For this step, various DNA capture approaches have been described that rely on sequence-defined probe sets. To avoid making assumptions on the sequences present in the targeted region, we accessed specific cytogenetic regions in preparation for next-generation sequencing. We directly microdissected the target region in metaphase chromosomes, amplified it by degenerate oligonucleotide-primed PCR, and obtained sufficient material of high quality for high-throughput sequencing. Sequence reads could be obtained from as few as six chromosomal fragments. The power of cytogenetic enrichment followed by next-generation sequencing is that it does not depend on earlier knowledge of sequences in the region being studied. Accordingly, this method is uniquely suited for situations in which the sequence of a reference region of the genome is not available, including population-specific or tumor rearrangements, as well as previously unsequenced genomic regions such as centromeres. © 2010 Macmillan Publishers Limited All rights reserved.


Karaer K.,Gazi University | Ergun M.A.,Gazi University | Weise A.,Institute of Human Genetics and Anthropology | Ewers E.,Institute of Human Genetics and Anthropology | And 3 more authors.
Genetic Counseling | Year: 2010

Infertility is defined as the inability to conceive after one year of regular unprotected intercourse. Constitutional numerical and/or structural chromosomal aberrations like sex-chromosome aberrations are one of the possible factors involved in fertility problems. Reciprocal translocations between an X-chromosome and an autosome are rarely seen in men. Male carriers of an X-autosome translocation are invariably sterile, regardless of the position of the breakpoint in the X-chromosome. Breakpoints in autosomal chromosomes could also be involved in male infertility. In this paper, we describe a 31-year-old male with azoospermia. GTG banding with high resolution multicolor-banding (MCB) techniques revealed a karyotype 46,Y,t(X;l)(p22.3;q25), and we discuss how the breakpoint of this translocation could affect male infertility. As a conclusion, cytogenetic evaluation of infertile subjects with azoospermia should be considered in the first place before in vitro fertilisation procedures are planned.


Pellestor F.,French Institute of Health and Medical Research | Puechberty J.,Hopital Arnaud de Villeneuve | Weise A.,Institute of Human Genetics and Anthropology | Lefort G.,Hopital Arnaud de Villeneuve | And 3 more authors.
Fertility and Sterility | Year: 2011

Objective: To directly study the meiotic segregation of a complex reciprocal translocation (CCR) as well as the occurrence of an interchromosomal effect. Design: In situ sperm fluorescence in situ hybridization (FISH) analysis. Setting: Department of Cytogenetics and INSERM research center. Patient(s): A male carrier of a balanced complex reciprocal translocation t(5;13;14)(q23;q21;q31). Intervention(s): Sperm samples from the carrier and direct FISH analysis on sperm slide preparations. Main Outcome Measure(s): Meiotic segregation pattern determined on sperm nuclei and estimation of the incidence of unbalanced spermatozoa and an interchromosomal effect (ICE). Result(s): Only 27% of spermatozoa displayed a normal or balanced chromosome complement. The rate of unbalanced sperm was 69.4%, including different types of 3:3, 4:2, and 5:1 segregations. There was no evidence for the occurrence of an interchromosomal effect in autosomal chromosomes, but the gonosomes displayed a statistically significant increase in disomy rates. Conclusion(s): These results are consistent with the formation of a hexavalent configuration at the pachytene stage of meiosis and a high prevalence of imbalance production. The mechanisms of formation of CCRs must be examined with regard to these direct results and new molecular data on the formation of genomic rearrangements. © 2011 by American Society for Reproductive Medicine.


Mrasek K.,Institute of Human Genetics and Anthropology | Schoder C.,Institute of Human Genetics and Anthropology | Teichmann A.-C.,Institute of Human Genetics and Anthropology | Behr K.,Institute of Human Genetics and Anthropology | And 6 more authors.
International Journal of Oncology | Year: 2010

Since the first description of human fragile sites (FS) more than 40 years ago, a variety of substances were reported to induce chromosomal breaks at non-random, breakage-prone regions. According to information available from human genome browsers aphidicolin, an inhibitor of DNA replication induces 77 of 88 known common FS. However, in the literature additional FS are reported, which are also, at least in part, inducible by aphidicolin. To the best of our knowledge, here we present the first and largest ever done systematic, whole genome-directed and comprehensive screening for aphidicolin-inducible breakage-prone regions. The study was performed on stimulated peripheral blood lymphocytes of 3 unrelated healthy individuals. Twenty-five thousand metaphase spreads were analyzed and overall 22,537 FS located in 230 different loci were recorded. Sixtyone of those FS were never observed before and 52 were already previously reported but not included in genome browsers and yet verified. Interestingly, aphidicolin was able to induce all types of rare and common FS, suggesting that these breakage-prone regions are less dependent on the inducing chemicals than originally supposed. Overall, we provide the first comprehensive genome wide map for FS and studied possible correlations of chromosome length and GTG-banding level with FS-frequency. To handle FS better in future, an extension of the already existing alphabetical nomenclature for FS on single chromosomes is suggested.


PubMed | Institute of Human Genetics and Anthropology
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2010

The linkage of disease gene mapping with DNA sequencing is an essential strategy for defining the genetic basis of a disease. New massively parallel sequencing procedures will greatly facilitate this process, although enrichment for the target region before sequencing remains necessary. For this step, various DNA capture approaches have been described that rely on sequence-defined probe sets. To avoid making assumptions on the sequences present in the targeted region, we accessed specific cytogenetic regions in preparation for next-generation sequencing. We directly microdissected the target region in metaphase chromosomes, amplified it by degenerate oligonucleotide-primed PCR, and obtained sufficient material of high quality for high-throughput sequencing. Sequence reads could be obtained from as few as six chromosomal fragments. The power of cytogenetic enrichment followed by next-generation sequencing is that it does not depend on earlier knowledge of sequences in the region being studied. Accordingly, this method is uniquely suited for situations in which the sequence of a reference region of the genome is not available, including population-specific or tumor rearrangements, as well as previously unsequenced genomic regions such as centromeres.

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