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13 pages, 2943 KiB

Open AccessArticle

Optical Genome Mapping as a Tool to Unveil New Molecular Findings in Hematological Patients with Complex Chromosomal Rearrangements

by Nicoletta Coccaro, Antonella Zagaria, Luisa Anelli, Francesco Tarantini, Giuseppina Tota, Maria Rosa Conserva, Cosimo Cumbo, Elisa Parciante, Immacolata Redavid, Giuseppe Ingravallo, Crescenzio Francesco Minervini, Angela Minervini, Giorgina Specchia, Pellegrino Musto and Francesco Albano

Genes 2023, 14(12), 2180; https://doi.org/10.3390/genes14122180 - 5 Dec 2023

Viewed by 1053

Abstract

Standard cytogenetic techniques (chromosomal banding analysis—CBA, and fluorescence in situ hybridization—FISH) show limits in characterizing complex chromosomal rearrangements and structural variants arising from two or more chromosomal breaks. In this study, we applied optical genome mapping (OGM) to fully characterize two cases of [...] Read more.

Standard cytogenetic techniques (chromosomal banding analysis—CBA, and fluorescence in situ hybridization—FISH) show limits in characterizing complex chromosomal rearrangements and structural variants arising from two or more chromosomal breaks. In this study, we applied optical genome mapping (OGM) to fully characterize two cases of complex chromosomal rearrangements at high resolution. In case 1, an acute myeloid leukemia (AML) patient showing chromothripsis, OGM analysis was fully concordant with classic cytogenetic techniques and helped to better refine chromosomal breakpoints. The OGM results of case 2, a patient with non-Hodgkin lymphoma, were only partially in agreement with previous cytogenetic analyses and helped to better define clonal heterogeneity, overcoming the bias related to clonal selection due to cell culture of cytogenetic techniques. In both cases, OGM analysis led to the identification of molecular markers, helping to define the pathogenesis, classification, and prognosis of the analyzed patients. Despite extensive efforts to study hematologic diseases, standard cytogenetic methods display unsurmountable limits, while OGM is a tool that has the power to overcome these limitations and provide a cytogenetic analysis at higher resolution. As OGM also shows limits in defining regions of a repetitive nature, combining OGM with CBA to obtain a complete cytogenetic characterization would be desirable. Full article

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

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15 pages, 8341 KiB

Open AccessArticle

Complex/cryptic EWSR1::FLI1/ERG Gene Fusions and 1q Jumping Translocation in Pediatric Ewing Sarcomas

by Ying S. Zou, Laura Morsberger, Melanie Hardy, Jen Ghabrial, Victoria Stinnett, Jaclyn B. Murry, Patty Long, Andrew Kim, Christine A. Pratilas, Nicolas J. Llosa, Brian H. Ladle, Kathryn M. Lemberg, Adam S. Levin, Carol D. Morris, Lisa Haley, Christopher D. Gocke and John M. Gross

Genes 2023, 14(6), 1139; https://doi.org/10.3390/genes14061139 - 24 May 2023

Viewed by 2187

Abstract

Ewing sarcomas (ES) are rare small round cell sarcomas often affecting children and characterized by gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors (usually FLI1 or ERG). [...] Read more.

Ewing sarcomas (ES) are rare small round cell sarcomas often affecting children and characterized by gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors (usually FLI1 or ERG). The detection of EWSR1 rearrangements has important diagnostic value. Here, we conducted a retrospective review of 218 consecutive pediatric ES at diagnosis and found eight patients having data from chromosome analysis, FISH/microarray, and gene-fusion assay. Three of these eight ES had novel complex/cryptic EWSR1 rearrangements/fusions by chromosome analysis. One case had a t(9;11;22)(q22;q24;q12) three-way translocation involving EWSR1::FLI1 fusion and 1q jumping translocation. Two cases had cryptic EWSR1 rearrangements/fusions, including one case with a cryptic t(4;11;22)(q35;q24;q12) three-way translocation involving EWSR1::FLI1 fusion, and the other had a cryptic EWSR1::ERG rearrangement/fusion on an abnormal chromosome 22. All patients in this study had various aneuploidies with a gain of chromosome 8 (75%), the most common, followed by a gain of chromosomes 20 (50%) and 4 (37.5%), respectively. Recognition of complex and/or cryptic EWSR1 gene rearrangements/fusions and other chromosome abnormalities (such as jumping translocation and aneuploidies) using a combination of various genetic methods is important for accurate diagnosis, prognosis, and treatment outcomes of pediatric ES. Full article

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

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8 pages, 1029 KiB

Open AccessCommunication

Fusion Gene-Based Classification of Variant Cytogenetic Rearrangements in Acute Myeloid Leukemia

by Mary Gudipati, Melody Butler, Rima Koka, Maria R. Baer and Yi Ning

Genes 2023, 14(2), 396; https://doi.org/10.3390/genes14020396 - 3 Feb 2023

Cited by 1 | Viewed by 1660

Abstract

Acute myeloid leukemia (AML) represents a heterogeneous disease entity that is continuously moving to a more genetically defined classification. The classification of AML with recurrent chromosomal translocations, including those involving core binding factor subunits, plays a critical role in diagnosis, prognosis, treatment stratification, [...] Read more.

Acute myeloid leukemia (AML) represents a heterogeneous disease entity that is continuously moving to a more genetically defined classification. The classification of AML with recurrent chromosomal translocations, including those involving core binding factor subunits, plays a critical role in diagnosis, prognosis, treatment stratification, and residual disease evaluation. Accurate classification of variant cytogenetic rearrangements in AML contributes to effective clinical management. We report here the identification of four variant t(8;V;21) translocations in newly diagnosed AML patients. Two patients showed a t(8;14) and a t(8;10) variation, respectively, with a morphologically normal-appearing chromosome 21 in each initial karyotype. Subsequent fluorescence in situ hybridization (FISH) on metaphase cells revealed cryptic three-way translocations t(8;14;21) and t(8;10;21). Each resulted in RUNX1::RUNX1T1 fusion. The other two patients showed karyotypically visible three-way translocations t(8;16;21) and t(8;20;21), respectively. Each resulted in RUNX1::RUNX1T1 fusion. Our findings demonstrate the importance of recognizing variant forms of t(8;21) translocations and emphasize the value of applying RUNX1::RUNX1T1 FISH for the detection of cryptic and complex rearrangements when abnormalities involving chromosome band 8q22 are observed in patients with AML. Full article

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

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8 pages, 933 KiB

Open AccessCase Report

Complex Genomic Rearrangements Involving ETV6::ABL1 Gene Fusion in an Individual with Myeloid Neoplasm

by Zhongxia Qi, Catherine Smith, Neil P. Shah and Jingwei Yu

Genes 2023, 14(10), 1851; https://doi.org/10.3390/genes14101851 - 23 Sep 2023

Cited by 1 | Viewed by 995

Abstract

ETV6::ABL1 gene fusion is a rare recurrent genomic rearrangement associated with hematologic malignancies, and frequently occurs with additional anomalies. Due to the opposite chromosome orientations of the ETV6 and ABL1 genes, an oncogenic in-frame ETV6::ABL1 gene fusion cannot be [...] Read more.

ETV6::ABL1 gene fusion is a rare recurrent genomic rearrangement associated with hematologic malignancies, and frequently occurs with additional anomalies. Due to the opposite chromosome orientations of the ETV6 and ABL1 genes, an oncogenic in-frame ETV6::ABL1 gene fusion cannot be formed by a simple translocation. The molecular mechanism of the ETV6::ABL1 fusion and the significance of co-occurring anomalies are not fully understood. We characterized genomic alterations in an individual with ETV6::ABL1 gene-fusion-positive myeloid neoplasm using various genomic technologies. Our findings uncovered a molecular mechanism of the ETV6::ABL1 fusion, in which a paracentric inversion within the short arm of chromosome 12 (12p) and a translocation between the long arm of a chromosome 9 and the 12p with the inversion were involved. In addition, we detected multiple additional anomalies in the individual, and our findings suggested that the ETV6::ABL1 fusion occurred as a secondary event in a subset of cells with the additional anomalies. We speculate that the additional anomalies may predispose to further pathogenic changes, including ETV6::ABL1 fusion, leading to neoplastic transformation. Full article

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

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8 pages, 663 KiB

Open AccessCase Report

3′ UTR Deletion of FBXO28 in a Patient with Brain Abnormalities and Developmental Delay

by Xin Bi, Maureen S. Mulhern, Erica Spiegel, Ronald J. Wapner, Brynn Levy, Jennifer M. Bain and Jun Liao

Genes 2023, 14(9), 1687; https://doi.org/10.3390/genes14091687 - 25 Aug 2023

Viewed by 901

Abstract

Constitutional deletions of chromosome 1q42 region are rare. The phenotype spectrum associated with this copy number change is variable, including developmental delay, intellectual disability, seizures, and dysmorphology. This study describes a patient with developmental delays and brain abnormalities. G-banded karyotype, FISH, SNP oligonucleotide [...] Read more.

Constitutional deletions of chromosome 1q42 region are rare. The phenotype spectrum associated with this copy number change is variable, including developmental delay, intellectual disability, seizures, and dysmorphology. This study describes a patient with developmental delays and brain abnormalities. G-banded karyotype, FISH, SNP oligonucleotide microarray analysis (SOMA), and whole exome sequencing analysis were performed. Postnatal reanalysis of prenatal SOMA and follow-up parental testing revealed a paternally inherited 63 kb deletion at 1q42.11 in the patient. We characterized the clinical features of this patient, providing insight into the clinical phenotype associated with deletions of the 1q42.11 sub-band. Our study provides new evidence supporting the potential functional importance of the FBXO28 3′ UTR region and the hypothesis that FBXO28 is a critical gene in the pathogenesis of chromosome 1q41q42 microdeletion syndrome. It also highlights the different goals and reporting criteria between prenatal and postnatal microarray tests. Full article

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

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9 pages, 918 KiB

Open AccessCase Report

7p22.2 Microduplication: A Pathogenic CNV?

by Alessia Bauleo, Alberto Montesanto, Vincenza Pace, Francesco Guarasci, Rosalbina Apa, Rossella Brando, Laura De Stefano, Simona Sestito, Daniela Concolino and Elena Falcone

Genes 2023, 14(6), 1292; https://doi.org/10.3390/genes14061292 - 19 Jun 2023

Viewed by 1311

Abstract

Partial duplication of the short arm of chromosome 7 is a rare chromosome rearrangement. The phenotype spectrum associated with this rearrangement is extremely variable even if in the last decade the use of high-resolution microarray technology for the investigation of patients carrying this [...] Read more.

Partial duplication of the short arm of chromosome 7 is a rare chromosome rearrangement. The phenotype spectrum associated with this rearrangement is extremely variable even if in the last decade the use of high-resolution microarray technology for the investigation of patients carrying this rearrangement allowed for the identification of the 7p22.1 sub-band causative of this phenotype and to recognize the corresponding 7p22.1 microduplication syndrome. We report two unrelated patients that carry a microduplication involving the 7.22.2 sub-band. Unlike 7p22.1 microduplication carriers, both patients only show a neurodevelopmental disorder without malformations. We better characterized the clinical pictures of these two patients providing insight into the clinical phenotype associated with the microduplication of the 7p22.2 sub-band and support for a possible role of this sub-band in the 7p22 microduplication syndrome. Full article

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

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12 pages, 1726 KiB

Open AccessCase Report

Rare 15q21.1q22.31 Duplication Due to a Familial Chromosomal Insertion and Diagnostic Investigation in a Carrier of Balanced Chromosomal Rearrangement and Intellectual Disability

by Carolina Gama Nascimento, Joana Rosa Marques Prota, Ilária Cristina Sgardioli, Samira Spineli-Silva, Nilma Lúcia Viguetti Campos, Vera Lúcia Gil-da-Silva-Lopes and Társis Paiva Vieira

Genes 2023, 14(4), 885; https://doi.org/10.3390/genes14040885 - 9 Apr 2023

Viewed by 1838

Abstract

Insertions are rare balanced chromosomal rearrangements with an increased risk of imbalances for the offspring. Moreover, balanced rearrangements in individuals with abnormal phenotypes may be associated to the phenotype by different mechanisms. This study describes a three-generation family with a rare chromosomal insertion. [...] Read more.

Insertions are rare balanced chromosomal rearrangements with an increased risk of imbalances for the offspring. Moreover, balanced rearrangements in individuals with abnormal phenotypes may be associated to the phenotype by different mechanisms. This study describes a three-generation family with a rare chromosomal insertion. G-banded karyotype, chromosomal microarray analysis (CMA), whole-exome sequencing (WES), and low-pass whole-genome sequencing (WGS) were performed. Six individuals had the balanced insertion [ins(9;15)(q33;q21.1q22.31)] and three individuals had the derivative chromosome 9 [der(9)ins(9;15)(q33;q21.1q22.31)]. The three subjects with unbalanced rearrangement showed similar clinical features, including intellectual disability, short stature, and facial dysmorphisms. CMA of these individuals revealed a duplication of 19.3 Mb at 15q21.1q22.31. A subject with balanced rearrangement presented with microcephaly, severe intellectual disability, absent speech, motor stereotypy, and ataxia. CMA of this patient did not reveal pathogenic copy number variations and low-pass WGS showed a disruption of the RABGAP1 gene at the 9q33 breakpoint. This gene has been recently associated with a recessive disorder, which is not compatible with the mode of inheritance in this patient. WES revealed an 88 bp deletion in the MECP2 gene, consistent with Rett syndrome. This study describes the clinical features associated with the rare 15q21.1–q22.31 duplication and reinforces that searching for other genetic causes is warranted for individuals with inherited balanced chromosomal rearrangements and abnormal phenotypes. Full article

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

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9 pages, 843 KiB

Open AccessCase Report

Familial 4p Interstitial Deletion Provides New Insights and Candidate Genes Underlying This Rare Condition

by Jing Di, Leonard Yenwongfai, Hillary T. Rieger, Shulin Zhang and Sainan Wei

Genes 2023, 14(3), 635; https://doi.org/10.3390/genes14030635 - 3 Mar 2023

Cited by 1 | Viewed by 2474

Abstract

Chromosome 4p deletions can lead to two distinct phenotypic outcomes: Wolf-–Hirschhorn syndrome (a terminal deletion at 4p16.3) and less frequently reported proximal interstitial deletions (4p11-p16). Proximal 4p interstitial deletions can result in mild to moderate intellectual disability, facial dysmorphisms, and a tall thin [...] Read more.

Chromosome 4p deletions can lead to two distinct phenotypic outcomes: Wolf-–Hirschhorn syndrome (a terminal deletion at 4p16.3) and less frequently reported proximal interstitial deletions (4p11-p16). Proximal 4p interstitial deletions can result in mild to moderate intellectual disability, facial dysmorphisms, and a tall thin body habitus. To date, only 35 cases of proximal 4p interstitial deletions have been reported, and only two of these cases have been familial. The critical region for this syndrome has been narrowed down to 4p15.33-15.2, but the underlying causative genes remain unclear. In this study, we report the case of a 3-year-old female with failure to thrive, developmental and motor delays, and morphological features. The mother also had a 4p15.2-p14 deletion, and the proband was found to have a 13.4-Mb 4p15.2-p14 deletion by chromosome microarray analysis. The deleted region encompasses 16 genes, five of which have a high likelihood of contributing to the phenotype: PPARGC1A, DHX15, RBPJ, STIM2, and PCDH7. These findings suggest that multiple genes are involved in this rare proximal 4p interstitial deletion syndrome. This case highlights the need for healthcare providers to be aware of proximal 4p interstitial deletions and the potential phenotypic manifestations. Full article

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

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15 pages, 322 KiB

Open AccessPerspective

Challenges and Opportunities for Clinical Cytogenetics in the 21st Century

by Eric Heng, Sanjana Thanedar and Henry H. Heng

Genes 2023, 14(2), 493; https://doi.org/10.3390/genes14020493 - 15 Feb 2023

Cited by 5 | Viewed by 3913

Abstract

The powerful utilities of current DNA sequencing technology question the value of developing clinical cytogenetics any further. By briefly reviewing the historical and current challenges of cytogenetics, the new conceptual and technological platform of the 21st century clinical cytogenetics is presented. Particularly, the [...] Read more.

The powerful utilities of current DNA sequencing technology question the value of developing clinical cytogenetics any further. By briefly reviewing the historical and current challenges of cytogenetics, the new conceptual and technological platform of the 21st century clinical cytogenetics is presented. Particularly, the genome architecture theory (GAT) has been used as a new framework to emphasize the importance of clinical cytogenetics in the genomic era, as karyotype dynamics play a central role in information-based genomics and genome-based macroevolution. Furthermore, many diseases can be linked to elevated levels of genomic variations within a given environment. With karyotype coding in mind, new opportunities for clinical cytogenetics are discussed to integrate genomics back into cytogenetics, as karyotypic context represents a new type of genomic information that organizes gene interactions. The proposed research frontiers include: 1. focusing on karyotypic heterogeneity (e.g., classifying non-clonal chromosome aberrations (NCCAs), studying mosaicism, heteromorphism, and nuclear architecture alteration-mediated diseases), 2. monitoring the process of somatic evolution by characterizing genome instability and illustrating the relationship between stress, karyotype dynamics, and diseases, and 3. developing methods to integrate genomic data and cytogenomics. We hope that these perspectives can trigger further discussion beyond traditional chromosomal analyses. Future clinical cytogenetics should profile chromosome instability-mediated somatic evolution, as well as the degree of non-clonal chromosomal aberrations that monitor the genomic system’s stress response. Using this platform, many common and complex disease conditions, including the aging process, can be effectively and tangibly monitored for health benefits. Full article

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

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