Supernumerary Ring Chromosome Research Articles

MDM2 amplification in rod-shaped chromosomes provides clues to early stages of circularized gene amplification in liposarcoma

Well-differentiated liposarcoma (WDLS) displays amplification of genes on chromosome 12 (Chr12) in supernumerary ring or giant marker chromosomes. These structures have been suggested to develop through chromothripsis, followed by circularization and breakage-fusion-bridge (BFB) cycles. To test this hypothesis, we compared WDLSs with Chr12 amplification in rod-shaped chromosomes with WDLSs with rings. Both types of amplicons share the same spectrum of structural variants (SVs), show higher SV frequencies in Chr12 than in co-amplified segments, have SVs that fuse the telomeric ends of co-amplified chromosomes, and lack interspersed deletions. Combined with the finding of cells with transient rod-shaped structures in tumors with ring chromosomes, this suggests a stepwise process starting with the gain of Chr12 material that, after remodeling which does not fit with classical chromothripsis, forms a dicentric structure with other chromosomes. Depending on if and when telomeres from other chromosomes are captured, circularized or linear gain of 12q sequences will predominate.

A D e Novo Supernumerary Ring Chromosome 1 Causes B-Cell Acute Lymphoblastic Leukemia in Monozygotic Twins Due to Independent and Partially Convergent Evolutionary Trajectories

Introduction B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer. In recent years, our understanding of B-ALL biology has benefited from genomic and transcriptomic analyses that identify driver alterations in 98% of patients. In addition, prior studies of monozygotic twins, who both developed B-ALL, have provided insight into the developmental timing and natural history of the disease, as well as the identification of novel mechanisms of leukemogenesis. Herein we study a case of monozygotic twins, who developed B-ALL (Table 1). We report the characterization of a de novo supernumerary ring chromosome 1 (SRC1) as an initiator event that followed independent but partially convergent clonal trajectories in each twin. Thus, SRC1 resulted in genomic rearrangements of MEF2D in both twins but targeted distinct fusion gene partners ( BCL9 versus ARNT). To our knowledge, this study represents the first description of MEF2D-ARNT as an event involved in B-ALL, and the association of SRC1 Syndrome with leukemia. Methods We performed integrative whole genome sequencing (WGS) and RNAseq analysis on B-ALL samples at diagnosis and compared this to WGS data from minimal residual disease negative bone marrow aspirates. Coverage levels for tumors and matched normals were: Twin A=104 & 59; Twin B=81 & 53. Tumor purity estimations were 0.80 in Twin A and 0.31 in Twin B. For RNAseq, expression profile efficiencies were 61% and 36% respectively. Comprehensive variant calling was performed using the Isabl platform (Medina et al, 2020) to map all putative somatic and germline events. ALLCatchR (Beder et. al, 2022) was used for molecular B-ALL subtype allocation in 26 samples from our pediatric cohort of patients including the twins (age range 1-23), and MutationTimeR (Gerstung et al, 2020) to calculate the relative timing of copy number gains. All research studies were approved by NYU and MSKCC Institutional Review Boards. Results The tumor mutational burdens for each leukemia sample were 0.86 for Twin A and 0.47 mutations/Mb for Twin B, and they showed independent alterations in oncogenic genes (Table 1). The only B-ALL driver that both twins had partially in common was an intrachromosomal translocation resulting in MEF2D fusions, but each with a distinct partner gene ( BCL9 versus ARNT) which was confirmed by RNAseq (supporting reads: Twin A=48, Twin B=107) and PCR assays (Fig. 1). Each sample demonstrated enhanced transcription levels of MEF2D compared to our reference B-ALL cohort (transcripts per million: Twin A=48.0, Twin B=77.4, median=27.7, sd=19.9), and were transcriptionally classified as MEF2D-subtype by the ALLCatchR classifier. These results functionally supported the role of MEF2D-ARNT as a new oncogenic event. Analysis of germline variants showed a tandem duplication flanking the pericentromeric region of chromosome 1 in both twins (1:120,163,074-157,714,717) where MEF2D BCL9and ARNT are localized, that had been previously identified as SRC1 in only one of them by constitutional genotyping (Table 1). Cell fractions in normal and tumor tissues were: Twin A=14.8% & 50%, Twin B=8.6% & 26.5%. PCR interrogation of parental germline DNA failed to identify SRC1, suggesting this to be a de novo event in the affected twins (Fig. 1). We compared the relative timepoint in which the SRC1 took place in each sample using MutationalTimeR, but we were only able to obtain results in Twin A due to a higher mutational burden (number of variants in SRC1: Twin A=44, Twin B=13). As expected, the tandem duplication that formed the SRC1 was identified as an early mutational event (confidence interval of relative time of appearance: 0-0.4). Conclusions Our results identify SRC1 as the common initiating genomic event leading to MEF2D fusion driven B-ALL in both twins. These findings support a model in which a tandem duplication around a pericentromeric area was an initiating event which caused the scission and circularization of DNA without the loss of genetic material. This led to a de novo acquisition of a SRC1, that after independent but partially convergent clonal trajectories gave rise to 2 distinct oncogenic MEF2D fusion driven leukemias in each twin . Moreover, ARNT is a novel partner gene to MEF2D which has not been previously described. This is the first report of B-ALL association with SRC1 Syndrome, which emphasises the utility of the study of monozygotic twins to identify novel alterations underlying B-ALL.

Biology and Management of Deep-seated Atypical Lipomatous Tumor of the Extremities.

Adipocytic neoplasms are frequently encountered in clinical practice. Atypical lipomatous tumor (ALT) is a locally aggressive but non-metastasizing adipocytic neoplasm that primarily occurs in the proximal extremities of middle-aged to older adults. Histologically, ALT is divided into adipocytic (lipoma-like), sclerosing and inflammatory subtypes. The sclerosing subtype is an unfavorable prognostic factor for local recurrence. ALT is characterized by supernumerary ring and/or giant rod chromosomes. These rings and giant markers invariably contain amplified sequences originating from the long arm of chromosome 12, including the MDM2 proto-oncogene (MDM2) and cyclin-dependent kinase 4 (CDK4) gene. MDM2 and/or CDK4 nuclear immunopositivity is present in most cases. Confidently differentiating deep-seated ALT from deep-seated ordinary lipoma is often difficult on imaging. Moreover, the sclerosing subtype may mimic a higher grade liposarcoma. Detection of MDM2 amplification by fluorescence in situ hybridization would be helpful diagnostically for ALT in more difficult cases. The standard treatment for deep-seated ALT is surgery. Although there is no consensus on the best surgical approach for deep-seated ALT of the extremities, the use of marginal resection is acceptable to preserve musculoskeletal function. This review provides an overview of the current knowledge on the clinical and imaging characteristics, pathogenesis, histopathology, and management of deep-seated ALT of the extremities.

The Multifaceted Syndromic Primary Immunodeficiencies in Children.

Disorders of immunity are poorly recognised in some rare multisystem genetic conditions. We aim to describe syndromic features and immunological defects in children with syndromic primary immunodeficiencies (sPIDs). This is a retrospective descriptive study of children aged 0-18 years with sPIDs under the care of the paediatric immunology service at the Bristol Royal Hospital for Children, United Kingdom, from January 2006 to September 2021. sPIDs were identified in 36 patients. Genetic diagnoses which are not commonly associated with PIDs and not included in the International Union of Immunological Societies classification were present in 7/36 (19%): Trisomy 22, Arboleda-Tham syndrome, 2p16.3 deletion syndrome, supernumerary ring chromosome 20 syndrome, Myhre syndrome, Noonan syndrome, and trichothiodystrophy/Cockayne syndrome complex. Recurrent and/or severe infections were the most common clinical features (n = 33, 92%). Approximately half had combined immunodeficiency or antibody deficiency. The most common extra-immunological manifestations include dysmorphism (72%), disorders of nervous (78%), musculoskeletal (69%), haematology/lymphatic (58%), and gastrointestinal, hepatic/pancreatic (58%) systems. Patients with sPIDs often have multiorgan involvement and some are non-immunologically mediated. There should be a low threshold to clinically assess and investigate for disorders of immunity in any patients with syndromic features especially when they present with recurrent/severe/opportunistic infections, features of immune dysregulation, autoinflammation or lymphoproliferation.

P329: Mosaic Potocki-Lupski syndrome due to a supernumerary ring chromosome containing RAI1

P329: Mosaic Potocki-Lupski syndrome due to a supernumerary ring chromosome containing RAI1

21. A case of supernumerary ring chromosome 20 involving the gene ASXL1 resulting in brain abnormalities

Reports in the medical literature of supernumerary ring chromosome 20 are rare. Previous studies of duplication and triplication involving the pericentromeric regions of chromosome 20 have shown that carriers present with various clinical features that may include developmental delay, subtle facial dysmorphisms, and abnormalities of the brain, skull and hands. The gene ASXL1 has been implicated in the pathogenicity of reported copy number gains. Conversely, heterozygous loss-of-function variants in ASXL1 are associated with Borhing-Opitz syndrome, which has overlapping clinical features with gains involving this gene.

SATB2 and MDM2 Immunoexpression and Diagnostic Role in Primary Osteosarcomas of the Jaw.

Primary osteosarcomas of the jaw (OSJ) are rare, accounting for 6% of all osteosarcomas. This study aims to determine the value of SATB2 and MDM2 immunohistochemistry (IHC) in differentiating OSJ from other jawbone mimickers, such as benign fibro-osseous lesions (BFOLs) of the jaw or Ewing sarcoma of the jaw. Certain subsets of osteosarcoma harbor a supernumerary ring and/or giant marker chromosomes with amplification of the 12q13–15 region, including the murine double-minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) genes. Special AT-rich sequence-binding protein 2 (SATB2) is an immunophenotypic marker for osteoblastic differentiation. Cases of OSJ, BFOLs (ossifying fibroma and fibrous dysplasia) of the jaw, and Ewing sarcoma of the jaw were retrieved from the Departments of Oral Pathology and Oral Medicine, Faculty of Dentistry, Obafemi Awolowo University and Lagos State University College of Medicine, Nigeria. All OSJ retrieved showed histologic features of high-grade osteosarcoma. IHC for SATB2 (clone EP281) and MDM2 (clone IF2), as well as fluorescence in situ hybridization (FISH) for MDM2 amplification, were performed on all cases. SATB2 was expressed in a strong intensity and diffuse staining pattern in all cases (11 OSJ, including a small-cell variant, 7 ossifying fibromas, and 5 fibrous dysplasias) except in Ewing sarcoma, where it was negative in neoplastic cells. MDM2 was expressed in a weak to moderate intensity and scattered focal to limited diffuse staining pattern in 27% (3/11) of cases of OSJ and negative in all BFOLs and the Ewing sarcoma. MDM2 amplification was negative by FISH in interpretable cases. In conclusion, the three cases of high-grade OSJs that expressed MDM2 may have undergone transformation from a low-grade osteosarcoma (LGOS). SATB2 is not a dependable diagnostic marker to differentiate OSJ from BFOLs of the jaw; however, it could serve as a valuable diagnostic marker in differentiating the small-cell variant of OSJ from Ewing sarcoma of the jaw, while MDM2 may be a useful diagnostic marker in differentiating OSJ from BFOLs of the jaw, especially in the case of an LGOS or high-grade transformed osteosarcoma.

Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives.

Dedifferentiated liposarcoma (DDL) is defined as the transition from well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) to non-lipogenic sarcoma, which arises mostly in the retroperitoneum and deep soft tissue of proximal extremities. It is characterized by a supernumerary ring and giant marker chromosomes, both of which contain amplified sequences of 12q13-15 including murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) cell cycle oncogenes. Detection of MDM2 (and/or CDK4) amplification serves to distinguish DDL from other undifferentiated sarcomas. Recently, CTDSP1/2-DNM3OS fusion genes have been identified in a subset of DDL. However, the genetic events associated with dedifferentiation of WDL/ALT remain to be clarified. The standard treatment for localized DDL is surgery, with or without radiotherapy. In advanced disease, the standard first-line therapy is an anthracycline-based regimen, with either single-agent anthracycline or anthracycline in combination with the alkylating agent ifosfamide. Unfortunately, this regimen has not necessarily led to a satisfactory clinical outcome. Recent advances in the understanding of the pathogenesis of DDL may allow for the development of more-effective innovative therapeutic strategies. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology and treatment of DDL.

Clinical Application of Chromosome Microarray Analysis in the Diagnosis of Lipomatous Tumors.

Well-differentiated liposarcoma/atypical lipomatous tumor (WDLS/ALT) and dedifferentiated liposarcoma (DDLS) have characteristic supernumerary ring and giant marker chromosomes involving the chromosomal region 12q13-15 which contains MDM2 (12q15), CDK4 (12q14.1), HMGA2 (12q14.3), YEATS4 (12q15), CPM (12q15), and FRS2 (12q15). Detecting MDM2 amplification by fluorescence in situ hybridization (FISH) is considered to be the gold standard for the diagnosis of WDLS/ALT and DDLS. In this study, formalin fixed paraffin embedded clinical specimens (16 liposarcomas and 19 benign lipomatous tumors) were used to detect MDM2 amplification and other chromosomal alterations in WDLS/ALT and DDLS by single nucleotide polymorphism-based chromosome microarray (CMA). All 16 liposarcomas showed MDM2 amplification with a MDM2/cep12 ratio from 2.4 to 8.4 by CMA. Ten (62.5%) of these cases had CDK4/cep12 ratio ≥2.0. All the cases without CDK4 amplification were from the thigh. The MDM2/cep12 ratio of all the benign lipomatous tumors (19/19) was within the normal limits. Twenty-one of the 35 benign lipomatous tumors and liposarcomas were also tested for MDM2 amplification by FISH. All the FISH results were consistent with the CMA results (100%). Along with MDM2 amplification, all 16 liposarcomas (100%) also showed amplification of YEATS4, CPM and FRS2. Only 11 of 16 (69%) cases showed HMGA2 amplification. In conclusion, this study demonstrated that CMA on routine formalin fixed paraffin embedded tissue is a sensitive and specific clinical test for detection of MDM2 gene amplification. Moreover, CMA allows simultaneous detection of genomic changes of interest including CDK4 and others, which provides enriched information for diagnosing lipomatous tumors.

A REVIEW ON LIPOMA AND ITS GENETIC INTERVENTIONS

Lipomas are benign soft tissue fatty tumours that most commonly appear in the third decade of life when fatty tissue accumulates. Histologically, lipoma is composed of mature fat cells with a thin fibrous capsule. Simple lipomas account for 80% of adipose tissue tumours. The aetiology may be genetic like Familial Multiple Lipomatosis. Some tumours, like the well differentiated Liposarcomas never metastasize unless they undergo de-differentiation. They can be introduced as Atypical Lipomatous Tissue, ALT. Southern blot analysis is performed by obtaining DNA from ALT, cases in which most of them are characterized by the presence of supernumerary ring and long marker chromosomes. The complex chromosome region contains genes MDM2, CDK4, HMGI- C, SAS, GLI, CHOP, OS4 and OSP. Most of ALTs, after analysis revealed amplification of CDK4 and MDM2 proto- oncogenes that play major role in permitting over ride of block operated on cell proliferation. Immuno-histochemical results have shown MDM2 over expression in about 50% of ALTs along with weak CDK4 immuno-positivity. Also the lipomas with Gene fusion transcripts have the expression of certain genes, HMGA2/LPP, HMGA2/RDCI and HMGA2/NFIB. Of these 98% of cases were analyzed for the possible expression of HMGA2/LPP and LPP- HMGA2 fusion genes using reverse transcription polymerase chain reaction. Over all these cases, shows non-enhanced adipocyte apoptosis and enhanced adipogenesis in lipoma tissue. Thus studies provide insights into molecular pathogenesis of lipomatous tumour and representation of distinctive subset of mesenchymal neoplasms with mature adipocyte differentiation.

Retraction: Suppression of HMGA2 Protein Synthesis Could Be a Tool for the Therapy of Well Differentiated Liposarcomas Overexpressing HMGA2.

Atypical lipomatous tumors (ALTs)/well-differentiated liposarcomas represent a distinctive subset of mesenchymal neoplasms featuring mature adipocytic proliferation. These tumors are characterized cytogenetically by the presence of supernumerary ring and/or long marker chromosomes that contain several copies of the chromosomal region 12q13-15, in which the HMGA2 gene is located. Deregulation of the HMGA2 gene is a common molecular alteration implicated in the development of a variety of benign tumors, such as lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. In this study, we observed HMGA2 overexpression in 7 of 12 ALT primary cell cultures examined. Subsequently, we generated an adenovirus containing the HMGA2 gene in the antisense orientation (Ad-A2as) to study the effect of HMGA2 protein suppression in ALT cells. The infection of six ALT cells, three of which were positive for HMGA2 expression, resulted in growth inhibition coupled with a significant increase in apoptosis. In addition, the growth of the ALT cells negative for HMGA2 expression was not affected by the infection with either the Ad-A2as or the control virus. On the basis of these findings, the targeting of the HMGA2 protein expression may represent a promising approach for treating the well-differentiated liposarcomas resistant to conventional therapies.

Consistent Amplification of FRS2 and MDM2 in Low-grade Osteosarcoma: A Genetic Study of 22 Cases With Clinicopathologic Analysis.

Low-grade osteosarcoma (LGOS) encompasses low-grade central osteosarcoma (LGCOS) and parosteal osteosarcoma (POS). LGOSs are characterized by a supernumerary ring and giant rod chromosomes containing the 12q13-15 amplicon. The fibroblast growth factor receptor substrate 2 (FRS2) gene is located close to MDM2 and CDK4. Recent studies identified consistent amplification of FRS2 gene in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma. The aim of this study was to evaluate the frequency of FRS2 amplification and its relationship with the clinicopathologic features of LGOSs. The amplification of FRS2 and MDM2 genes were analyzed by fluorescence in situ hybridization using 22 LGOSs (3 LGCOSs, 14 classic POSs, and 5 dedifferentiated POSs) and 85 control samples of bone and soft tissue. The clinicopathologic features of the 22 LGOSs were described. Amplification of FRS2 was detected in 21/22 (95%) of the LGOSs, including 3 (100%) LGCOSs and 18 (95%) POSs. All 22 LGOSs showed MDM2 amplification (100%). The only MDM2/FRS2 LGOS was dedifferentiated POS (the dedifferentiated component was conventional osteosarcoma). In the control group, all of the atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated liposarcomas (DDLs) (10/10, 100%) were FRS2-amplified, whereas the remaining 75 control cases were FRS2-nonamplified. These findings indicate that the FRS2 gene is consistently amplified in classic and dedifferentiated LGOSs but not in their histologic mimics. These results offer another avenue for investigating the biology of LGOSs. Whether FRS2-nonamplified tumors exhibit unusual clinicopathologic features needs further investigation. Some so-called "high-grade osteosarcomas harboring 12q13-15 amplification" may be unrecognized dedifferentiated LGOSs.

6. Human ring chromosome registry: Developing an interactive web resource for constitutional and cancer cytogenomic diagnosis

Constitutional ring chromosomes causing developmental disorders and somatic ring chromosomes in the form of double minutes, ring and marker chromosomes in various types of tumors have been documented. However, there are no organized efforts to compile and curate cytogenomic and clinical findings from ring chromosome cases. We have developed a web-based interactive Human Ring Chromosome Registry (HRCR) using a Microsoft Access based relational database to present cytogenomic and clinical findings from ring chromosome cases (http://web.gxmu.edu.cn/shengwu/HRC/home.asp). To validate the functional modules in this registry, constitutional ring chromosome cases reported in Chinese patients were compiled as a testing data set. From a total of 113 cases, relative frequencies, cytogenomic findings, and clinical features were summarized. An initial effort, focused on constitutional ring chromosome 21, classified the patients into three groups based on the cytogenomic findings and provided specific recommendations for prenatal and postnatal genetic counseling of ring chromosome 21. Furthermore, cytogenomic and genomic sequencing results from supernumerary ring chromosomes and derived giant marker chromosomes identified in liposarcoma were summarized to reveal the gene content of genomic imbalances, underlying mechanisms of ring formation, and implications for tumor classification and treatment. The development of HRCR has provided an interactive platform to compile and curate cytogenomic and clinical findings for constitutional and somatic ring chromosome cases. We propose a collaborative effort of clinical cytogeneticists and molecular geneticists to contribute to this online ring chromosome resource for establishing genotype-phenotype correlation and developing diagnostic guidelines and recommendations for genetic counseling and precise treatment.

Detection of paternal uniparental disomy 9 in a neonate with prenatally detected mosaicism for a small supernumerary marker chromosome 9 and a supernumerary ring chromosome 9

ObjectiveWe present the association of paternal uniparental disomy (UPD) 9 with mosaicism for a small supernumerary marker chromosome 9 [sSMC(9)] and a supernumerary ring chromosome 9 [r(9)]. Materials and methodsA 38-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+mar [25]/48,XY,+mar,+r(9) [4]/47,XY,+r(9) [1]/46,XY [6]. The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) of cultured amniocytes revealed a result of de novo 9p13.1q21.11 (38,792,472–71,026,063) × 2.64. The marker chromosome was determined to be an sSMC(9) by spectral karyotyping and aCGH. A phenotypically normal baby was delivered at 38 weeks of gestation. During pediatric follow-ups at age two years, the neonate manifested normal psychomotor and growth development. Cytogenetic analysis, metaphase fluorescence in situ hybridization (FISH), single nucleotide polymorphism (SNP) aCGH and polymorphic DNA marker analysis were performed on the peripheral blood of the neonate. ResultsThe neonate's blood had the following results. Metaphase FISH confirmed coexistence of the sSMC(9) and the supernumerary r(9). The karyotype was 47,XY,+sSMC(9) [14]/48,XY, +sSMC(9),+r(9) [10]/47,XY,+r(9) [6]/46,XY [10]. SNP aCGH revealed arr 9p22.3q21.11 (14,234,165–71,035,608) × 2–3, arr 9p24.3p22.3 (216,123–14,629,321)hmz, arr 9p21.3p13.2 (24,769,722–36,732,597)hmz and arr 9q21.11q34.3 (71,013,799–141,011,581)hmz. Polymorphic DNA marker analysis showed paternal isodisomy 9. ConclusionIndividuals with mosaicism for sSMC(9) and supernumerary r(9) may be associated with paternal UPD 9.

Scattered genomic amplification in dedifferentiated liposarcoma

BackgroundAtypical lipomatous tumor (ALT), well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes, although DDLS tend to have somewhat more complex rearrangements. In contrast, pleomorphic liposarcomas (PLS) have highly aberrant and heterogeneous karyotypes. The ring and giant marker chromosomes contain discontinuous amplicons, in particular including multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q, but often also sequences from other chromosomes.ResultsThe present study presents a DDLS with an atypical hypertriploid karyotype without any ring or giant marker chromosomes. SNP array analyses revealed amplification of almost the entire 5p and discontinuous amplicons of 12q including the classical target genes, in particular CDK4. In addition, amplicons from 1q, 3q, 7p, 9p, 11q and 20q, covering from 2 to 14 Mb, were present. FISH analyses showed that sequences from 5p and 12q were scattered, separately or together, over more than 10 chromosomes of varying size. At RNA sequencing, significantly elevated expression, compared to myxoid liposarcomas, was seen for TRIO and AMACR in 5p and of CDK4, HMGA2 and MDM2 in 12q.ConclusionsThe observed pattern of scattered amplification does not show the characteristics of chromothripsis, but is novel and differs from the well known cytogenetic manifestations of amplification, i.e., double minutes, homogeneously staining regions and ring chromosomes. Possible explanations for this unusual distribution of amplified sequences might be the mechanism of alternative lengthening of telomeres that is frequently active in DDLS and events associated with telomere crisis.

56 - Neocentric Supernumerary Ring Chromosome 8 Balanced With Homolog Deletion Along With Presence of a 7.4 Mb Deletion of 2q24.3q31.1 in a Child With Seizures

56 - Neocentric Supernumerary Ring Chromosome 8 Balanced With Homolog Deletion Along With Presence of a 7.4 Mb Deletion of 2q24.3q31.1 in a Child With Seizures

Dermatofibrosarcoma protuberans of the breast: A case report.

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant tumor of subcutaneous tissue characterized by slow infiltrative growth. The tumor occurs in patients of all ages, with the highest frequency occurring between the second and the fifth decades of age. Genetically, DFSP is characterized by a reciprocal translocation t(17;22)(q22;q13), or more often, as a supernumerary ring chromosome involving chromosomes 17 and 22. Standard treatment of a localized tumor is surgical excision with wide margins. In the present study, a case report of a 43-year-old woman with a growing tumor in the left breast is discussed. The patient underwent breast-conserving surgery. Histological and cytogenetic examinations of the tumor resulted in a diagnosis of DFSP. The clinical and morphological characteristics of the tumor, in addition to the treatment options, were also evaluated.

Duplication of chromosome segment 12q13-15 in a lipomatous tumor with minimal nuclear atypia: A case report.

Ordinary lipoma is cytogenetically characterized by structural rearrangements, particularly translocations, of 12q13-15. By contrast, atypical lipomatous tumors exhibit supernumerary ring or giant marker chromosomes that are composed mainly of amplified material from the 12q13-15 chromosome segment. The present study describes the cytogenetic and molecular cytogenetic findings from a lipomatous tumor with minimal nuclear atypia that was identified in a 49-year-old female patient. Magnetic resonance imaging of the right shoulder revealed a 13-cm fatty mass in the subcutaneous layer that possessed only pencil-line septa. Contrast-enhanced fat-suppressed T1-weighted images demonstrated faint enhancement. A marginal excision was performed. Histologically, the tumor was composed of lobules that consisted of mature adipocytes separated by thin fibrous septa. There was minimal nuclear atypia in certain cells, and a small number of binucleated cells were also observed within the tumor. Immunohistochemically, the tumor cells did not reveal the expression of murine double-minute 2 (MDM2). Cytogenetic analysis revealed a complex karyotype with several numerical and structural alterations, including 12q rearrangements. Spectral karyotyping demonstrated a duplication of chromosome segment 12q13-15. Interphase fluorescence in situ hybridization analysis revealed no MDM2 gene amplification. The present case indicates that duplication of 12q may be associated with minimal nuclear atypia in a subset of lipomatous tumors.

Rare structural chromosomal abnormalities in prenatal diagnosis; clinical and cytogenetic findings on 10125 prenatal cases.

Objective: The aim of this study was presentation of the ultrasonographic findings and perinatal autopsy of cases with rare chromosomal abnormalities. A total of 10125 prenatal cases over 17 years including 8731 amniocentesis, 973 chorionic villus sampling, and 421 fetal blood sampling cases were evaluated for prenatal cytogenetic diagnosis. Conventional cytogenetic studies, fluorescence in situ hybridization studies, and Array-CGH analysis techniques were used for genetic analysis. A structural chromosomal abnormality was observed in 95 cases. The most frequently observed structural abnormalities were balanced translocations with a frequency of 53.7% (51 cases) followed by unbalanced translocations (16.8%), inversions (11.6%), supernumerary marker chromosomes (8.4%), duplications (4.2%), deletions and ring chromosomes (2.1%) and complex translocation (1.1%). Rare structural chromosomal abnormalities including de novo balanced translocations, unbalanced translocations, inversions, duplications, deletions, ring chromosomes, and supernumerary marker chromosomes were detected in 24 cases. The rate of rare chromosomal abnormalities varies from 2.4% (South East Ireland) to 12.9% (Northern England) in Europe with a total rate of 7.4/10 000 births. In our study, the overall rate of chromosomal abnormality in prenatal cytogenetic diagnosis was 3.7%, similar to South East Ireland. Ultrasonographic and perinatal autopsy findings of the cases with rare structural chromosomal abnormalities are important for proper genetic counseling for further similar cases.

Gain of FAM123B and ARHGEF9 in an Obese Man with Intellectual Disability, Congenital Heart Defects and Multiple Supernumerary Ring Chromosomes

In a 24-year-old man with mild intellectual disability, congenital heart defects and obesity, we identified up to 4 small supernumerary marker chromosomes (sSMCs) in blood metaphases. The ring-shaped sSMCs were derived from chromosomes 11, 12 and X as well as a fourth, unidentified chromosome. In interphase nuclei of epithelial cells from the urinary tract and buccal mucosa, the presence of the r(11), r(12) and r(X) was confirmed by FISH. Using Illumina Infinium 317K SNP-arrays, we detected 3 copies of the pericentromeric regions of chromosomes 11, 12 and X. The r(X) was present in 84–89% of cells in the various tissues examined, lacks the XIST gene, but contains FAM123B, a potential dosage-sensitive candidate gene for congenital cardiac abnormalities, and ARHGEF9, a candidate gene for intellectual disability. ARHGEF9 encodes collybistin (CB), which is required for localization of the inhibitory receptor-anchoring protein gephyrin and for formation and maintenance of postsynaptic GABA_A and glycine receptors. We propose that the 2-fold increase in dosage of ARHGEF9 disturbs the stoichiometry of CB with its interacting proteins at inhibitory postsynapses. SNP alleles and short tandem repeat markers on the r(11) and r(X) were compatible with a maternal origin of both sSMCs through a meiosis II error. The sSMCs may have resulted from predivision chromatid nondisjunction, leading to anaphase lagging, followed by incomplete degradation of the supernumerary chromosomes.