Deletion In Arm Research Articles

Ewing Sarcoma and Atypical Teratoid Rhabdoid Tumor: A FISH and Immunohistochemical Comparison

Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) and atypical teratoid rhabdoid tumor (ATRT) are high-grade malignancies of childhood, each of which is associated with genetic abnormalities on chromosome 22. ES is typically characterized by rearrangement of the EWSR1 locus and ATRT by deletion of SMARCB1. We report a case with an unusual FISH signal pattern consistent with EWSR1 rearrangement that was shown to have loss of INI1 expression by immunohistochemistry due to deletion in the long arm of one chromosome 22. In light of the unusual findings in this case as well as the proximity of the EWSR1 locus and SMARCB1 locus on chromosome 22 and frequent CD99 staining in both tumors, we examined 16 ES cases and 17 ATRT, renal rhabdoid tumor (RRT), and extrarenal rhabdoid tumor (ERRT) cases for CD99 and INI1 staining and for EWSR1 rearrangement. Staining with INI1 was negative in ATRT, RRT, and ERRT and positive in ES cases; CD99 was positive in ES cases and variable in ATRT cases. All but 2 cases of ES, and no cases of ATRT, showed rearrangement of EWSR1. The present case appears to be best classified as a unique variant of ATRT based on immunohistochemistry, EWSR1 FISH and RT-PCR, and SMARCB1 gene sequencing.

The 5q deletion size in myeloid malignancies is correlated to additional chromosomal aberrations and to TP53 mutations.

Deletions in the long arm of chromosome 5 (del(5q)) are recurrent abnormalities in myeloid malignancies. We analyzed del(5q) and accompanying molecular mutations in MDS, MPN and MDS/MPN cases. A high del(5q) frequency was revealed in MDS (1869/11398 cases; 16%), followed by MDS/MPN (37/1107; 3%) and MPN (97/6373; 2%). To investigate potential associations of the del(5q) size with the respective phenotypes, we applied array CGH analyses in selected cohorts of 61 MDS, 22 MDS/MPN and 23 MPN cases. The size varied between 16 and 119 Mb with no differences between the entities. However, MPN and MDS/MPN cases with del(5q) sole showed a significantly smaller del(5q) than cases with additional aberrations. Sequence analysis of 27 genes revealed ≥1 mutation in 91% of patients. The highest mutation frequencies in the total cohort were observed for TP53 (31%), JAK2 (23%) and DNMT3A (18%). The molecular mutation patterns in the del(5q) cohorts were different between the entities but resembled known patterns of cohorts not selected for del(5q). Further, TP53 mutations were significantly more frequent in cases with a larger deletion size (P = 0.003). The results suggest a correlation of large del(5q) with TP53 mutations and with additional chromosomal aberrations possibly contributing to more severe courses of these cases. © 2016 Wiley Periodicals, Inc.

A case of whole arm deletion of chromosome 18p

A case of whole arm deletion of chromosome 18p

A new familial case of microdeletion syndrome 10p15.3

In 2012 a small terminal deletion in the short arm of chromosome 10 in the region 10p15.3 was reported as a novel microdeletion syndrome. By now 21 patients, including a single familial case, have been reported. Characteristic findings comprise variable cognitive impairment or developmental delay, disorder of speech development, as well as various dysmorphic signs. We here report on a new patient, an eight year old girl, with a microdeletion syndrome 10p15.3. She is a foster child showing intellectual deficits, disorder of speech development, behavioral problems, congenital heart defect, and several dysmorphic signs. The same microdeletion was subsequently found in the six year old maternal half-sister, showing very similar developmental and cognitive issues, including major speech impairment. The mother has not obtained a school degree. She was described as being a dissocial person with severe alcohol abuse and showing minor cognitive disability. Thus inheritance of the microdeletion from a probably symptomatic mother can be assumed. The patients presented here add up to the as yet small number of reported cases of microdeletion 10p15.3 and thereby might help to establish a more comprehensive clinical spectrum of this rather newly discovered syndrome.

Chromosome 12p Deletion Spanning the GRIN2B Gene Presenting With a Neurodevelopmental Phenotype: A Case Report and Review of Literature.

The GRIN2B (glutamate receptor, ionotropic, N-methyl-d-aspartate 2B) gene, located in the short arm of chromosome 12, encoding the NR2B subunit of the N-methyl-D-aspartate receptor, has recently been recognized to play an important role in corticogenesis and brain plasticity. Deletions in the short arm of chromosome 12 are rare. Hemizygous loss of function of the GRIN2B gene results in developmental delay, whereas gain of function leads to epilepsy, and infantile spasms in particular. In addition, GRIN2B variants have been associated with autism spectrum disorder and schizophrenia. Here the authors report a child with global developmental delay, autistic behavioural features, central hypotonia, dysmorphic features and isolated congenital anomalies of the fingers and toes, and a de novo heterozygous deletion in chromosome locus 12p13.2-p13.1, involving loss of several genes, including GRIN2B. This report and our review of the literature help clarify the distinct phenotypes associated with loss or gain of GRIN2B function.

Acquired retinal pigmentary degeneration in a child with 13q deletion syndrome

Orbeli syndrome, or 13q deletion syndrome, is a rare condition caused by a distal deletion in the long arm of chromosome 13. The syndrome is characterized by severe physical malformations and developmental delays and has been associated with numerous ocular manifestations. We report the case of a 10-year-old boy with 13q deletion syndrome, who was evaluated for impaired vision and found to have bilateral retinal pigmentary changes resembling those seen in retinitis pigmentosa. There has only been one other case of retinal pigment variation in association with 13q deletion syndrome; however, this represents the first case of bilateral symmetric retinal pigmentary changes with corresponding rod and cone dysfunction on electroretinography.

Variability of epilepsy, autism, brachydactyly, and other clinical features in familial and sporadic 2q37.3 deletion

Chromosomal microdeletion syndromes are frequently associated with neurological disease including epilepsy and behavioral abnormalities. Yet, for most microdeletions, neurological phenotypes are variable and the exact molecular cause of neurological disease is not yet understood. Terminal deletions in the long arm of chromosome 2 (2q37.3) are among the most common microdeletion syndromes diagnosed, and have been associated with epilepsy, autistic-like features, short stature, obesity, and brachydactyly type E (short 4th and 5th metacarpals and metatarsals). However, neither epilepsy nor any of the other clinical features are invariant in 2q37.3 deletion. To elucidate the genetic mechanisms underlying this clinical variability we report what is, to our knowledge, the first description of inherited 2q37.3 deletion (without other complex chromosomal rearrangements) in three family members and present two sporadic cases and accompanying chromosomal microarray data. The clinical features of the three familial and two sporadic cases combined with the chromosomal microarray results suggest that all of the clinical features seen in 2q37.3 deletion may be variably expressed.

Growth profiles of 34 patients with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) encompasses multiple congenital anomalies and mental retardation and is caused by partial deletions in the short arm of chromosome 4. Prenatal-onset growth deficiency is one of the WHS characteristics. Assessing and recording growth profiles of patients with WHS were the aims of this study. Anonymous questionnaire surveys were conducted with cooperation of a WHS peer-support group in Japan, and data from 34 WHS patients (12 males and 22 females; age, 1-23 years) were retrospectively collected. Height, weight, and head circumference (occipitofrontal head circumference) were measured and plotted on the standard growth charts of healthy Japanese children. Results indicated that most WHS patients showed growth retardation under the 3rd percentile since the first year of life and extremely poor body-weight gain after pubertal age. These findings are characteristic of WHS patients. The assessed growth patterns in this study could help monitoring and documentation of growth of WHS patients.

Can Diffusion and Perfusion Weighted Imaging predict 1p/19q codeled lower grade gliomas?

2056 Background: Several factors influence prognosis of lower grade gliomas, including age, histological diagnosis, 1p/19q chromosome arm deletion (codel 1p/19q), isocitrate dehydrogenase (IDH1/IDH...

Dysregulation of X chromosome inactivation in high grade ovarian serous adenocarcinoma.

BackgroundOne of the two copies of the X chromosome is randomly inactivated in females as a means of dosage compensation. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers, and is frequent in basal-like subtype and BRCA1 mutation-associated breast cancers. We investigated the clinical implications of the loss of XCI in ovarian cancer and the association between the loss of XCI and BRCA1 dysfunction.Materials and MethodsWe used open source data generated by The Cancer Genome Atlas (TCGA) Genome Data Analysis Centers. Ward’s hierarchical clustering method was used to classify the methylation status of the X chromosome.ResultsWe grouped 584 high grade serous ovarian adenocarcinomas (HG-SOA) according to methylation status, loss of heterozygosity and deletion or gain of X chromosome into the following five groups: preserved inactivated X chromosome (Xi) group (n = 175), partial reactivation of Xi group (n = 100), p arm deletion of Xi group (n = 35), q arm deletion of Xi group (n = 44), and two copies of active X group (n = 230). We found four genes (XAGE3, ZNF711, MAGEA4, and ZDHHC15) that were up-regulated by loss of XCI. HG-SOA with loss of XCI showed aggressive behavior (overall survival of partial reactivation of Xi group: HR 1.7, 95% CI 1.1–2.5, two copies of active X group: HR 1.4, 95% CI 1.0–1.9). Mutation and hypermethylation of BRCA1 were not frequent in HG-SOA with loss of XCI.ConclusionsLoss of XCI is common in HG-SOA and is associated with poor clinical outcome. The role of BRCA1 in loss of XCI might be limited. XCI induced aberrant expression of cancer-testis antigens, which may have a role in tumor aggressiveness.

Increased progesterone production in cumulus-oocyte complexes of female mice sired by males with the Y-chromosome long arm deletion and its potential influence on fertilization efficiency.

It was revealed previously that B10.BR(Y(del)) females sired by males with the Y-chromosome long arm deletion differ from genetically identical B10.BR females sired by males with the intact Y chromosome. This is interpreted as a result of different epigenetic information which females of both groups inherit from their fathers. In the following study, we show that cumulus-oocyte complexes ovulated by B10.BR(Y(del)) females synthesize increased amounts of progesterone, which is important sperm stimulator. Because their extracellular matrix is excessively firm, the increased progesterone secretion belongs presumably to factors that compensate this feature enabling unchanged fertilization ratios. Described compensatory mechanism can act only on sperm of high quality, presenting proper receptors. Indeed, low proportion of sperm of Y(del) males that poorly fertilize B10.BR(Y(del)) oocytes demonstrates positive staining of membrane progesterone receptors. This proportion is significantly higher for sperm of control males that fertilize B10.BR(Y(del)) and B10.BR oocytes with the same efficiency.

Whole arm deletions of 18p: medical and developmental effects.

Deletions of the short arm of chromosome 18 have been well-described in case reports. However, the utility of these descriptions in clinical practice is limited by varied and imprecise breakpoints. As we work to establish genotype-phenotype correlations for 18p-, it is critical to have accurate and complete clinical descriptions of individuals with differing breakpoints. In addition, the developmental profile of 18p- has not been well-delineated. We undertook a thorough review of the medical histories of 31 individuals with 18p- and a breakpoint in the centromeric region. We collected developmental data using mailed surveys and questionnaires. The most common findings included neonatal complications; cardiac anomalies; hypotonia; MRI abnormalities; endocrine dysfunction; strabismus; ptosis; and refractive errors. Less common features included holoprosencephaly and its microforms; hearing loss; and orthopedic anomalies. The developmental effects of the deletion appear to be less severe than reported in the literature, as average IQ scores were in the range of borderline intellectual functioning. Based on responses to standardized questionnaires, it appears this population has marked difficulty with activities of daily living, though several young adults were able to live independent of their parents. This manuscript represents the most comprehensive description of a cohort of 18p- individuals with identical breakpoints. Despite identical breakpoints, a great deal of phenotype variability remained among this population, suggesting that many of the genes on 18p- cause low-penetrance phenotypes when present in a hemizygous state. Future efforts will focus on the clinical description of individuals with more distal breakpoints and the identification of critical regions and candidate genes.

A prenatally ascertained de novo terminal deletion of chromosomal bands 1q43q44 associated with multiple congenital abnormalities in a female fetus.

Terminal deletions in the long arm of chromosome 1 result in a postnatally recognizable disorder described as 1q43q44 deletion syndrome. The size of the deletions and the resulting phenotype varies among patients. However, some features are common among patients as the chromosomal regions included in the deletions. In the present case, ultrasonography at 22 weeks of gestation revealed choroid plexus cysts (CPCs) and a single umbilical artery (SUA) and therefore amniocentesis was performed. Chromosomal analysis revealed a possible terminal deletion in 1q and high resolution array CGH confirmed the terminal 1q43q44 deletion and estimated the size to be approximately 8 Mb. Following termination of pregnancy, performance of fetopsy allowed further clinical characterization. We report here a prenatal case with the smallest pure terminal 1q43q44 deletion, that has been molecularly and phenotypically characterized. In addition, to our knowledge this is the first prenatal case reported with 1q13q44 terminal deletion and Pierre-Robin sequence (PRS). Our findings combined with review data from the literature show the complexity of the genetic basis of the associated syndrome.

Case Report: Interstitial Deletion 21q22.13-Q22.3 in a Male Patient with Developmental Delay, Holoprosencephaly, Dysmorphic Features, and Multiple Congenital Anomalies

We report on a new case with developmental delay, dysmorphic features, holoprosencephaly that showed deletion in long arm of chromosome 21 (21q22.13-q22.3). The patient is a male 3 months old presented with frontonasal dysplasia, scoliosis, abnormal ears, VSD, hypospadias, undescended testis. MRI has shown holoprosencephaly and agenesis of corpus callosum. Array-comparative genomic hybridization using the Agilent 2×400 oligoarray showed an interstitial deletion in chr21q22.13-q22.3, (start-end: 36,854,967-46,006,008 bp) deletion size is 9 Mb (9,151,042 bp) and includes 75 genes (Data base of genomic variants, hg18). The deletion was found to be maternal in origin. The findings from this report underscore the role of the genes at chromosome 21q22.13-q22.3 in brain development and indicate the usefulness of array-CGH in identification of the deletion size and detection of genes that could be correlated to the patient’s phenotype.

Activation of human telomerase reverse transcriptase through gene fusion in clear cell sarcoma of the kidney

Clear cell sarcoma of the kidney (CCSK) is a rare tumor type affecting infants and young children. Most CCSKs display few genomic aberrations, and no general underlying mechanism for tumor initiation has yet been identified, although a YWHAE-NUTM2B/NUTM2E fusion gene has been observed in a minority of cases. We performed RNA-sequencing of 22 CCSKs to investigate the presence of additional fusion transcripts. The presence of the YWHAE-NUTM2B/NUTM2E fusion was confirmed in two cases. In addition, a novel IRX2-TERT fusion transcript was identified in one case. SNP-array analyses revealed the underlying event to be an interstitial deletion in the short arm of chromosome 5 (5p15.33). TERT was dramatically upregulated under the influence of the IRX2 promoter. In line with TERT expression being driven by active IRX2 regulatory elements, we found a high expression of IRX2 in CCSKs irrespective of fusion gene status. IRX2 was also expressed in human fetal kidney – the presumed tissue of origin for CCSK. We conclude that in addition to promoter mutations and epigenetic events, TERT can also be activated in tumors via formation of fusion transcripts.

The butterfly pattern in a patient with chromosome 7 deletion.

The butterfly pattern in a patient with chromosome 7 deletion.

FEMALE PATIENT WITH A VARIANT OF TURNER SYNDROME

AbstractThe X chromosome contains determinants necessary to assure normal structural growth. Deletions of proportions of the X chromosome have been reported in a huge number of patients. We report on a mosaic short arm deletion of X chromosome (Xp-) in 14-years-old female patient with short stature, low set ears and no secondary sexual characteristics, a rare Turner syndrome variant. Chromosomal analysis using GTG-banding showed in 85% of cells and 46, X, del(Xp) in 15% of cells. The Fluorescence in situ hybridization technique of the cultured cells helped to perceive low grade cell line. Hence, molecular cytogenetics methods are essential to detect low level mosaicism which is important in better counseling.

Abstract 2404: Cumulative dosage effect of TSGs and OGs drives aneuploidy patterns in cancer

Abstract Since Boveri's postulates in 1914, aneuploidy has been recognized as a hallmark of human cancer. However, no comprehensive theory exists to explain the patterns of aneuploidy and its role in tumor evolution. Recurrent gains or losses of specific chromosomes have been observed in cancer, but it is not clear whether a recurrent pattern of aneuploidy exists among cancer karyotypes and whether the recurrent patterns just happen to occur more frequently or are specifically selected during tumor evolution. We have developed the Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method for the prediction of tumor suppressor genes (TSGs) and oncogenes (OGs) through the analysis of the pattern of somatic mutations in cancer (Davoli et al., Cell, 2013). By analyzing >8200 tumor-normal pairs from more than 20 tumor types we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. The TUSON Explorer analysis on the entire dataset has identified new potential TSGs such as RASA1, TP53BP1, USP28 and OGs such as PPP2R1A and PPP6C. The TUSON Explorer was also applied to individual tumor types, leading to the identification of new potential tissue-specific drivers. In addition, we have integrated our prediction of TSGs and OGs with information of copy number alterations. We found that the distribution on chromosome and the potency of TSGs and OGs can predict the frequency of arm-level and chromosome-level deletions and amplification. For example, the density and potency of TSGs strongly positively and negatively correlated with the frequency of arm and chromosome deletion and amplification, respectively (r value=∼0.6, p<10-4). The opposite behavior is seen for the OG density and potency. We find that by combining the TSG, OG and essential gene density and potency in a unified score, we can predict a high fraction of the recurrent arm and chromosome deletions and amplifications (r value= ∼0.8, p<10-9). We propose that it is the decrease or increase in the gene dosage of cancer drivers and essential genes in deletion and amplification to determine the recurrent patterns of aneuploidy selected during tumor evolution. In this view the aneuploidy state of tumor cells, first recognized by Bovery exactly a century ago, represents a driving force during the evolution of human cancer. Citation Format: Teresa Davoli, Andrew Wei Xu, Kristen E. Mengwasser, Laura M. Sack, John C. Yoon, Peter J. Park, Stephen J. Elledge. Cumulative dosage effect of TSGs and OGs drives aneuploidy patterns in cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2404. doi:10.1158/1538-7445.AM2014-2404

Microscopic chromosome Xp distal deletions – a challenging issue in prenatal genetic counseling

A prenatal diagnosis of chromosome X short arm deletions may present a challenge in prenatal genetic counseling. We present clinical and molecular data of carriers of Xp distal deletions. We assessed prenatal and postnatal phenotypes of individuals from three families with large Xp distal deletions and from a fourth family with a small Xp distal deletion. The work-up included karyotyping, chromosomal microarray analysis, and assessment of the X inactivation pattern. Five out of eight women with large deletions had a short stature (<3rd percentile). Subjects from one family had developmental and emotional problems. All female carriers with small deletions had markedly short stature, whereas the men had mildly short stature. Chromosomal microarray analysis revealed 11.7-19.3 Mb deletions in three families and a small ~1 Mb deletion in the fourth. The pseudoautosomal region 1 of the X chromosome was deleted in two families with large deletions. X inactivation was skewed in all tested cases with large deletions. Xp distal deletions are mainly associated with short stature. Skewing of the abnormal X chromosome may attenuate the phenotype in cases with large deletions. We suggest that prenatal evaluation in such cases should include sonographic follow-up and assessment of the X inactivation pattern.

1p36 Deletions in Two Cases with Thalassemia

ABSTRACTSummaryTerminal deletions in the short arm of chromosome one are generally associated with characteristic phenotype with dysmorphic features, including congenital anomalies and mental retardation with various degrees. Different outcomes depend on the sizes and locations of the deleted areas characterized by moderate to severe intellectual disability, delayed growth, hypotonia, seizures, limited speech ability, malformations, hearing and vision impairment and distinct facial features. The symptoms may vary, depending on the exact location of the chromosomal deletion but not a single reported case showed any ‘feature of anemia’.We report here one male and one female individual with partial deletions on chromosome no. one, both at 1p36 region. Cytogenetic analysis of blood lymphocytes was studied with high resolution GTG-banding analysis, using cyto-vision software on their chromosomes. Results revealed 46, XY, del(1)(p36.21) in the male who was also diagnosed as a ‘beta thalassemia trait’ and the other case was 46, XX, del(1)(p36.3) in the female who was diagnosed as a case of ‘HbE-beta thalassemia’.This report provides additional cases to the growing literature.Purpose/backgroundDeletion 1p36 is the most common terminal deletion syndrome with an estimated occurrence of 1:5000 live births. We report two patients with 1p36 deletions among which one shows ‘atypical’ proximal interstitial deletion at 1p36.21 using HR-GTG banding analysis. Interestingly, both the patients manifest one extra clinical characteristic that is different from those seen in ‘classical’ monosomy 1p36 syndrome, is ‘microcytic anemia’.Based on the analysis of the clinical and molecular data from our patients and those reported in the literature, we suggest that deletion 1p36.21 chromosomal abnormality may constitute yet another deletion syndrome distinct from the classical distal 1p36 deletion syndrome.Our aim was to find out further information regarding anemia since there are previously reported cases of anemias associated with this 1p36 region—one is presence of a ‘putative tumor suppressor gene’ important in the evolution of chronic myelocytic leukemia and the other is one inherited erythroblastopenia, commonly known as ‘Diamond-Blackfan anemia’ (DBA), caused by mutation in the gene encoding ribosomal protein L11 (RPL11) to answer families’ questions in the clinical setting.Materials and methodsStandard cytogenetic analysis was used with high resolution GTG-banding analysis, using cytovision software for karyotyping and high performance liquid chromatography (HPLC) and amplification refractory mutation mutation system (ARMS-PCR) to detect the five common Indian b-thalassemia mutations: [IVS-I-5 (G &gt;C), Cod 15 (G-A), Cod 8/9 (+G), Fr 41/42 (–TTCT) and Cod 26 (G-A)].ResultsResults showed 46, XY, del(1)(p36.21) in the male, additionally diagnosed as a ‘beta thalassemia trait’ and in another case 46, XX, del(1)(p36.3) in female who was diagnosed as a case of ‘HbE-beta thalassemia’.ConclusionThese two patients with deletion 1p36 represent association with other genetic disorder which is characterized by hematological abnormalities.How to cite this articleDe P, Chakravarty S, Chakravarty A. 1p36 Deletions in Two Cases with Thalassemia. Int J Infertil Fetal Med 2014;5(2):69-74.