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18 pages, 5109 KiB

Open AccessArticle

The Precise Breakpoint Mapping in Paracentric Inversion 10q22.2q23.3 by Comprehensive Cytogenomic Analysis, Multicolor Banding, and Single-Copy Chromosome Sequencing

by Tatyana V. Karamysheva, Tatyana A. Gayner, Eugeny A. Elisaphenko, Vladimir A. Trifonov, Elvira G. Zakirova, Konstantin E. Orishchenko, Mariya A. Prokhorovich, Maria E. Lopatkina, Nikolay A. Skryabin, Igor N. Lebedev and Nikolay B. Rubtsov

Biomedicines 2022, 10(12), 3255; https://doi.org/10.3390/biomedicines10123255 - 14 Dec 2022

Cited by 1 | Viewed by 2550

Abstract

Detection and precise genomic mapping of balanced chromosomal abnormalities in patients with impaired fertility or a clinical phenotype represent a challenge for current cytogenomics owing to difficulties with precise breakpoint localization in the regions enriched for DNA repeats and high genomic variation in [...] Read more.

Detection and precise genomic mapping of balanced chromosomal abnormalities in patients with impaired fertility or a clinical phenotype represent a challenge for current cytogenomics owing to difficulties with precise breakpoint localization in the regions enriched for DNA repeats and high genomic variation in such regions. Here, we present a comprehensive cytogenomic approach to breakpoint mapping in a rare paracentric inversion on 10q (in a patient with oligoasthenoteratozoospermia and necrozoospermia) that does not affect other phenotype traits. Multicolor banding, chromosomal microarray analysis, chromosome microdissection with reverse painting, and single-copy sequencing of the rearranged chromosome were performed to determine the length and position of the inverted region as well as to rule out a genetic imbalance at the breakpoints. As a result, a paracentric 19.251 Mbp inversion at 10q22.2q23.3 was described. The most probable location of the breakpoints was predicted using the hg38 assembly. The problems of genetic counseling associated with enrichment for repeats and high DNA variability of usual breakpoint regions were discussed. Possible approaches for cytogenomic assessment of couples with balanced chromosome rearrangements and problems like reproductive failures were considered and suggested as useful part of effective genetic counseling. Full article

(This article belongs to the Special Issue Advances in Molecular Cytogenetics)

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14 pages, 2827 KiB

Open AccessArticle

Telomere Dysfunction Is Associated with Altered DNA Organization in Trichoplein/Tchp/Mitostatin (TpMs) Depleted Cells

by Angela Lauriola, Pierpaola Davalli, Gaetano Marverti, Andrea Caporali, Sabine Mai and Domenico D’Arca

Biomedicines 2022, 10(7), 1602; https://doi.org/10.3390/biomedicines10071602 - 5 Jul 2022

Cited by 3 | Viewed by 1899

Abstract

Recently, we highlighted a novel role for the protein Trichoplein/TCHP/Mitostatin (TpMs), both as mitotic checkpoint regulator and guardian of chromosomal stability. TpMs-depleted cells show numerical and structural chromosome alterations that lead to genomic instability. This condition is a major driving force in malignant [...] Read more.

Recently, we highlighted a novel role for the protein Trichoplein/TCHP/Mitostatin (TpMs), both as mitotic checkpoint regulator and guardian of chromosomal stability. TpMs-depleted cells show numerical and structural chromosome alterations that lead to genomic instability. This condition is a major driving force in malignant transformation as it allows for the cells acquiring new functional capabilities to proliferate and disseminate. Here, the effect of TpMs depletion was investigated in different TpMs-depleted cell lines by means of 3D imaging and 3D Structured illumination Microscopy. We show that TpMs depletion causes alterations in the 3D architecture of telomeres in colon cancer HCT116 cells. These findings are consistent with chromosome alterations that lead to genomic instability. Furthermore, TpMs depletion changes the spatial arrangement of chromosomes and other nuclear components. Modified nuclear architecture and organization potentially induce variations that precede the onset of genomic instability and are considered as markers of malignant transformation. Our present observations connect the tumor suppression ability of TpMs with its novel functions in maintaining the proper chromosomal segregation as well as the proper telomere and nuclear architecture. Further investigations will investigate the connection between alterations in telomeres and nuclear architecture with the progression of human tumors with the aim of developing personalized therapeutic interventions. Full article

(This article belongs to the Special Issue Advances in Molecular Cytogenetics)

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18 pages, 1822 KiB

Open AccessArticle

Tandem Repeat Diversity in Two Closely Related Hamster Species—The Chinese Hamster (Cricetulus griseus) and Striped Hamster (Cricetulus barabensis)

by Nadezhda G. Ivanova, Irina V. Kartavtseva, Vera N. Stefanova, Dmitrii I. Ostromyshenskii and Olga I. Podgornaya

Biomedicines 2022, 10(4), 925; https://doi.org/10.3390/biomedicines10040925 - 18 Apr 2022

Cited by 3 | Viewed by 2928

Abstract

The Chinese hamster (Cricetulus griseus) and striped hamster (Cricetulus barabensis) are very closely related species with similar karyotypes. The karyotypes differ from each other by one Robertsonian rearrangement and X-chromosome morphology. The level of the tandem repeat (TR) sequences’ [...] Read more.

The Chinese hamster (Cricetulus griseus) and striped hamster (Cricetulus barabensis) are very closely related species with similar karyotypes. The karyotypes differ from each other by one Robertsonian rearrangement and X-chromosome morphology. The level of the tandem repeat (TR) sequences’ evolutional variability is high. The aim of the current work was to trace the TR distribution on the chromosomes of two very closely related species. The striped hamster genome has not yet been sequenced. We classified the Chinese hamster TR in the assemblies available and then compared the mode of the TR distribution in closely related species. Chinese and striped hamsters are separate species due to the relative species specificity of Chinese hamster TR and prominent differences in the TR distribution in both species. The TR variation observed within homologous striped hamster chromosomes is caused by a lack of inbreeding in natural populations. The set of TR tested could be used to examine the CHO lines’ instability that has been observed in heterochromatic regions. Full article

(This article belongs to the Special Issue Advances in Molecular Cytogenetics)

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11 pages, 971 KiB

Open AccessArticle

Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of “8p Inverted Duplication/Deletion Syndrome”

by Darya A. Yurchenko, Marina E. Minzhenkova, Elena L. Dadali, Zhanna G. Markova, Galina E. Rudenskaya, Galina N. Matyushchenko, Ilya V. Kanivets and Nadezda V. Shilova

Biomedicines 2022, 10(3), 567; https://doi.org/10.3390/biomedicines10030567 - 28 Feb 2022

Cited by 4 | Viewed by 3147

Abstract

Inverted duplication syndrome with an adjacent terminal deletion of the short arm of chromosome 8—inv dup del(8p)—is a rare complex structural chromosomal rearrangement with a wide range of clinical manifestations. Molecular cytogenetic variants of chromosomal imbalance depend on the mechanism of rearrangement formation. [...] Read more.

Inverted duplication syndrome with an adjacent terminal deletion of the short arm of chromosome 8—inv dup del(8p)—is a rare complex structural chromosomal rearrangement with a wide range of clinical manifestations. Molecular cytogenetic variants of chromosomal imbalance depend on the mechanism of rearrangement formation. We analyzed the clinical–genetic and molecular cytogenetic characteristics of the 8p inverted duplication/deletion syndrome, as well as the genotype–phenotype correlation in eight unrelated cases with the rearrangement of inv dup del(8p). The main clinical manifestations in all cases are psychomotor and language delay, muscle hypotonia, and dysmorphic facial features. Malformations of the central nervous system, such as corpus callosum agenesis, were found in five cases. Seizures were reported in only one case. We found that the cause of the formation of the rearrangement was generally ectopic recombination (seven out of eight cases) and this was due to U-type exchange in only one case. Depending on the mechanism of formation, the characteristics of the genomic imbalance were different, which made it possible to identify two molecular cytogenetic variants in the cases we describe here. No association between molecular cytogenetic variants and clinical manifestations was found. Full article

(This article belongs to the Special Issue Advances in Molecular Cytogenetics)

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21 pages, 2689 KiB

Open AccessArticle

Cytogenomic Profile of Uterine Leiomyoma: In Vivo vs. In Vitro Comparison

by Alla S. Koltsova, Olga A. Efimova, Olga V. Malysheva, Natalia S. Osinovskaya, Thomas Liehr, Ahmed Al-Rikabi, Natalia Yu. Shved, Iskender Yu. Sultanov, Olga G. Chiryaeva, Maria I. Yarmolinskaya, Nikolai I. Polenov, Vladislava V. Kunitsa, Maka I. Kakhiani, Tatyana G. Tral, Gulrukhsor Kh. Tolibova, Olesya N. Bespalova, Igor Yu. Kogan, Andrey S. Glotov, Vladislav S. Baranov and Anna A. Pendina

Biomedicines 2021, 9(12), 1777; https://doi.org/10.3390/biomedicines9121777 - 26 Nov 2021

Cited by 8 | Viewed by 2953

Abstract

We performed a comparative cytogenomic analysis of cultured and uncultured uterine leiomyoma (UL) samples. The experimental approach included karyotyping, aCGH, verification of the detected chromosomal abnormalities by metaphase and interphase FISH, MED12 mutation analysis and telomere measurement by Q-FISH. An abnormal karyotype was [...] Read more.

We performed a comparative cytogenomic analysis of cultured and uncultured uterine leiomyoma (UL) samples. The experimental approach included karyotyping, aCGH, verification of the detected chromosomal abnormalities by metaphase and interphase FISH, MED12 mutation analysis and telomere measurement by Q-FISH. An abnormal karyotype was detected in 12 out of 32 cultured UL samples. In five karyotypically abnormal ULs, MED12 mutations were found. The chromosomal abnormalities in ULs were present mostly by complex rearrangements, including chromothripsis. In both karyotypically normal and abnormal ULs, telomeres were ~40% shorter than in the corresponding myometrium, being possibly prerequisite to chromosomal rearrangements. The uncultured samples of six karyotypically abnormal ULs were checked for the detected chromosomal abnormalities through interphase FISH with individually designed DNA probe sets. All chromosomal abnormalities detected in cultured ULs were found in corresponding uncultured samples. In all tumors, clonal spectra were present by the karyotypically abnormal cell clone/clones which coexisted with karyotypically normal ones, suggesting that chromosomal abnormalities acted as drivers, rather than triggers, of the neoplastic process. In vitro propagation did not cause any changes in the spectrum of the cell clones, but altered their ratio compared to uncultured sample. The alterations were unique for every UL. Compared to its uncultured counterpart, the frequency of chromosomally abnormal cells in the cultured sample was higher in some ULs and lower in others. To summarize, ULs are characterized by both inter- and intratumor genetic heterogeneity. Regardless of its MED12 status, a tumor may be comprised of clones with and without chromosomal abnormalities. In contrast to the clonal spectrum, which is unique and constant for each UL, the clonal frequency demonstrates up or down shifts under in vitro conditions, most probably determined by the unequal ability of cells with different genetic aberrations to exist outside the body. Full article

(This article belongs to the Special Issue Advances in Molecular Cytogenetics)

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19 pages, 9387 KiB

Open AccessArticle

Prenatal Diagnosis of Small Supernumerary Marker Chromosome 10 by Array-Based Comparative Genomic Hybridization and Microdissected Chromosome Sequencing

by Igor N. Lebedev, Tatyana V. Karamysheva, Eugeny A. Elisaphenko, Alexey I. Makunin, Daria I. Zhigalina, Maria E. Lopatkina, Gleb V. Drozdov, Aleksander D. Cheremnykh, Natalia B. Torkhova, Gulnara N. Seitova, Stanislav A. Vasilyev, Anna A. Kashevarova, Ludmila P. Nazarenko and Nikolay B. Rubtsov

Biomedicines 2021, 9(8), 1030; https://doi.org/10.3390/biomedicines9081030 - 17 Aug 2021

Cited by 6 | Viewed by 3172

Abstract

Interpreting the clinical significance of small supernumerary marker chromosomes (sSMCs) in prenatal diagnosis is still an urgent problem in genetic counselling regarding the fate of a pregnancy. We present a case of prenatal diagnosis of mosaic sSMC(10) in a foetus with a normal [...] Read more.

Interpreting the clinical significance of small supernumerary marker chromosomes (sSMCs) in prenatal diagnosis is still an urgent problem in genetic counselling regarding the fate of a pregnancy. We present a case of prenatal diagnosis of mosaic sSMC(10) in a foetus with a normal phenotype. Comprehensive cytogenomic analyses by array-based comparative genomic hybridization (aCGH), sSMC microdissection with next-generation sequencing (NGS) of microdissected library, fluorescence in situ hybridization (FISH) with locus-specific and telomere-specific DNA probes and quantitative real-time PCR revealed that sSMC(10) had a ring structure and was derived from the pericentromeric region of chromosome 10 with involvement of the 10p11.21-p11.1 and 10q11.21-q11.23 at 1.243 Mb and 7.173 Mb in size, respectively. We observed a difference in the length of sSMC(10) between NGS data of the DNA library derived from a single copy of sSMC(10), and aCGH results that may indicate instability and structural mosaicism for ring chromosomes in foetal cells. The presence of a 9 Mb euchromatin region in the analysed sSMC(10) did not lead to clinical manifestations, and a healthy girl was born at term. We suggest that the ring structure of sSMCs could influence sSMC manifestations and should be taken into account in genetic counselling during prenatal diagnosis. Full article

(This article belongs to the Special Issue Advances in Molecular Cytogenetics)

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10 pages, 1362 KiB

Open AccessArticle

BTK, NUTM2A, and PRPF19 Are Novel KMT2A Partner Genes in Childhood Acute Leukemia

by Elena Zerkalenkova, Svetlana Lebedeva, Aleksandra Borkovskaia, Olga Soldatkina, Olga Plekhanova, Grigory Tsaur, Michael Maschan, Aleksey Maschan, Galina Novichkova and Yulia Olshanskaya

Biomedicines 2021, 9(8), 924; https://doi.org/10.3390/biomedicines9080924 - 30 Jul 2021

Cited by 7 | Viewed by 2869

Abstract

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with acute leukemias, especially in infants. KMT2A is rearranged with a big variety of partner genes and in multiple breakpoint locations. Detection of all types of KMT2A rearrangements is an essential part [...] Read more.

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with acute leukemias, especially in infants. KMT2A is rearranged with a big variety of partner genes and in multiple breakpoint locations. Detection of all types of KMT2A rearrangements is an essential part of acute leukemia initial diagnostics and follow-up, as it has a strong impact on the patients’ outcome. Due to their high heterogeneity, KMT2A rearrangements are most effectively uncovered by next-generation sequencing (NGS), which, however, requires a thorough prescreening by cytogenetics. Here, we aimed to characterize uncommon KMT2A rearrangements in childhood acute leukemia by conventional karyotyping, FISH, and targeted NGS on both DNA and RNA level with subsequent validation. As a result of this comprehensive approach, three novel KMT2A rearrangements were discovered: ins(X;11)(q26;q13q25)/KMT2A-BTK, t(10;11)(q22;q23.3)/KMT2A-NUTM2A, and inv(11)(q12.2q23.3)/KMT2A-PRPF19. These novel KMT2A-chimeric genes expand our knowledge of the mechanisms of KMT2A-associated leukemogenesis and allow tracing the dynamics of minimal residual disease in the given patients. Full article

(This article belongs to the Special Issue Advances in Molecular Cytogenetics)

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10 pages, 17376 KiB

Open AccessCase Report

The First Neocentric, Discontinuous, and Complex Small Supernumerary Marker Chromosome Composed of 7 Euchromatic Blocks Derived from 5 Different Chromosomes

by André Weber, Thomas Liehr, Ahmed Al-Rikabi, Simal Bilgen, Uwe Heinrich, Jenny Schiller and Markus Stumm

Biomedicines 2022, 10(5), 1102; https://doi.org/10.3390/biomedicines10051102 - 10 May 2022

Cited by 4 | Viewed by 2545

Abstract

Background: The majority of small supernumerary marker chromosomes (sSMCs) are derived from one single chromosome. Complex sSMCs instead consist of two to three genomic segments, originating from different chromosomes. Additionally, discontinuous sSMCs have been seen; however, all of them are derived from one [...] Read more.

Background: The majority of small supernumerary marker chromosomes (sSMCs) are derived from one single chromosome. Complex sSMCs instead consist of two to three genomic segments, originating from different chromosomes. Additionally, discontinuous sSMCs have been seen; however, all of them are derived from one single chromosome. Here, we reported a 41 year-old patient with infertility, hypothyroidism, rheumatism, and degenerative spine and schizoaffective disorder, being a carrier of a unique, complex, and discontinuous sSMC. Methods: The sSMC was characterized in detail by banding and molecular cytogenetics including fluorescence in situ hybridization (FISH) and array-comparative genomic hybridization (aCGH), as well as by optical genome mapping (OGM). Results: The neocentric sSMC characterized here contained seven portions of five different chromosomes and was present in ~50% of both peripheral blood cells and buccal mucosa cells. aCGH and OGM revealed gains of 8q12.3q12.3, 8q22.3–8q23.1, 9q33.3–9q34.11, 14q21.1–14q21.1, 14q21.1–14q21.2, 15q21.2–15q21.2, and 21q21.1–21q21.1. Furthermore, glass-needle based microdissection and reverse FISH, as well as FISH with locus-specific probes confirmed these results. The exact order of the involved euchromatic blocks could be decoded by OGM. Conclusions: Among the >7000 reported sSMCs in the literature, this is the only such complex, discontinuous, and neocentric marker with a centric minute shape. Full article

(This article belongs to the Special Issue Advances in Molecular Cytogenetics)

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