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author:("lihr, Thomas")
1.  Hyperdiploidy associated with T315I mutation in BCR-ABL kinase domain in an accelerated phase-chronic myeloid leukemia case 
Molecular Cytogenetics  2014;7(1):89.
Background
Chronic myeloid leukemia (CML) is genetically characterized by the occurrence of a reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22, i.e. the Philadelphia (Ph) chromosome. During CML progression 60–80% of the cases acquire additional genetic changes. Even though hyperdiploidy is not a rare finding in advanced phase-CML, hyperdiploidy together with a T315I kinase domain (KD) mutation in the BCR-ABL gene has not yet been reported.
Results
A complete cytogenetic and molecular cytogenetic analysis; molecular biology methods such as quantitative reverse transcription polymerase chain reaction (RQ-PCR) and allele-specific oligonucleotide (ASO)-PCR; and immunophenotypically confirmed CML in acceleration phase (AP). Our case revealed the presence of hyperdiploidy including multiple copies of the Ph chromosome, presence of b3a2 fusion transcript,T315I mutation in BCR-ABL KD in pre imatinib mesylate (IM) treatment. The ratio of BCR-ABL/ABL expression in post nilotinib treatment was 0.07% on international scale.
Conclusions
The patient demonstrated a good response to nilotinib after imatinib failure; while the hyperdiploid clone disappeared the T315I mutation remained during follow-up. The underlying mechanisms and prognostic implications of these cytogenetic abnormalities are discussed.
doi:10.1186/s13039-014-0089-0
PMCID: PMC4305221  PMID: 25621010
Chronic myeloid leukemia; Philadelphia chromosome; Hyperdiploidy; T315I mutation; Prognostic factors
2.  Comprehensive chronic lymphocytic leukemia diagnostics by combined multiplex ligation dependent probe amplification (MLPA) and interphase fluorescence in situ hybridization (iFISH) 
Molecular Cytogenetics  2014;7(1):79.
Background
Banding-karyotyping and metaphase-directed-fluorescence-in-situhybridization (FISH) may be hampered by low mitotic index in leukemia. Interphase FISH (iFISH) is a way out here, however, testing many probes at the same time is protracted and expensive. Here multiplex-ligation-dependent-probe-amplification (MLPA) was used retrospectively in chronic lymphocytic leukemia (CLL) samples initially studied by banding cytogenetics and iFISH. Detection rates of iFISH and MLPA were compared and thus a cost-efficient scheme for routine diagnostics is proposed.
Results
Banding cytogenetics was done successfully in 67/85 samples. DNA was extracted from all 85 CLL samples. A commercially available MLPA probe set directed against 37 loci prone to be affected in hematological malignancies was applied. Besides, routine iFISH was done by commercially available probes for following regions: 11q22.3, 12p11.2-q11.1, 13q14.3, 13q34, 14q32.33 and 17p13.1. MLPA results were substantiated by iFISH using corresponding locus-specific probes.
Aberrations were detected in 67 of 85 samples (~79%) applying banding cytogenetics, iFISH and MLPA. A maximum of 8 aberrations was detected per sample; however, one aberration per sample was found most frequently. Overall 163 aberrations were identified. 15 of those (~9%) were exclusively detected by banding cytogenetics, 95 were found by MLPA (~58%) and 100 (~61%) by routine iFISH. MLPA was not able to distinguish reliably between mono- and biallelic del(13)(q14.3q14.3), which could be easily identified as well as quantified by routine iFISH. Also iFISH was superior to MLPA in samples with low tumor cell load. On the other hand MLPA detected additional aberrations in 22 samples, two of them being without any findings after routine iFISH.
Conclusions
Both MLPA and routine iFISH have comparable detection rates for aberrations being typically present in CLL. As MLPA can detect also rare chromosomal aberrations it should be used as an initial test if routine cytogenetics is not possible or non-informative. Still iFISH should be used additionally to distinguish mono- from biallelic deletions and also to determine rate of mosaicism for 13q14.2 to 13q14.3. In case MLPA is negative the corresponding CLL samples should be tested at least by iFISH using the standard probe set to.
Electronic supplementary material
The online version of this article (doi:10.1186/s13039-014-0079-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13039-014-0079-2
PMCID: PMC4247644  PMID: 25435911
Chronic lymphocytic leukemia (CLL); Chromosomal aberrations; Multiplex ligation-dependent probe amplification (MLPA); Fluorescence in situ hybridization (FISH)
3.  A Novel Cryptic Three-Way Translocation t(2;9;18)(p23.2;p21.3;q21.33) with Deletion of Tumor Suppressor Genes in 9p21.3 and 13q14 in a T-Cell Acute Lymphoblastic Leukemia 
Acute leukemia often presents with pure chromosomal resolution; thus, aberrations may not be detected by banding cytogenetics. Here, a case of 26-year-old male diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and a normal karyotype after standard GTG-banding was studied retrospectively in detail by molecular cytogenetic and molecular approaches. Besides fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and high resolution array-comparative genomic hybridization (aCGH) were applied. Thus, cryptic chromosomal aberrations not observed before were detected: three chromosomes were involved in a cytogenetically balanced occurring translocation t(2;9;18)(p23.2;p21.3;q21.33). Besides a translocation t(10;14)(q24;q11) was identified, an aberration known to be common in T-ALL. Due to the three-way translocation deletion of tumor suppressor genes CDKN2A/INK4A/p16, CDKN2B/INK4B/p15, and MTAP/ARF/p14 in 9p21.3 took place. Additionally RB1 in 13q14 was deleted. This patient, considered to have a normal karyotype after low resolution banding cytogenetics, was treated according to general protocol of anticancer therapy (ALL-BFM 95).
doi:10.1155/2014/357123
PMCID: PMC4206928  PMID: 25374696
4.  Supraphysiological androgen levels induce cellular senescence in human prostate cancer cells through the Src-Akt pathway 
Molecular Cancer  2014;13(1):214.
Background
Prostate cancer (PCa) is the second leading cause of cancer mortality of men in Western countries. The androgen receptor (AR) and AR-agonists (androgens) are required for the development and progression of the normal prostate as well as PCa. However, it is discussed that in addition to their tumor promoting activity, androgens may also exhibit tumor suppressive effects. A biphasic growth response to androgens a growth-promoting and -inhibition has been observed that suggests that administration of supraphysiological androgen levels mediates growth reduction in AR expressing PCa cells.
Methods
Detection of senescence markers, three dimensional interphase fluorescence in situ hybridization (3D-iFISH), qRT-PCR, Western blotting, detection of GFP fusions, prostatectomy, ex vivo culturing.
Results
Here, we describe that supraphysiological levels of androgens induce cell cycle arrest and markers of cellular senescence in human PCa cells, which may in part explain the growth inhibitory role of androgens. The expression of the senescence associated beta galactosidase is observed by treatment with the natural androgen DHT or the less metabolized synthetic androgen R1881. The induction of senescence marker was detected in human PCa cell lines as well as in human primary PCa tissue derived from prostatectomy treated ex vivo. Using interphase FISH (iFISH) suggests that the androgen-induced cellular senescence is associated with localizing the genomic E2F1 locus to senescence associated heterochromatic foci. Analysis of different signaling pathways in LNCaP cells suggest that the p16-Rb-E2F1 pathway is essential for the induction of cellular senescence since treatment with siRNA directed against p16 reduces the level of androgen-induced cellular senescence. Based on the rapid induction of androgen-mediated cellular senescence we identified the Src-PI3K-Akt-signaling pathway and autophagy being in part involved in androgen regulation.
Conclusions
Taken together, our data suggest that AR-agonists at supraphysiological levels mediate induction of cellular senescence in human PCa cells, which may have a protective anti-cancer role. These results provide also new insights for understanding androgen-mediated regulation of PCa growth.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-214) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-4598-13-214
PMCID: PMC4171558  PMID: 25216853
Nuclear receptor; Non-genomic signaling; Tumor suppression; Cellular senescence; Autophagy
5.  An adult B-cell precursor acute lymphoblastic leukemia with multiple secondary cytogenetic aberrations 
Molecular Cytogenetics  2014;7(1):60.
Background
We report a clinically diagnosed acute lymphoblastic leukemia (ALL) with yet unreported secondary chromosomal aberrations.
Results
A complete cytogenetic and molecular cytogenetic analysis, using GTG banding, fluorescence in situ hybridization (FISH) and array-proven multicolor banding (aMCB), for a female patient with clinically diagnosed ALL and immunophenotypically confirmed pre-B ALL (FAB classifications), revealed the presence of a complex structural rearrangement, der (2) (20qter- > 20q13.33::2q21- > 2p14::2q21 > 2qter) along with t (9;22) (q34;q11), t (12;14) (q12;p12) and a monosomy of chromosome 7.
Conclusions
Molecular cytogenetic studies are suited best for identification and characterization of chromosomal rearrangements in acute leukemia. Single case reports as well as large scale studies are necessary to provide further insights in karyotypic changes taking place in human malignancies.
doi:10.1186/s13039-014-0060-0
PMCID: PMC4172788  PMID: 25254075
Acute lymphoblastic leukemia; Secondary chromosomal abnormalities; Philadelphia chromosome; Fluorescence in situ hybridization; Array-proven multicolor banding; Prognostic factors
6.  Genomic organization of repetitive DNAs and its implications for male karyotype and the neo-Y chromosome differentiation in Erythrinus erythrinus (Characiformes, Erythrinidae) 
Comparative Cytogenetics  2014;8(2):139-151.
Studies have demonstrated the effective participation of repetitive DNA sequences in the origin and differentiation of the sex chromosomes in some biological groups. In this study several microsatellites and retrotranposable sequences were cytogenetically mapped in the Erythrinus erythrinus (Bloch & Schneider, 1801) male genome (karyomorph C), focusing on the distribution of these sequences in the sex chromosomes and in the evolutionary processes related to their differentiation. Males of E. erythrinus – karyomorph C – present 2n = 51 chromosomes (7m + 2sm + 6st + 36a), including the X1X2Y sex chromosomes. The C-positive heterochromatin has a predominant localization on the centromeric region of most chromosome pairs, but also in some telomeric regions. The 5S rDNA sites are located in the centromeric region of 27 chromosomes, including 26 acrocentric ones and the metacentric Y chromosome. The retrotransposons Rex 1 and Rex 6 show a dispersed pattern in the karyotype, contrasting with the Rex 3 distribution which is clearly co-localized with all the 27 5S rDNA sites. The microsatellite sequences show a differential distribution, some of them restricted to telomeric and/or interstitial regions and others with a scattered distribution on the chromosomes. However, no preferential accumulation of these elements were observed in the neo-Y chromosome, in contrast to what usually occurs in simple sex chromosome systems.
doi:10.3897/CompCytogen.v8i2.7597
PMCID: PMC4137284  PMID: 25147625
FISH; microsatellites; retrotransposable sequences; sex chromosomes
7.  De novo 393 kb microdeletion of 7p11.2 characterized by aCGH in a boy with psychomotor retardation and dysmorphic features 
Meta Gene  2014;2:274-282.
We report on a 27 month old boy presenting with psychomotor delay and dysmorphic features, mainly mild facial asymmetry, prominent cup-shaped ears, long eyelashes, open mouth appearance and slight abnormalities of the hands and feet. Array comparative genomic hybridization revealed a 393 kb microdeletion in 7p11.2. We discuss the possible involvement of CHCHD2, GBAS, MRPS17, SEPT14 and PSPH on our patient's phenotype. Additionally, we studied the expression of two other genes deleted in the patient, CCT6A and SUMF2, for which there is scarce data in the literature. Based on current knowledge and the de novo occurrence of this finding in our proband we presume that the aberration is likely to be pathogenic in our case. However, a single gene disorder, elsewhere in the genome or in this very region cannot be ruled out. Further elucidation of the properties of this chromosomal region, as well as of the role of the genes involved will be needed in order to draw safe conclusions regarding the association of the chromosomal deletion with the patient's features.
Highlights
•We report in detail the clinical and cytogenetic findings of a 27-month old male.•We compare our findings with current literature and online databases.•We discuss the possible involvement of certain genes in our patient’s phenotype.
doi:10.1016/j.mgene.2014.03.004
PMCID: PMC4287824  PMID: 25606410
Deletion 7p11.2; Psychomotor delay; Dysmorphic features; CHCHD2; GBAS; MRPS17; SEPT14; PSPH; CCT6A; SUMF2
8.  First Molecular Cytogenetic High Resolution Characterization of the NIH 3T3 Cell Line by Murine Multicolor Banding 
Since being established in 1963, the murine fibroblast cell line NIH 3T3 has been used in thousands of studies. NIH 3T3 immortalized spontaneously and became tetraploid shortly after its establishment. Here we report the first molecular cytogenetic characterization of NIH 3T3 using fluorescence in situ hybridization based multicolor banding (mcb). Overall, a complex rearranged karyotype presenting 16 breakpoints was characterized. Also it was possible to deduce the resulting gains and losses of copy numbers in NIH 3T3. Overall, only 1.8% of the NIH 3T3 genome is disome, 26.2% tri-, 60% tetra-, 10.8% quinta-, and 1.2% hexasome. Strikingly, the cell line gained only 4 derivative chromosomes since its first cytogenetic description in 1989. An attempt to align the observed imbalances of the studied cell line with their homologous regions in humans gave the following surprising result: NIH 3T3 shows imbalances as typically seen in human solid cancers of ectodermal origin.
doi:10.1369/0022155413476868
PMCID: PMC3621507  PMID: 23321776
NIH 3T3 cell line; murine multicolor banding (mcb); cytogenetics; genetics; fluorescence in situ hybridization (FISH)
9.  Chromosomal Mapping of Repetitive DNAs in Triportheus trifurcatus (Characidae, Characiformes): Insights into the Differentiation of the Z and W Chromosomes 
PLoS ONE  2014;9(3):e90946.
Repetitive DNA sequences play an important role in the structural and functional organization of chromosomes, especially in sex chromosome differentiation. The genus Triportheus represents an interesting model for such studies because all of its species analyzed so far contain a ZZ/ZW sex chromosome system. A close relationship has been found between the differentiation of the W chromosome and heterochromatinization, with the involvement of different types of repetitive DNA in this process. This study investigated several aspects of this association in the W chromosome of Triportheus trifurcatus (2n = 52 chromosomes), including the cytogenetic mapping of repetitive DNAs such as telomeric sequences (TTAGGG)n, microsatellites and retrotransposons. A remarkable heterochromatic segment on the W chromosome was observed with a preferential accumulation of (CAC)10, (CAG)10, (CGG)10, (GAA)10 and (TA)15. The retrotransposons Rex1 and Rex3 showed a general distribution pattern in the chromosomes, and Rex6 showed a different distribution on the W chromosome. The telomeric repeat (TTAGGG)n was highly evident in both telomeres of all chromosomes without the occurrence of ITS. Thus, the differentiation of the W chromosome of T. trifurcatus is clearly associated with the formation of heterochromatin and different types of repetitive DNA, suggesting that these elements had a prominent role in this evolutionary process.
doi:10.1371/journal.pone.0090946
PMCID: PMC3954618  PMID: 24632562
10.  X chromosome aneuploidy in the Alzheimer’s disease brain 
Background
Although the link between brain aging and Alzheimer’s disease (AD) is a matter of debate, processes hallmarking cellular and tissue senescence have been repeatedly associated with its pathogenesis. Here, we have studied X chromosome aneuploidy (a recognized feature of aged cell populations) in the AD brain.
Results
Extended molecular neurocytogenetic analyses of X chromosome aneuploidy in 10 female AD as well as 10 age and sex matched female control postmortem brain samples was performed by multiprobe/quantitative FISH. Additionally, aneuploidy rate in the brain samples of 5 AD and as 5 age and sex matched control subjects were analyzed by interphase chromosome-specific multicolor banding (ICS-MCB). Totally, 182,500 cells in the AD brain and 182,500 cells in the unaffected brain were analyzed. The mean rate of X chromosome aneuploidy in AD samples was approximately two times higher than in control (control: mean - 1.32%, 95% CI 0.92- 1.71%; AD: mean - 2.79%, 95% CI 1.88-3.69; P = 0.013). One AD sample demonstrated mosaic aneuploidy of chromosome X confined to the hippocampus affecting about 10% of cells. ICS-MCB confirmed the presence of X chromosome aneuploidy in the hippocampal tissues of AD brain (control: mean - 1.74%, 95% CI 1.38- 2.10%; AD: mean - 4.92%, 95% CI 1.14-8.71; P < 0.001).
Conclusions
Addressing X chromosome number variation in the brain, we observed that somatically acquired (post-zygotic) aneuploidy causes large-scale genomic alterations in neural cells of AD patients and, therefore, can be involved in pathogenesis of this common neurodegenerative disorder. In the context of debates about possible interplay between brain aging and AD neurodegeneration, our findings suggest that X chromosome aneuploidy can contribute to both processes. To this end we conclude that mosaic aneuploidy in the brain is a new non-heritable genetic factor predisposing to AD.
doi:10.1186/1755-8166-7-20
PMCID: PMC3995993  PMID: 24602248
Alzheimer’s disease; Aneuploidy; Brain; Chromosome instability; Chromosome X; Molecular cytogenetics; Aging
11.  The strength of combined cytogenetic and mate-pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2 
Next-generation mate-pair sequencing (MPS) has revealed that many constitutional complex chromosomal rearrangements (CCRs) are associated with local shattering of chromosomal regions (chromothripsis). Although MPS promises to identify the molecular basis of the abnormal phenotypes associated with many CCRs, none of the reported mate-pair sequenced complex rearrangements have been simultaneously studied with state-of-the art molecular cytogenetic techniques. Here, we studied chromothripsis-associated CCR involving chromosomes 2, 5 and 7, associated with global developmental and psychomotor delay and severe speech disorder. We identified three truncated genes: CDH12, DGKB and FOXP2, confirming the role of FOXP2 in severe speech disorder, and suggestive roles of CDH12 and/or DGKB for the global developmental and psychomotor delay. Our study confirmes the power of MPS for detecting breakpoints and truncated genes at near nucleotide resolution in chromothripsis. However, only by combining MPS data with conventional G-banding and extensive fluorescence in situ hybridizations could we delineate the precise structure of the derivative chromosomes.
doi:10.1038/ejhg.2013.147
PMCID: PMC3925275  PMID: 23860044
mate-pair sequencing; complex chromosomal rearrangements; chromothripsis; FOXP2; CDH12; DGKB
12.  Monitoring of gas station attendants exposure to benzene, toluene, xylene (BTX) using three-color chromosome painting 
Background
Chronic exposure of BTX (benzene, toluene, xylene) may lead to progressive degeneration of bone marrow, aplastic anemia and/or leukemia. In Brazil there is no self-service fuel in gas stations and attendants fill the fuel themselves. Due to this they are chronically exposed to high concentration of BTX. Occupational exposure to benzene has been associated with increased chromosomal aberrations in peripheral blood lymphocytes. Fluorescence in situ hybridization (FISH) using whole chromosome painting (wcp) probes allows the rapid detection of chromosomal aberration. In the present study three-color wcp probes for chromosomes 1, 2 and 4 were used for monitoring 60 gas station attendants.
Results
Blood tests were done and interviews were conducted for each worker. For searching for possible associations between the clinical characteristics and the frequency of chromosomal aberrations the workers were divided into two groups (≤ 10 chromosomal abnormalities per 1,000 metaphases and > 10 chromosomal abnormalities per 1,000 metaphases).The studied workers had a low median age (36 year), albeit long period of BTX exposure (median was 16 years). Low prevalence of smoking and moderate consumption of alcoholic beverages were found in this population. The cytogenetic analysis showed 16.6% (10/60) of workers with a high frequency of chromosomal abnormalities (>10 chromosomal abnormalities per 1,000 metaphases). Translocations were the most frequently observed chromosome aberration. The statistical analysis revealed highly significant differences in skin color (p = 0.002) and a weak significant differences in gender (p = 0.052) distribution between the two groups.
Conclusion
16.6% of the studied population showed elevated frequencies of chromosomal abnormalities, which is highly likely to be correlated with their exposure to BTX during their work. Therefore, further studies are needed for better characterize the work associated damage of the genome in gas station workers. It is necessary to better understand the risks that these workers are exposed, so that we can be effective in preventing diseases and maintaining the health of these workers and possibly the offspring.
doi:10.1186/1755-8166-7-15
PMCID: PMC3974043  PMID: 24576355
Benzene; Toluene; Xylene; Monitoring; Cytogenetic; Painting; Chromosome
13.  Reviewer acknowledgement 2014 
Contributing reviewers
The Editors of Molecular Cytogenetics would like to thank all our reviewers who have contributed to the journal in volume 6 (2013).
doi:10.1186/1755-8166-7-11
PMCID: PMC3924429  PMID: 24529454
14.  Proximal 10q duplication in a child with severe central hypotonia characterized by array-comparative genomic hybridization: A case report and review of the literature 
Proximal 10q duplication is a well-defined but rare genetic syndrome. Duplication of proximal segments of the long arm of chromosome 10 results in a pattern of malformations, which are distinct from those of the more common distal 10q trisomy syndrome. The present study describes the case of a boy with phenotypic abnormalities (severe central hypotonia, mild ataxia, moderate developmental delay and mild dysmorphic features), due to duplication of chromosome region, 10q11.21→q11.22, which was characterized by the array-comparative genomic hybridization (CGH) technique. The phenotypic findings were compared with those in eight additional similar published cases. Major similarities have emerged, suggesting a likely minimal critical region. However, only detailed characterization of additional cases may provide firm conclusions.
doi:10.3892/etm.2014.1520
PMCID: PMC3964923  PMID: 24669257
10q duplication syndrome; array-comparative genomic hybridization; developmental delay; 10q11.21→q11.22
15.  16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2 
Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2–p12.2 from microscopically similar euchromatic variants of 16p11.2. Patient 1 was a girl of 18 with autism, moderate intellectual disability, behavioural difficulties, dysmorphic features and a 7.71-Mb (megabase pair) duplication (16:21 521 005–29 233 146). Patient 2 had a 7.81-Mb duplication (16:21 382 561–29 191 527), speech delay and obsessional behaviour as a boy and, as an adult, short stature, macrocephaly and mild dysmorphism. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An additional 1.11-Mb CNV of 10q11.21 in Patient 1 was a possible modifier containing the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene. In contrast, the euchromatic variants in Patients 3 and 4 were amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353–32 898 635). Paralogous pyrosequencing gave a total copy number of 3–8 in controls and 8 to >10 in Patients 3 and 4. The 16p11.2–p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2–p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis.
doi:10.1038/ejhg.2012.144
PMCID: PMC3548261  PMID: 22828807
chromosomes, human, pair 16; chromosome duplication; 16p11.2–p12.2; DNA array; euchromatic variant; copy number variation
16.  Uniparental disomy - clinical consequences due to imprinting and activation of recessive genes 
Molecular Cytogenetics  2014;7(Suppl 1):I21.
doi:10.1186/1755-8166-7-S1-I21
PMCID: PMC4042265  PMID: 24940361
17.  Small supernumerary marker chromosomes – an update 
Molecular Cytogenetics  2014;7(Suppl 1):I11.
doi:10.1186/1755-8166-7-S1-I11
PMCID: PMC4043994  PMID: 24940369
19.  In memoriam of Anna D Polityko (17.12.1959 — 20.04.2013) 
doi:10.1186/1755-8166-7-2
PMCID: PMC3895789  PMID: 24423091
20.  De novo acute myeloid leukemia subtype-M4 with initial trisomy 8 and later acquired t(3;12)(q26;p12) leading to ETV6/MDS1/EVI1 fusion transcript expression: A case report 
Oncology Letters  2014;7(3):787-790.
The t(3;12)(q26;p13) translocation is a recurrent chromosomal aberration observed in myeloid malignancies. The translocation results in the generation of the ETV6/myelodysplastic syndrome 1 (MDS1)/ectopic viral integration site 1 (EVI1) fusion gene. However, the present case report is the first to present this rearrangement in acute myelogeneous leukemia (AML)-M4. Notably, this case is the first report of AML-M4 with an initial trisomy 8 and secondary acquired t(3;12)(q26;p13). Cells harboring the t(3;12) translocation were found to exhibit a higher proliferative capacity than cells with pure trisomy 8, which is consistent with the role of the ETV6/MDS1/EVI1 fusion transcript in the development and progression of malignancy.
doi:10.3892/ol.2014.1784
PMCID: PMC3919885  PMID: 24527086
t(3;12)(q26;p13); ETV6/MDS1/EVI1; acute myeloid leukemia M4; trisomy 8
21.  Characterization of a rare short arm heteromorphism of chromosome 22 in a girl with down-syndrome like facies 
Chromosomal heteromorphisms are described as interindividual variation of chromosomes without phenotypic consequence. Chromosomal polymorphisms detected include most regions of heterochromatin of chromosomes 1, 9, 16 and Y and the short arms of all acrocentric chromosomes. Here, we report a girl with Down-syndrome such as facies and tremendously enlarged short arm of a chromosome 22. Fluorescence in situ hybridization (FISH) with a probe specific for all acrocentric short arms revealed that the enlargement p arms of the chromosome 22 in question contained exclusively heterochromatic material derived from an acrocentric short arm. Parental studies identified a maternal origin of this heteromorphism. Cryptic trisomy 21 of the Down-syndrome critical region was excluded by a corresponding FISH-probe. Here, we report, to the best of our knowledge, largest ever seen chromosome 22 short arm, being ~×1.5 larger than the normal long arm.
doi:10.4103/0971-6866.132767
PMCID: PMC4065488  PMID: 24959023
Acrocentric p arms; fluorescence in situ hybridization; heteromorphism; karyotype
22.  First detailed reconstruction of the karyotype of Trachypithecus cristatus (Mammalia: Cercopithecidae) 
Background
The chromosomal homologies of human (Homo sapiens = HSA) and silvered leaf monkey (Trachypithecus cristatus = TCR) have been previously studied by classical chromosome staining and by fluorescence in situ hybridization (FISH) applying chromosome-specific DNA probes of all human chromosomes in the 1980s and 1990s, respectively.
Results
However, as the resolution of these techniques is limited we used multicolor banding (MCB) at an ~250-band level, and other selected human DNA probes to establish a detailed chromosomal map of TCR. Therefore it was possible to precisely determine evolutionary conserved breakpoints, orientation of segments and distribution of specific regions in TCR compared to HSA. Overall, 69 evolutionary conserved breakpoints including chromosomal segments, which failed to be resolved in previous reports, were exactly identified and characterized.
Conclusions
This work also represents the first molecular cytogenetic one characterizing a multiple sex chromosome system with a male karyotype 44,XY1Y2. The obtained results are compared to other available data for old world monkeys and drawbacks in hominoid evolution are discussed.
doi:10.1186/1755-8166-6-58
PMCID: PMC3914712  PMID: 24341374
Evolutionary conserved breakpoints; Multicolor banding; Old world monkeys; XY1Y2 sex system
23.  Karyotype and cytogenetic mapping of 9 classes of repetitive DNAs in the genome of the naked catfish Mystus bocourti (Siluriformes, Bagridae) 
Background
In the present study, conventional and molecular cytogenetic studies were performed in the naked catfish Mystus bocourti (Siluriformes, Bagridae). Besides the conventional Giemsa staining, fluorescence in situ hybridization (FISH) using nine classes of repetitive DNAs namely 5S and 18S rDNAs, U2 snRNA, the microsatellites (CA)15 and (GA)15, telomeric repeats, and the retrotransposable elements Rex1, 3 and 6. was also performed.
Results
M. bocourti had 2n = 56 chromosomes with a karyotype composed by 11 m + 11 sm + 6 st/a and a fundamental number (NF) equal to 100 in both sexes. Heteromorphic sex chromosome cannot be identified. The U2 snRNA, 5S and 18S rDNA were present in only one pair of chromosomes but none of them in a syntenic position. Microsatellites (CA)15 and (GA)15 showed hybridization signals at subtelomeric regions of all chromosomes with a stronger accumulation into one specific chromosomal pair. FISH with the telomeric probe revealed hybridization signals on each telomere of all chromosomes and interstitial telomeric sites (ITS) were not detected. The retrotransposable elements Rex1, 3 and 6 were generally spread throughout the genome.
Conclusions
In general, the repetitive sequences were not randomly distributed in the genome, suggesting a pattern of compartmentalization on the heterochromatic region of the chromosomes. Little is known about the structure and organization of bagrid genomes and the knowledge of the chromosomal distribution of repetitive DNA sequences in M. bocourti represents the first step for achieving an integrated view of their genomes.
doi:10.1186/1755-8166-6-51
PMCID: PMC4176197  PMID: 24266901
Fish cytogenetics; Major + minor rDNA sites heterochromatin; Molecular cytogenetics
24.  Complex small supernumerary marker chromosomes – an update 
Background
Complex small supernumerary marker chromosomes (sSMC) constitute one of the smallest subgroups of sSMC in general. Complex sSMC consist of chromosomal material derived from more than one chromosome; the best known representative of this group is the derivative chromosome 22 {der(22)t(11;22)} or Emanuel syndrome. In 2008 we speculated that complex sSMC could be part of an underestimated entity.
Results
Here, the overall yet reported 412 complex sSMC are summarized. They constitute 8.4% of all yet in detail characterized sSMC cases. The majority of the complex sSMC is contributed by patients suffering from Emanuel syndrome (82%). Besides there are a der(22)t(8;22)(q24.1;q11.1) and a der(13)t(13;18)(q11;p11.21) or der(21)t(18;21)(p11.21;q11.1) = der(13 or 21)t(13 or 21;18) syndrome. The latter two represent another 2.6% and 2.2% of the complex sSMC-cases, respectively. The large majority of complex sSMC has a centric minute shape and derives from an acrocentric chromosome. Nonetheless, complex sSMC can involve material from each chromosomal origin. Most complex sSMC are inherited form a balanced translocation in one parent and are non-mosaic. Interestingly, there are hot spots for the chromosomal breakpoints involved.
Conclusions
Complex sSMC need to be considered in diagnostics, especially in non-mosaic, centric minute shaped sSMC. As yet three complex-sSMC-associated syndromes are identified. As recurrent breakpoints in the complex sSMC were characterized, it is to be expected that more syndromes are identified in this subgroup of sSMC. Overall, complex sSMC emphasize once more the importance of detailed cytogenetic analyses, especially in patients with idiopathic mental retardation.
doi:10.1186/1755-8166-6-46
PMCID: PMC4129180  PMID: 24171835
Complex small supernumerary marker chromosomes (sSMC); Genotype-phenotype correlation; Mosaicism; SSMC shape; Emanuel syndrome
25.  Chromosomal abnormalities in couples with repeated fetal loss: An Indian retrospective study 
Indian Journal of Human Genetics  2013;19(4):415-422.
BACKGROUND:
Recurrent pregnancy loss is a common occurrence and a matter of concern for couples planning the pregnancy. Chromosomal abnormalities, mainly balanced rearrangements, are common in couples with repeated miscarriages.
PURPOSE:
The purpose of this study is to evaluate the contribution of chromosomal anomalies causing repeated spontaneous miscarriages and provide detailed characterization of a few structurally altered chromosomes.
MATERIALS AND METHODS:
A retrospective cytogenetic study was carried out on 4859 individuals having a history of recurrent miscarriages. The cases were analyzed using G-banding and fluorescence in situ hybridization wherever necessary.
RESULTS:
Chromosomal rearrangements were found in 170 individuals (3.5%). Translocations were seen in 72 (42.35%) cases. Of these, reciprocal translocations constituted 42 (24.70%) cases while Robertsonian translocations were detected in 30 (17.64%) cases. 7 (4.11%) cases were mosaic, 8 (4.70%) had small supernumerary marker chromosomes and 1 (0.6%) had an interstitial microdeletion. Nearly, 78 (1.61%) cases with heteromorphic variants were seen of which inversion of Y chromosome (57.70%) and chromosome 9 pericentromeric variants (32.05%) were predominantly involved.
CONCLUSIONS:
Chromosomal analysis is an important etiological investigation in couples with repeated miscarriages. Characterization of variants/marker chromosome enable calculation of a more precise recurrent risk in a subsequent pregnancy thereby facilitating genetic counseling and deciding further reproductive options.
doi:10.4103/0971-6866.124369
PMCID: PMC3897136  PMID: 24497706
Break points; chromosomal abnormalities; recurrent loss of pregnancy; small supernumerary marker chromosome; translocations

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