Publications by authors named "Katayoon Shirneshan"

19 Publications

  • Page 1 of 1

Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7.

Leukemia 2020 09 17;34(9):2441-2450. Epub 2020 Feb 17.

Department of Haematological Medicine, King's College Hospital, NHS Foundation Trust, London, UK.

Monosomy 7 [-7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with -7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated -7 or del(7q).
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http://dx.doi.org/10.1038/s41375-020-0728-xDOI Listing
September 2020

Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes.

Genes Chromosomes Cancer 2019 10 30;58(10):689-697. Epub 2019 Apr 30.

Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.

The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the new comprehensive cytogenetic scoring system for MDS, chromosome 7 anomalies are no longer generally assigned to poor risk features but are thoroughly separated. However, der(1;7)(q10;p10), hereinafter der(1;7), is merged into the group labeled "any other single" and belongs to the intermediate risk group, just by definition due to lack of adequate clinical data. The aim of our international collaborative was to clarify the "real" prognostic impact of der(1;7) on a homogenous and well-documented data base. We performed detailed analysis of 63 MDS patients with isolated der(1;7) constituting the largest cohort hitherto reported. Furthermore, clinical data are compared with those of patients with isolated del(7q) and isolated monosomy 7. Median overall survival (OS) of patients with der(1;7) is 26 months (hazard ratio (HR) 0.91 for del(7q) vs der(1;7) and 2.53 for monosomy 7 vs der(1;7)). The der(1;7) is associated with profound thrombocytopenia most probably causing the reduced OS which is in striking contrast to the low risk for AML transformation (HR 3.89 for del(7q) vs der(1;7) and 5.88 for monosomy 7 vs der(1;7)). Molecular karyotyping indicates that der(1;7) is generated in a single step during mitosis and that a chromosomal imbalance rather than a single disrupted gene accounts for malignancy. Thus, the current cytogenetic scoring system assigning isolated der(1;7) to the intermediate risk group is now confirmed by a sufficient data set.
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http://dx.doi.org/10.1002/gcc.22760DOI Listing
October 2019

Detailed analysis of clonal evolution and cytogenetic evolution patterns in patients with myelodysplastic syndromes (MDS) and related myeloid disorders.

Blood Cancer J 2018 03 7;8(3):28. Epub 2018 Mar 7.

Department of Hematology and Medical Oncology, University Medicine Göttingen (UMG), Göttingen, Germany.

Clonal cytogenetic evolution (CE) (i.e., acquisition of new chromosomal aberrations over time) is relevant for the progression of myelodysplastic syndromes (MDS). We performed detailed analysis of CE in 729 patients with MDS and related disorders. Patients with CE showed shorter survival (median OS 18.0 versus 53.9 months; P < 0.01), higher leukemic transformation rate (48.0% versus 21.4%; P < 0.01) and shorter intervals to leukemic transformation (P < 0.01). Two main CE patterns were detected: early versus late CE (median onset 5.3 versus 21.9 months; P < 0.01) with worse survival outcomes for early CE. In the case of CE, del (7q)/-7 (P = 0.020) and del (17p) (P = 0.002) were especially unfavorable. Extending the evolution patterns from Tricot et al. (1985) forming five subgroups, prognosis was best (median OS not reached) in patients with "transient clones/changing clone size", whereas those with "CE at diagnosis" showed very poor outcomes (P < 0.01 for comparison of all). Detailed sequential cytogenetic analysis during follow-up improves prognostication in MDS patients and acknowledges the dynamic biology of the disease. Evidence, time-point, and patterns of cytogenetic clonal evolution should be included into future prognostic scoring systems for MDS.
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http://dx.doi.org/10.1038/s41408-018-0061-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841340PMC
March 2018

Peripheral blood cytogenetics allows treatment monitoring and early identification of treatment failure to lenalidomide in MDS patients: results of the LE-MON-5 trial.

Ann Hematol 2017 Jun 3;96(6):887-894. Epub 2017 Apr 3.

Department of Hematology and Medical Oncology, University Medicine of Goettingen, Robert-Koch-Str. 40, 37075, Goettingen, Germany.

Transfusion-dependent patients with low- or intermediate-1-risk myelodysplastic syndrome, <5% bone marrow (BM) blasts and isolated 5q-deletion received lenalidomide within the German MDS study group phase-II clinical trial LE-MON-5 (EudraCT:2008-001866-10) of the University of Duesseldorf, Germany. Cytogenetic monitoring was performed by chromosome banding analyses (CBA) of BM cells and fluorescence in situ hybridization (FISH) analyses of peripheral blood (PB) mononuclear CD34+ cells using extended probe panels. Out of 144 patients screened for study enrollment, 24% failed to meet inclusion criteria due to cytogenetic findings. Eighty-seven patients were followed with a median observation time of 30 months. Cytogenetic response detected by FISH and CBA in 74 and 66% of patients, respectively, was predictive for hematologic response as well as of high prognostic relevance. After 2 years, AML rate was 8% for all patients. Karyotype evolution was detected in 21 (FISH)-34% (CBA) of patients associated with significantly shorter AML-free survival. Disease progression was first detectable on the cytogenetic level on average 5-6 months before recurrence of transfusion dependence. Our data show for the first time in a prospective setting that a cytogenetic monitoring from the PB helps to early identify treatment failure and progressive disease in lenalidomide-treated patients to improve clinical management.

Trial Registration: EudraCT:2008-001866-10.
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http://dx.doi.org/10.1007/s00277-017-2983-0DOI Listing
June 2017

Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data.

Oncotarget 2016 Jul;7(30):47061-47081

Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.

To discover new regulatory pathways in B lymphoma cells, we performed a combined analysis of experimental, clinical and global gene expression data. We identified a specific cluster of genes that was coherently expressed in primary lymphoma samples and suppressed by activation of the B cell receptor (BCR) through αIgM treatment of lymphoma cells in vitro. This gene cluster, which we called BCR.1, includes numerous cell cycle regulators. A reduced expression of BCR.1 genes after BCR activation was observed in different cell lines and also in CD10+ germinal center B cells. We found that BCR activation led to a delayed entry to and progression of mitosis and defects in metaphase. Cytogenetic changes were detected upon long-term αIgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc co-regulated genes in distinct groups of lymphoma patients was observed. Finally, we showed that the BCR.1 index discriminates activated B cell-like and germinal centre B cell-like diffuse large B cell lymphoma supporting the functional relevance of this new regulatory circuit and the power of guided clustering for biomarker discovery.
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http://dx.doi.org/10.18632/oncotarget.9219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216924PMC
July 2016

New data shed light on Y-loss-related pathogenesis in myelodysplastic syndromes.

Genes Chromosomes Cancer 2015 Dec 23;54(12):717-24. Epub 2015 Sep 23.

Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.

Loss of the Y-chromosome (LOY) is described as both a normal age-related event and a marker of a neoplastic clone in hematologic diseases. To assess the significance of LOY in myelodysplastic syndromes (MDS), we determined the percentage of LOY in clonal CD34+ peripheral blood cells in comparison to normal CD3+ T-cells of 27 MDS patients using fluorescence in situ hybridization (FISH) analysis. Results were compared with the percentage of LOY in CD34+ and CD3+ cells of 32 elderly men without hematologic diseases and in 25 young blood donors. While LOY could not be detected in CD3+ cells of young men, it was observed in CD3+ cells of elderly men without hematologic diseases (2.5% LOY) as well as in CD3+ cells of elderly MDS patients (5.8% LOY). The percentage of CD34+ cells affected by LOY was significantly higher in MDS patients compared to elderly men without hematologic diseases (43.3% vs. 13.2%, P = 0.005), indicating that LOY has an age-related basis but is also associated with MDS. Furthermore, we aimed to define a threshold between age- and disease-associated LOY in MDS. Statistical analysis revealed that a value of 21.5% LOY in CD34+ peripheral blood cells provided the best threshold to discriminate between these two conditions in MDS. We conclude that LOY is clonal in a substantial number of MDS based on an age-related predisposition.
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http://dx.doi.org/10.1002/gcc.22282DOI Listing
December 2015

Influence of total genomic alteration and chromosomal fragmentation on response to a combination of azacitidine and lenalidomide in a cohort of patients with very high risk MDS.

Leuk Res 2015 Oct 28;39(10):1079-87. Epub 2015 Jun 28.

Department of Hematology and Medical Oncology, University Hospital, University Göttingen, Göttingen, Germany.

We genetically analyzed a group of high risk MDS/AML patients treated by a combination of azacitidine and lenalidomide. In our cohort, the extent of genetic rearrangements was associated with outcome and response to treatment. The size of total genomic aberrations as defined by molecular karyotyping (SNP-array analysis) was a predictive marker for overall survival. TP53 mutations were associated with therapy refractoriness only if accompanied by heavily rearranged chromosomes. This study suggests a potential value of molecular karyotyping as a method to objectivate comprehensively the extent of genetic alterations in high risk patients with complex karyotypes, especially if the clinical value of the size of total genomic aberrations and the fragmentation status of single chromosomes could be evaluated in larger therapy trials.
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http://dx.doi.org/10.1016/j.leukres.2015.06.011DOI Listing
October 2015

Validation of cytogenetic risk groups according to International Prognostic Scoring Systems by peripheral blood CD34+FISH: results from a German diagnostic study in comparison with an international control group.

Haematologica 2015 Feb 24;100(2):205-13. Epub 2014 Oct 24.

Department of Hematology and Medical Oncology, University Medicine of Goettingen, Germany.

International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5%-20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on fluorescence in situ hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34(+)) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes. For cytogenetic risk classification by fluorescence in situ hybridization analyses of CD34(+) peripheral blood cells, the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of fluorescence in situ hybridization analyses of peripheral CD34(+) blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel (clinicaltrials.gov identifier:01355913).
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http://dx.doi.org/10.3324/haematol.2014.110452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803133PMC
February 2015

Molecular cytogenetic monitoring from CD34+ peripheral blood cells in myelodysplastic syndromes: first results from a prospective multicenter German diagnostic study.

Leuk Res 2013 Aug 25;37(8):900-6. Epub 2013 Apr 25.

Department of Hematology and Oncology, University of Goettingen, Germany.

The gold standard of cytogenetic analysis in myelodysplastic syndromes (MDS) is conventional chromosome banding (CCB) analysis of bone marrow (BM) metaphases. Most aberrations can also be detected by fluorescence-in situ-hybridization (FISH). For this prospective multicenter German diagnostic study (www.clinicaltrials.gov: #NCT01355913) 360 patients, as yet, were followed up to 3 years by sequential FISH analyses of immunomagnetically enriched CD34+ peripheral blood (PB) cells using comprehensive FISH probe panels, resulting in a total number of 19,516 FISH analyses. We demonstrate that CD34+ PB FISH correlates significantly with CCB analysis and represents a feasible method for a reliable non-invasive cytogenetic monitoring from PB.
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http://dx.doi.org/10.1016/j.leukres.2013.03.019DOI Listing
August 2013

Spongiform encephalopathy in siblings with no evidence of protease-resistant prion protein or a mutation in the prion protein gene.

J Neurol 2013 Jul 2;260(7):1871-9. Epub 2013 Apr 2.

National Reference Center for TSE Surveillance, Department of Neurology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075 Göttingen, Germany.

We discuss relevant aspects in two siblings with a neurodegenerative process of unclear aetiology who developed progressive dementia with global aphasia and hyperoral behaviour at the ages of 39 and 46 years and who died 6 and 5 years after disease onset. The cases were reported to the National Reference Center for TSE Surveillance in Göttingen, Germany. Detailed clinical examinations, CSF, blood samples, and copies of the important diagnostic tests (magnetic resonance imaging, electroencephalogram, laboratory tests) were obtained. Further neuropathological and genetic analyses were performed. Cerebral magnetic resonance imaging of both siblings showed prominent changes in signal intensity, especially in the left medial temporal cortex, but also the hippocampal formation. Neuropathological examination revealed spongiform changes, neuronal loss, and astrocytic gliosis, which are typical in Creutzfeldt-Jakob disease. However, no prion protein deposits were detectable by immunohistochemical analysis, Western blot, or PET blot, though abundant tau protein deposits were observed. A mutation in the coding region of the prion protein genes of both siblings was excluded. A detailed search of the literature revealed no other cases with a similar clinical and neuropathological appearance. While the disease aetiology remains unclear, the findings point to a neurodegenerative process and most likely a genetic disease.
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http://dx.doi.org/10.1007/s00415-013-6897-zDOI Listing
July 2013

INSL5-deficient mice display an alteration in glucose homeostasis and an impaired fertility.

Endocrinology 2012 Oct 20;153(10):4655-65. Epub 2012 Jul 20.

Institute of Human Genetics, Heinrich-Düker-Weg 12, D-37073 Göttingen, Germany.

Insulin-like factor 5 (INSL5), a member of the insulin superfamily, is expressed in the colorectum and hypothalamus. To facilitate studies into the role of INSL5, we generated Insl5(-/-) mice by gene targeting. Insl5(-/-) mice were born in the expected Mendelian ratio, reached normal body weight, but displayed impaired male and female fertility that are due to marked reduction in sperm motility and irregular length of the estrous cycle. Furthermore, Insl5(-/-) mice showed impairment in glucose homeostasis with characteristic elevation of serum glucose levels at an advanced age. Glucose and insulin tolerance tests revealed that the increased blood glucose in Insl5(-/-) mice was due to glucose intolerance resulting from reduced insulin secretion. Morphometric and immunohistological analyses revealed that the Insl5(-/-) mice had markedly reduced average islets area and β-cell numbers. Furthermore, immunohistochemistry showed the expression of INSL5 in enteroendocrine cells in the colorectal epithelium and the presence of its putative receptor relaxin family peptide receptor 4 in pancreatic islet cells. These results suggest the potential role of INSL5 signaling in the regulation of insulin secretion and β-cell homeostasis.
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http://dx.doi.org/10.1210/en.2012-1161DOI Listing
October 2012

FISH analysis of circulating CD34+ cells as a new tool for genetic monitoring in MDS: verification of the method and application to 27 MDS patients.

Leuk Res 2010 Oct 11;34(10):1296-301. Epub 2010 Mar 11.

Department of Hematology and Oncology, Georg-August University, Robert-Koch-Str 40, 37075 Goettingen, Germany.

In myelodysplastic syndromes (MDS) chromosomal anomalies can be identified in 50-80% of patients. They have a diagnostic and prognostic impact and are increasingly considered for therapeutic decisions. Cytomorphology and cytogenetic analyses of bone marrow (bm) cells define the goldstandard to diagnose MDS patients and to document treatment response. We present a novel method using peripheral blood (pb) for frequent cytogenetic monitoring: after immunomagnetic cell separation circulating CD34+ cells were analysed by fluorescence in situ hybridization (FISH). We compared FISH analyses of enriched and non-enriched pb and bm cells with conventional chromosome banding analyses of bm metaphases: analysing circulating CD34+ cells by FISH is a sensitive, reliable method to measure the abnormal cell clones in pb. This method is practicable, non-invasive, representative for the clonal situation in the bm, and has a predictive value. Its feasibility was proven in a cohort of 27 MDS patients.
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http://dx.doi.org/10.1016/j.leukres.2010.01.010DOI Listing
October 2010

Inactivation of insulin-like factor 6 disrupts the progression of spermatogenesis at late meiotic prophase.

Endocrinology 2009 Sep 11;150(9):4348-57. Epub 2009 Jun 11.

Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany.

Insulin-like factor 6 (INSL6), a member of the insulin-like superfamily, is predominantly expressed in male germ cells. Expression of the Insl6 is first detected in mouse testis at postnatal d 15 when the first wave of spermatogenesis progresses to pachytene spermatocytes. To elucidate the role of INSL6 in germ cell development, we generated Insl6-deficient mice. The majority of the Insl6-deficient males on a hybrid genetic background exhibited impaired fertility, whereas females were fertile. The number of mature sperm and sperm motility were drastically reduced in the epididymis. The reduced sperm count could be due to apoptotic death of a significant number of developing germ cells. Analysis of germ cell development during the juvenile life showed an arrest of the first wave of spermatogenesis in late meiotic prophase. RNA analysis revealed a significant decrease in expression of late meiotic- and postmeiotic-specific marker genes, whereas expression of early meiotic-specific genes remains unaffected in the Insl6(-/-) testes. These results demonstrate that INSL6 is required for the progression of spermatogenesis.
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http://dx.doi.org/10.1210/en.2009-0201DOI Listing
September 2009

Comparative methylation profiles and telomerase biology of mouse multipotent adult germline stem cells and embryonic stem cells.

Mol Hum Reprod 2009 Jun 18;15(6):345-53. Epub 2009 Mar 18.

Institute of Human Genetics, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany.

Recently, several groups described the isolation of mouse spermatogonial stem cells (SSCs) and their potential to develop to embryonic stem cell (ESC)-like cells, so-called multipotent germline stem cells (mGSCs). We were the first to derive such mGSCs from SSCs isolated from adult mouse testis and, therefore, called these mGSCs multipotent adult germline stem cells (maGSCs). Here, we comparatively analyzed gene-specific and global DNA methylation profiles as well as the telomerase biology of several maGSC and male ESC lines. We show that undifferentiated maGSCs are very similar to undifferentiated male ESCs with regard to global DNA methylation, methylation of pluripotency marker gene loci, telomerase activity and telomere length. Imprinted gene methylation levels were generally lower in undifferentiated maGSCs than in undifferentiated male ESCs, but, compared with undifferentiated mGSCs derived by other groups, more similar to those of male ESCs. Differentiation of maGSCs increased the methylation of three of the four analyzed imprinted genes to almost somatic methylation patterns, but dramatically decreased global DNA methylation. Our findings further substantiate the pluripotency of maGSCs and their potential for regenerative medicine.
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http://dx.doi.org/10.1093/molehr/gap023DOI Listing
June 2009

Directed overexpression of insulin in Leydig cells causes a progressive loss of germ cells.

Mol Cell Endocrinol 2008 Nov 23;295(1-2):79-86. Epub 2008 Jul 23.

Institute of Human Genetics, University of Göttingen, Heinrich-Düker-Weg 12, D-37073 Göttingen, Germany.

The primary goal of this study was to determine the 5'region of the Insl3 gene that specifically targets the expression of human insulin to Leydig cells, and to explore whether the testicular proinsulin is efficiently processed to insulin that is able to rescue the diabetes in different mouse models of diabetes. We show here that the sequence between nucleotides -690 and +4 of mouse Insl3 promoter is sufficient to direct the Leydig cell-specific expression of the human insulin transgene (Insl3-hIns). We also found that the 3'untranslated region (3'UTR) of Insl3 was effective in enhancing transgene expression of the insulin in vivo. Expression analysis revealed that the temporal expression pattern of the hIns transgene in Leydig cells of transgenic testes is roughly the same as that of the endogenous Insl3. Despite the Leydig cells translate human proinsulin and secrete a significant level of free C-peptide into the serum, the Leydig cell-derived insulin is not able to overcome the diabetes in different mouse models of diabetes, suggesting a lack of glucose sensing mechanisms in the Leydig cells. A consequence of overexpression of the human proinsulin in Leydig cells was the decrease of fertility of transgenic males at older ages. Germ cells in transgenic males were able to initiate and complete spermatogenesis. However, there was a progressive and age-dependent degeneration of the germ cells that lead to male infertility with increasing age.
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http://dx.doi.org/10.1016/j.mce.2008.07.007DOI Listing
November 2008

Prenatal diagnosis of Roberts syndrome and detection of an ESCO2 frameshift mutation in a Pakistani family.

Prenat Diagn 2008 Jan;28(1):42-5

Institute of Human Genetics, Otto-von-Guericke University Magdeburg, Germany.

Objectives: We report two siblings with Roberts syndrome (RBS), and an attempt to delineate the underlying molecular mechanism leading to familial recurrence.

Methods: Cytogenetic studies and direct sequencing of the ESCO2 gene were carried out in the second affected fetus and the parents. Fetal DNA was obtained from amniocytes after amniocentesis. Parental DNA was obtained from peripheral blood samples.

Results: Cytogenetic analysis of amniocytes revealed a normal male karyotype in 20 analyzed metaphases and chromosomal aneuploidies in 10 metaphases. All metaphases displayed premature separation of centromeres and puffing of heterochromatic regions near the centromere. A homozygous mutation leading to a frameshift in ESCO2 was identified in the fetal DNA sample. Both parents are heterozygous carriers of the same mutation.

Conclusion: The present case demonstrates the prenatal diagnosis of RBS associated with a frameshift mutation in ESCO2.
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http://dx.doi.org/10.1002/pd.1904DOI Listing
January 2008