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Showing papers on "Ring chromosome published in 2011"


Journal ArticleDOI
TL;DR: The progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.
Abstract: In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.

178 citations


Journal ArticleDOI
TL;DR: The clinical phenotype of patients with ring chromosomes may be related with different factors, including gene haploinsufficiency, gene duplications and ring instability, as observed in patients with complete r(14) and r(22).
Abstract: Background The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients.

102 citations


Journal ArticleDOI
TL;DR: It is demonstrated that r(20) is molecularly heterogeneous and formed by two distinct mechanisms, which, in turn, produce different phenotypic spectrums.
Abstract: BACKGROUND: The ring chromosome 20 syndrome (R20) is a rare genetic disorder associated with a refractory electroclinical epilepsy syndrome and variably expressed comorbidities of intellectual disability and dysmorphism. METHODS: To understand the structure and composition of the ring chromosome 20 (r(20)) in this patient cohort, blood specimens from 28 affected individuals were analysed by cytogenetic, fluorescence in situ hybridisation, and/or high resolution whole genome single nucleotide polymorphism array analysis. RESULTS: These studies revealed two distinct groups of patients. Group 1 (N=21) was mosaic for the r(20) and a normal cell line with no detectable deletions or duplications of chromosome 20 in either cell line. The mosaic nature of these rings suggests a postzygotic origin with formation of the ring by fusion of the telomeric regions with no apparent loss of subtelomeric or telomeric DNA. Group 2 (N=7) had non-mosaic ring chromosomes with a deletion at one or both ends of the chromosome, near the ring fusion point. The non-mosaic nature of these rings is consistent with a meiotic origin. The age of onset of seizures was significantly lower in the non-mosaic patients (group 2, median age of onset 2.1 years) than in the mosaic patients (group 1, median age of onset 6.0 years). Patients from group 2 had more extensive comorbidities. CONCLUSIONS: These studies demonstrate that r(20) is molecularly heterogeneous and formed by two distinct mechanisms, which, in turn, produce different phenotypic spectrums.

60 citations


Journal ArticleDOI
TL;DR: Two novel examples of neocentromeres that have formed in chromosome band 8q21 each with a unique DNA and CENP-A chromatin configuration are presented, suggesting that chromosomal rearrangement and DNA breakage may be involved in neocentromere formation.
Abstract: Endogenous human centromeres form on megabase-sized arrays of tandemly repeated alpha satellite DNA. Human neocentromeres form epigenetically at ectopic sites devoid of alpha satellite DNA and permit analysis of centromeric DNA and chromatin organization. In this study, we present molecular cytogenetic and CENP-A chromatin immunoprecipitation (ChIP) on CHIP analyses of two neocentromeres that have formed in chromosome band 8q21 each with a unique DNA and CENP-A chromatin configuration. The first neocentromere was found on a neodicentric chromosome 8 with an inactivated endogenous centromere, where the centromeric activity and CENP-A domain were repositioned to band 8q21 on a large tandemly repeated DNA. This is the first example of a neocentromere forming on repetitive DNA, as all other mapped neocentromeres have formed on single copy DNA. Quantitative fluorescent in situ hybridization (FISH) analysis showed a 60% reduction in the alpha satellite array size at the inactive centromere compared to the active centromere on the normal chromosome 8. This neodicentric chromosome may provide insight into centromere inactivation and the role of tandem DNA in centromere structure. The second neocentromere was found on a neocentric ring chromosome that contained the 8q21 tandemly repeated DNA, although the neocentromere was localized to a different genomic region. Interestingly, this neocentromere is composed of two distinct CENP-A domains in bands 8q21 and 8q24, which are brought into closer proximity on the ring chromosome. This neocentromere suggests that chromosomal rearrangement and DNA breakage may be involved in neocentromere formation. These novel examples provide insight into the formation and structure of human neocentromeres.

45 citations


Journal ArticleDOI
TL;DR: The co-occurrence of ring chromosome 13 syndrome and 47, XYY syndrome in the same individual is rare and its clinical presentation is variable depending on the predominating abnormality or a combination of the effect of both.
Abstract: The co-occurrence of ring chromosome 13 syndrome and 47, XYY syndrome in the same individual is rare. To the best of our knowledge, this is the first report of the co-existence of this kind of chromosome aberrations. At present, the deletion 13q syndrome is divided into three groups based on the deletion's location relative to chromosomal band 13q32. Group 1 (proximal to q32) and group 2 (including q32) have shown distinctive phenotypes including mental retardation and growth deficiency. Group 3 (q33-34 deletion) is defined by the presence of mental retardation but there is usually an absence of major malformations. We describe a 10-month-old Chinese Han boy presenting with severe mental retardation, profound congenital bilateral hearing loss with a terminal 13q33.2 deletion and multiple malformations. Routine chromosome analysis disclosed a de novo complex karyotype 47, XYY, r(13)(p11q34). Further investigation by high resolution array-based comparative genomic hybridization delineated an 8.5 Mb terminal deletion on the long arm of chromosome 13(13q33.2→q34). The co-occurrence of double syndromes in the same individual is rare and its clinical presentation is variable depending on the predominating abnormality or a combination of the effect of both. Hearing impairment is suggested as another new clinical feature to 13qter deletion. This case report will contribute to more accurate genetic counselling and provide further insight to the syndrome.

21 citations


Journal ArticleDOI
TL;DR: In most tumours exhibiting chromosomal instability, including highgrade malignant pancreatic, ovarian, and head- and neck carcinomas, as well as osteo- and soft tissue sarcomas, the two types of instability occur together, however, in some low-grade mesenchymal and neuroglial tumours, rarely showing numerical changes, BFB events involving telomeric associations and ring chromosomes dominate the mitotic process.
Abstract: May 2001 Summary Many human malignant tumours exhibit abnormal chromosomal segregation at cell division. It is believed that these anomalies play a role in tumorigenesis by increasing the rate of chromosome mutations, including deletion and amplification of genes involved in cellular proliferation and/or survival. In vitro experiments have also shown that mitotic instability may be a mechanism for developing resistance to cytotoxic drugs. Abnormal mitotic mechanisms may result in numerical or structural aberrations in the daughter cells. Numerical aberrations can be caused either by the loss of chromosomes at metaphase/anaphase or by multipolar divisions associated with abnormal number or structure of centrosomes. Structural rearrangements have been associated with chromosomal breakage-fusion-bridge (BFB) cycles that can be initiated by telomeric dysfunction, giving rise to unstable dicentric or ring chromosomes. In most tumours exhibiting chromosomal instability, including highgrade malignant pancreatic, ovarian, and head- and neck carcinomas, as well as osteo- and soft tissue sarcomas, the two types of instability occur together. However, in some low-grade mesenchymal and neuroglial tumours, rarely showing numerical changes, BFB events involving telomeric associations and ring chromosomes dominate the mitotic process. At progression towards higher malignancy in these tumours, complex structural and numerical aberrations become more frequent. This may be explained by a process initiated by telomeric dysfunction and anaphase bridging, which, in turn, may give rise to an increased frequency of multinucleated cells through failure of cytokinesis. These cells will contain an abnormal number of centrosomes leading to multipolar mitotic figures at the next cell division. Further understanding of these events may lead to novel strategies for detection and treatment of malignancy.

21 citations


Book ChapterDOI
25 Aug 2011
TL;DR: Phelan–McDermid syndrome, also known as the 22q13 deletion syndrome, is a genetic condition characterized by neonatal hypotonia, developmental delay, absent or impaired speech, and minor dysmorphic features.
Abstract: Clinical characteristics Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguishes Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior. Diagnosis/testing The diagnosis of Phelan-McDermid syndrome is established in a proband with typical clinical findings and detection of a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of SHANK3, or a heterozygous pathogenic variant in SHANK3 on molecular genetic testing. Individuals diagnosed by chromosomal microarray should have a karyotype to evaluate for the presence of a ring chromosome 22. Management Treatment of manifestations: Early referral for developmental support / special education; assistive technology for communication, oral-motor therapy to alleviate chewing and swallowing problems; standard treatment of seizures, hearing loss, recurrent ear infection, visual problems, and other identified medical needs. Regular professional dental hygiene, routine brushing, and fluoride treatment are important as enamel may be damaged from persistent chewing. Surveillance: Evaluation by a neurologist for epilepsy or if changes in behavior or regression of skills become evident; monitoring for lymphedema, which may appear in adolescence or adulthood; monitoring for symptoms of neurofibromatosis type 2 (NF2) in individuals with ring chromosome 22. Agents/circumstances to avoid: Exposure to high temperatures and extended periods in the sun because of decreased perspiration; exposure to dangers such as sources of excessive heat or cold, sharp objects, or clothes/shoes that are too tight, due to decreased perception of pain. Genetic counseling Phelan-McDermid syndrome, caused by a deletion of 22q13.3 that includes at least a part of SHANK3 or a pathogenic variant in SHANK3, is inherited in an autosomal dominant manner. The deletion may be de novo or the result of a balanced translocation in one of the parents; pathogenic variants in SHANK3 are almost always de novo. Prenatal testing and preimplantation genetic testing for Phelan-McDermid syndrome are possible for a pregnancy at increased risk.

20 citations


Journal ArticleDOI
TL;DR: A case of de novo mosaic r(18) is reported with a characterization by array-based comparative genomic hybridization analysis, and the phenotypic correlation in r( 18) is discussed also through a comparison with previously described cases of the literature.

19 citations


Journal ArticleDOI
TL;DR: Two men of the same family presented with ring chromosome 22 and azoospermia and appropriate counselling should be offered, in view of the varying phenotypic manifestations of ring chromosomes in the resulting progeny, and prenatal diagnosis or preimplantation diagnosis must be considered.
Abstract: Two men of the same family presented with ring chromosome 22 and azoospermia. The literature on all autosomal ring chromosomes and semen abnormalities was reviewed. Autosomal ring chromosomes were often associated with a low sperm count. This is probably as a result of gamete instability at meiosis due to the ring chromosome which leads to an increased breakdown. In addition, ring chromosomes transmitted from the parents may manifest quite differently in the progeny. Prior to treating these patients with assisted reproduction, appropriate counselling should be offered, in view of the varying phenotypic manifestations of ring chromosomes in the resulting progeny, and prenatal diagnosis or preimplantation diagnosis must be considered.

18 citations


Journal ArticleDOI
TL;DR: Fluorescence in situ hybridization analysis revealed that miniδ1 is dicentric just likeminiδ, whereas mini δ1-1 is monocentric, and ring structure without telomeres itself seems not to limit the female transmission.
Abstract: A dicentric ring minichromosome (miniδ) was identified in transgenic Arabidopsis thaliana and added to a wild type as a supernumerary chromosome. This line is relatively stable and has been maintained for generations, notwithstanding its ring and dicentric structure. To determine the mechanism for stable transmission of miniδ, the structure and behavior of two new types of ring minichromosomes (miniδ1 and miniδ1-1) derived from miniδ were investigated. Fluorescence in situ hybridization analysis revealed that miniδ1 is dicentric just like miniδ, whereas miniδ1-1 is monocentric. The estimated sizes of miniδ1 and miniδ1-1 were 3.8~5.0 and 1.7 Mb, respectively. The sizes of the two centromeres on miniδ1 were identical (ca. 270 kb) and similar to that of miniδ1-1 (ca. 250 kb). Miniδ1 was relatively stable during mitosis and meiosis, as is miniδ, whereas miniδ1-1 was unstable during mitosis, and the number of minichromosomes per cell varied. This possibly resulted from misdivision caused by a short centromere on monocentric miniδ1-1. Transmission through the female was quite limited for all three ring minichromosomes (0–3.2%), whereas that through the male was relatively high (15.4–27.3%) compared with that of other supernumerary chromosomes in Arabidopsis. Ring structure without telomeres itself seems not to limit the female transmission.

12 citations


Journal ArticleDOI
TL;DR: A study ofHMGA2 expression in a variety of adipocytic tumors showed aberrant expression in lipomas with 12q13-15 aberrations and ring chromosomes as well as in ALTs and well-differentiated liposarcomas (WDLSs), and frequent differential expression of HMGA2 exons 1-2 versus that of exons 4-5.

Journal ArticleDOI
TL;DR: A method to construct ring-X chromosomes in Drosophila via I-CreI-mediated exchange in rDNA, and then rapidly diagnose the recovery of ring chromosomes via FLP-mediated sister chromatid exchange within the ring is described.
Abstract: Ring chromosomes are of basic interest to the geneticist and cell biologist who study their behavior in meiotic and mitotic divisions. In addition, the mitotic instability associated with some ring-X chromosomes has proven useful in Drosophila as a means to produce gynandromorphs for developmental studies. We describe a method to construct ring-X chromosomes in Drosophila via I-CreI-mediated exchange in rDNA, and then rapidly diagnose the recovery of ring chromosomes via FLP-mediated sister chromatid exchange within the ring. The method we describe provides a ready means to tailor the genetic content of ring-X chromosomes, making it suited to produce ring-X chromosomes for a variety of experimental purposes.

Journal ArticleDOI
TL;DR: The experience in examining the clinical, cognitive, and behavioral findings in an 18.5-year-old female studied with chromosomal microarray hybridization and reviewed earlier reported patients with 14q32 deletions are reported.
Abstract: Deletions of the chromosome 14q32 region are rare but common clinical features indicate the presence of a cytogenetic syndrome. This condition is characterized by developmental delay, hypotonia, and a particular face (broad and flat nasal bridge, broad philtrum, thin upper lip, and prominent forehead). Further delineation of this syndrome is needed to clarify cognitive, physical, and behavioral aspects. A ring chromosome 14 defect produces a similar phenotype but often results in seizures, visual problems, and retinal abnormalities, and will not be discussed further in this report. We report our experience in examining the clinical, cognitive, and behavioral findings in an 18.5-year-old female studied with chromosomal microarray hybridization and reviewed earlier reported patients with 14q32 deletions.

Journal ArticleDOI
TL;DR: Two unrelated girls presented with multiple disseminated, paired, small café‐au‐lait spots and hypopigmented macules, suggesting didymosis (twin spotting), and it was hypothesized that the underlying gene locus is a hot spot for postzygotic recombination, resulting in multiple pigmentary twin spots.
Abstract: Two unrelated girls presented with multiple disseminated, paired, small cafe-au-lait spots and hypopigmented macules, suggesting didymosis (twin spotting). The girls also had growth retardation, microcephaly, hypertelorism, triangular facies, and a 46,XY, r(15) karyotype. The term cutis tricolor parvimaculata has been proposed to describe a twin spot phenomenon characterized by small, paired hypochromic and hyperchromic macules on a background of normal intermediate-pigmented skin. It has been hypothesized that the underlying gene locus of this phenomenon is a hot spot for postzygotic recombination, resulting in multiple pigmentary twin spots. Future clinical research may show whether analogous "simple" twin-spot phenotypes in the form of cutis tricolor parvimaculata may be considered a further cutaneous sign of the ring chromosome 15 syndrome.

Journal ArticleDOI
TL;DR: SKY, FISH, and aCGH are helpful in genetic counseling of prenatally detected sSMCs by providing the immediate and thorough information on the origin and genetic component of the sS MC.
Abstract: Objective To present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from ring chromosome, or r(4) by spectral karyotyping (SKY), fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH). Materials, Methods, and Results A 37-year-old, primigravid woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a de novo ring-shaped sSMC in 16 of 31 amniocyte colonies. The parental karyotypes were normal. Level II ultrasound findings were unremarkable. Repeated amniocentesis revealed a karyotype of 47,XX,+mar[17]/46,XX[19]. The sSMC was characterized by SKY and FISH, which showed a chromosome 4 origin of the sSMC. aCGH demonstrated a 21.7-Mb gain in the gene dosage encompassing the region of 4p12→q13.2. The sSMC was r(4)(p12q13.2). The fetal karyotype was 47,XX,+r(4)(p12q13.2)[17]/46,XX[19]. The pregnancy was subsequently terminated. The fetus postnatally manifested hypertelorism, epicanthic folds, a prominent nose, a triangular face, low-set ears, clinodactyly of the fingers, and small big toes. Postnatal cytogenetic analyses of fetal and extraembryonic tissues revealed the karyotypes of 47,XX,+r(4)[18]/46,XX[21] in cord blood, 47,XX,+r(4)[20]/48,XX,+r(4),+r(4)[1]/46,XX[9] in umbilical cord, 47,XX,+r(4)[14]/47,XX,+dic r(4)[1]/46,XX[25] in skin, 47,XX,+r(4)[15]/46,XX[25] in amnion, and 47,XX,+r(4)[12]/47,XX,+dic r(4)[1]/46,XX[2] in placenta. Conclusion SKY, FISH, and aCGH are helpful in genetic counseling of prenatally detected sSMCs by providing the immediate and thorough information on the origin and genetic component of the sSMC.

Journal ArticleDOI
TL;DR: Ring 21 Chromosome Presenting With Epilepsy and Intellectual Disability: Clinical Report and Review of the Literature
Abstract: Ring 21 Chromosome Presenting With Epilepsy and Intellectual Disability: Clinical Report and Review of the Literature Nicola Specchio,* Antonio Carotenuto, Marina Trivisano, Simona Cappelletti, Cristina Digilio, Rossella Capolino, Matteo Di Capua, Lucia Fusco, and Federico Vigevano Division of Neurology, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy Medical School, University of Naples, Naples, Italy Clinic for Nervous System Diseases, University of Foggia, Foggia, Italy Unit of Clinical Psychology, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy Division of Medical Genetics, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy

F Xu, Cc Zou, L Liang, Xm Huang, Yn Shao 
01 Jan 2011
TL;DR: Ring chromosome 15 syndrome should be considered in patients with short stature and cafe-au-lait spots and timely recognition and hereditary tendency counseling is required.
Abstract: Objective: This report aimed to add our knowledge on the clinical features, diagnosis and management of ring chromosome 15 syndrome. Methods: Case report and literatures review. Results: A 4.5-year-old girl was admitted to our unit because of short stature. She was 86 cm in height and 9 kg in weight. Physical examination showed sparse temporal hair, right simian crease, fifth finger clinodactyly, and many irregular cafe-au-lait spots on the chest, abdomen, and inner thigh. Mental retardation was found. The results of cranial magnetic resonance imaging (MRI) as well as abdominal and cardiac ultrasonography were normal. Growth hormone (GH) provocative tests showed normal GH peak. Karyotyping of the lymphocytes showed 46,XX, r(15) pattern. Recombination human GH (rhGH) with a dose of 0.1 U/kg -1 ·d -1 was administered for 4 months with height increment of 3 cm. Conclusion: Ring chromosome 15 syndrome should be considered in patients with short stature and cafe-au-lait spots. Timely recognition and hereditary tendency counseling is required. rhGH therapy may improve the growth velocity.

Journal ArticleDOI
TL;DR: A case of an African-American female with hyperthyroidism, type 1 diabetes mellitus, vitiligo and IgA deficiency associated with a r(18) chromosome complement is reported, which suggests that a gene or genes on chromosome 18 might play a role in the autoimmune process.
Abstract: Phenotypic and clinical features of individuals with ring chromosome 18 [r(18)] vary with the extent of deletion of the short (18p-) or long arm (18q-). Most patients with r(18), therefore, demonstrate a clinical spectrum of both 18p- and 18q- deletions. Short stature, microcephaly, mental and motor retardation, craniofacial dysmorphism and extremity abnormalities are the most commonly reported features in patients with r(18). Abnormalities of chromosome 18, especially 18p- syndrome, are often reported with autoimmune thyroid disease and growth hormone deficiency, but reports of endocrine abnormalities associated with r(18) are rare. Here, we report a case of an African-American female with hyperthyroidism, type 1 diabetes mellitus, vitiligo and IgA deficiency associated with a r(18) chromosome complement. This patient additionally had mild intellectual disability and dysmorphic features. Karyotype analysis showed a de novo ring chromosome 18 (deletion 18q23-18qter and deletion 18p11.3-18pter). Although this unique association of autoimmune polyglandular endocrinopathy with ring chromosome 18 could be coincidental, we speculate that a gene or genes on chromosome 18 might play a role in the autoimmune process.

Journal ArticleDOI
TL;DR: It is reported here the first cytogenetic description of a case of malignant melanotic schwannoma, a rare entity that generally occurs in young adults and commonly arises from the sympathetic nervous system even if soft tissue and visceral organs can also be affected.
Abstract: Melanotic schwannoma is a rare entity that generally occurs in young adults and commonly arises from the sympathetic nervous system even if soft tissue and visceral organs can also be affected [1]. Although most cases are benign, the outcome of this tumor is difficult to predict. Indeed, 15% of the reported patients have died of metastatic disease [1]. We report here the first cytogenetic description of a case of malignant melanotic schwannoma. A 47-year-old male presented with abdominal pain of 2 months duration. A computed tomography scan of the abdomen revealed a 19 9 17 9 10 cm retroperitoneal mass involving the small intestine, the bladder and the left diaphragm. A biopsy was performed. Histological examination showed a proliferation mainly made up of spindle cells and a component of epithelioid cells (Fig. 1a). In some areas, spindles cells were arranged in fascicles mimicking the architecture of a schwannoma. The cytoplasm of some cells contained brown pigment positively labeled by the Masson Fontana silver stain for melanin. The nuclei were uniform showing only mild atypia and some of them containing small nucleoli. The number of mitosis was very low (1 at Gx400/10 fields). The tumor cells were strongly and diffusely positive for S-100 protein, HMB-45, and negative for EMA, CD34, chromogranin A and actin (Fig. 1b). There was no clinical evidence of primary cutaneous or gastrointestinal melanoma. Therefore, a diagnosis of melanotic schwannoma was established. Clinical workup for the manifestations of the Carney complex was performed and included screening for cardiac myxomas, pigmentation abnormalities, and endocrine diseases. No abnormality was observed and the melanotic schwannoma was considered as sporadic. The patient underwent surgery, which was not radical because of vascular involvement. The disease progressed during 2 months following surgery. Palliative chemotherapy was started with stable disease as best tumor response. Three years later, the patient developed liver metastasis. He died from progressive metastatic disease 4 years after initial diagnosis. A fresh fragment was prepared for cytogenetic analysis. The RHG-banded karyotype showed a ring chromosome 11 and additional material on the short arm of chromosome 14 suspected to originate from the short arm of chromosome 6 (Fig. 1c). Fluorescence in situ hybridization (FISH) with whole chromosomes painting (WCP) probes for chromosomes 6 and 11 was performed according to the manufacturer’s instructions (Q-BIOgene, Illkirch, France). These experiments confirmed the chromosome 11 origin of the ring chromosome as well as the composition of the derivative chromosome consisting of the short arm of chromosome 6 and long arm of chromosome 14 (Fig. 1d). This unbalanced whole-arm translocation resulted in trisomy 6p. The karytoype was: A. Italiano A.-C. Peyron F. Pedeutour Laboratory of Solid Tumors Genetics, Faculty of Medicine, Nice University Hospital, Nice, France

Journal ArticleDOI
TL;DR: This is the 19th reported case of complete ring chromosome 7 mosaicism and the first survived case with mosaic supernumerary ring 7 without a normal karyotype detected in the peripheral lymphocytes.
Abstract: Aim: Clinical and molecular cytogenetic investigations of a newborn girl exhibiting facial dysmorphism with developmental delay. Methods: Phenotypic evaluation was first applied to examine the proband’s developmental status. Computed tomography and colour transcranial Doppler were used then to investigate her brain structure and function. Subsequently, chromosomal abnormalities were examined by karyotyping and fluorescent in situ hybridization was performed to investigate size of fragments lost at the two distal ends of the ring chromosome 7. In addition, multicolour banding was applied to rule out structural rearrangement occurs in between the ring chromosome 7. Results: The proband was born with mosaic supernumerary ring chromosome 7, without a normal karyotype detected in the peripheral blood lymphocytes. The distal arm of chromosome 7p (at least 255 kb from the telomere) was part of an extra ring chromosome 7. In addition, the distal arm of 7q, at least 8 kb from the telomere, was missing. There was no other chromosomal rearrangement detected by multicolour banding. Interpretation: This is the 19 th reported case of complete ring chromosome 7 mosaicism and the first survived case with mosaic supernumerary ring 7 without a normal karyotype detected in the peripheral lymphocytes.

Journal ArticleDOI
TL;DR: The findings strongly suggest that the patient's phenotype is largely attributable to partial 7pter trisomy and partial 7qter monosomy rather than mosaic supernumerary ring chromosome 19.
Abstract: We report on a patient with severe intellectual disability, microcephaly, short stature, and dysmorphic features who, based on standard karyotyping, has two cytogenetic abnormalities: an apparently balanced paracentric inversion of chromosome 7, inv(7)(q31.2q36), and a small supernumerary ring chromosome derived entirely of material from chromosome 19. While the inversion was detected in all cells, mosaicism was observed for the ring chromosome. Interestingly, apparently identical cytogenetic abnormalities were detected in the patient's mother, who presented with normal stature, few dysmorphic features, and normal cognition without microcephaly. While the level of mosaicism could not adequately explain the phenotypic discordance, comparative genome hybridization revealed a de novo terminal deletion of chromosome 7, del(7)(q36.2), and a terminal duplication of chromosome 7, dup(7)(p22.1) in the patient. Additional cytogenetic investigation revealed that the patient inherited a recombinant chromosome derived from a cryptic maternal pericentric inversion: inv(7)(p22q36). The patient's distinctive features are consistent with the wide phenotypic spectrum reported in 7p duplication and 7q terminal deletion syndromes. These chromosomal regions contain several candidate genes of clinical significance, including SHH, EN2, and FAM20C. Our findings strongly suggest that our patient's phenotype is largely attributable to partial 7pter trisomy and partial 7qter monosomy rather than mosaic supernumerary ring chromosome 19.

Journal ArticleDOI
TL;DR: Partial duplication of this gene, which has a role in the clotting cascade, suggests a potential mechanism for generating a pro-thrombotic state that may have contributed to a premature cerebrovascular event.

Journal ArticleDOI
TL;DR: A 23‐year‐old man with craniofacial findings of the holoprosencephaly spectrum disorder, including microcephaly, hypotelorism, depressed nasal bridge, single median maxillary central incisor, fusion of C2–C3 vertebrae, intellectual disability, and severe sleep apnea is reported on.
Abstract: We report on a 23-year-old man with craniofacial findings of the holoprosencephaly spectrum disorder (microcephaly, hypotelorism, depressed nasal bridge, single median maxillary central incisor), fusion of C2-C3 vertebrae, intellectual disability, and severe sleep apnea. Chromosome analysis of blood lymphocytes showed 75% ring (18) cells and 25% normal cells, karyotype mos 46,XY,r(18)(::p11→q21::)[75]/46,XY[25]. His mother was phenotypically normal except for a double ureter and bifid renal pelvis as in his son. She had a supernumerary ring (18) in 10% of blood lymphocytes, karyotype mos 47,XX,+r(18)(::p11→q21::)[10]/46,XX[90]. Familial ring (18) is a rare cytogenetic abnormality. This is the first report of a mother with a supernumerary ring (18) and a son with ring (18) mosaicism. Interestingly, the son showed a true mosaicism (mixoploidy) of ring (18) and normal cells. The mother's 46,XX cells could be easily explained by mitotic instability and ring loss during cell division. However, the coexistence of ring (18) and normal cells in the son is unusual. Possibly, during early postzygotic divisions of a 47,XY,+r(18) zygote, two (possibly subsequent) genetic events could have occurred, one when one normal chromosome 18 was lost (resulting in a cell line with ring 18), and one when the ring 18 was lost (resulting in a cell line without ring, "escape to normal"). Alternatively, the zygote of the son could have been 46,XY,r(18), and postzygotic loss of the ring 18 could have resulted in monosomy 18 cells followed by duplication of chromosome 18 in these cells (a rare mechanism for cell survival previously described as "compensatory" isodisomy).

Journal ArticleDOI
TL;DR: This case of a girl with short stature, developmental delay, and dysmorphic features represents a rare case where a neocentromere can form even in the presence of existing alpha-satellite DNA.
Abstract: Background/Aims: The ‘McClintock mechanism’ of chromosome breakage and centromere misdivision, in which a deleted chromosome with its concomitant excised marker or ring chromosome i

Journal ArticleDOI
TL;DR: This is the first patient with r(3) studied using molecular techniques that determined the exact breakpoints in order to establish a better karyotype-phenotype correlation.
Abstract: Ring chromosome 3 is a rare abnormality with only 10 patients described in the literature. We report a patient with r(3) and ∼6-Mb distal 3p deletion. Single nucleotide polymorphism array, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization techniques revealed that the ring was formed by a break in 3p26.1 and fusion with the subtelomeric region of 3q. The patient presents delayed psychomotor development, growth failure, minor anomalies and other features similar to patients with 3p monosomy. The analysis of 300 metaphase cells using G-banding and fluorescence in situ hybridization with centromeric probe revealed ring instability resulting in cells with secondary aberrations and with ring loss that could also be related to some phenotypic characteristics such as growth delay. This is the first patient with r(3) studied using molecular techniques that determined the exact breakpoints in order to establish a better karyotype-phenotype correlation.

Journal ArticleDOI
TL;DR: This case highlights the importance of karyotyping as an initial step in the management of couples referred for in vitro fertilization.
Abstract: An amniotic fluid sample from an in vitro fertilized pregnancy was referred for cytogenetic analysis based on a Down syndrome screening risk of 1:21. Routine cytogenetic analysis showed a nonmosaic karyotype of 46,XX,r(21)(p11.2q22.3), with partial monosomy for chromosome 21 due to a ring chromosome replacing one of the normal homologues. Detailed ultrasound scanning for the remainder of the pregnancy did not reveal any unusual findings. Parental bloods showed that the mother was mosaic for the ring 21 with a karyotype of 46,XX,r(21)(p11.2q22.3)/46,XX and the father had an unrelated Robertsonian translocation, with a karyotype of 45,XY,rob(13;14)(q10;q10). Microarray analysis of cultured amniocytes determined the extent of the deletion of chromosome 21 material in the ring. The parents were given genetic counselling, and a phenotypically normal female baby was delivered at term. This case highlights the importance of karyotyping as an initial step in the management of couples referred for in vitro fertilization.

Journal ArticleDOI
TL;DR: A developmentally normal Amish child who has a karyotype with 47 chromosomes, including a supernumerary ring‐shaped chromosome 18 in each metaphase studied, and genes in the triplicated region that possibly are contributing to her skeletal phenotype are described.
Abstract: We describe a developmentally normal Amish child who has a karyotype with 47 chromosomes, including a supernumerary ring-shaped chromosome 18 in each metaphase studied. The only phenotypic findings in the patient were hemivertebrae and rib anomalies. Further analysis of interphase cells revealed an additional, less frequent mosaic, apparently normal cell population. Genes in the triplicated region that possibly are contributing to her skeletal phenotype include GATA6, MC2R, MC5R, RBBP8, ESCO1, and ROCK1, among others. By studying such patients with abnormal genetic dosage, genotype-phenotype correlations can be used to refine gene function.

Journal ArticleDOI
TL;DR: In the present foetus with monosomy 18p, INT was observed as the only abnormal ultrasonographic finding during pregnancy and the parents decided to terminate the pregnancy based on the chromosomal abnormality.
Abstract: Fetal chromosomal abnormality and increased nuchal translucency (INT) association is well established (6). There are several reports about the association between foetal chromosomal abnormalities including triploidy, trisomies 13, 18, 22, tetrasomy 12p and increased nuchal translucency (INT) during the first trimester of pregnancy (6). More than 70% of cases with trisomy 21 can be detected by screening for INT (8). In the present foetus with monosomy 18p, we observed INT as the only abnormal ultrasonographic finding during pregnancy. Amniocentesis was performed at 18 weeks of gestation on a 41 years old Turkish female referred for prenatal diagnosis because of advanced maternal age. INT was observed at the time of amniocentesis (2.8 cm). The couple had a healthy four year-old girl with 46,XX karyotype. Conventional cytogenetic analysis of cultured amniocytes showed an unbalanced whole arm translocation between the long arm of one chromosome 18 and the long arm of one chromosome 22, 45,XX, der(18)t(18;22)(ql0;ql0), which led to monosomy 18p in the foetus (Fig. Ia). Parental karyotypes were normal, thus the aberration had occurred de novo. The derivative chromosome had one centromere revealed by conventional C banding staining. Whether the centromere originated from chromosome 18 or chromosome 22 could not be determined by FISH. Chromosome 18p STS markers D18S498, D18S481 and D 18Sl 70 were used for genotyping of the foetus and parents, to determine the origin of derivative chromosome 18. Marker D 18Sl 70 was informative: while her parents were heterozygous for this marker, the foetus had only the paternal allele, thus the maternal chromosome 18 was found to be involved in the translocation (Fig. Ib). The parents decided to terminate the pregnancy at 21 weeks of gestation based on the chromosomal abnormality. At autopsy, 362.62 g weight of foetus, supraorbital flatness, depressed nasal bridge, flared nostrils and low set ears were observed. Placenta weight was lower (170 g) than average (normal range relative to 21 weeks of gestation is 180 g) (1). Deletion of the short arm of chromosome 18, the del(18p) syndrome, is the second most frequent autosomal deletion syndromes. Since the del(18p) syndrome was first described by de Grouchy et al. (2), more than 150 cases have been reported. Most cases appear as a result of de now terminal deletions (85%) or ring chromosomes, and about 15% of del(18p) originate from unbalanced translocations between the long arms of chromosome 18 and acrocentric chromosomes, predominantly chromosomes 14, 21 or 22 (7). Clinical manifestations of monosomy 18p varies widely (3), but usually comprises mental and growth retardation, craniofacial dysmorphism including round face, dysplastic ears, wide mouth, and dental anomalies. Cardiac defects and genital anomalies, and even prenatally detected holoprosencephaly have also been reported (5, 9, 10). Variable phenotypes are related to del(18p) syndrome, which makes the prenatal diagnosis and genetic counseling of the cases with 18p monosomy difficult (7). In the detailed autopsy analyses of our case performed following termination of the pregnancy, corpus callosum agenesis, holoprosencephaly, hydrocephaly, cardiac defects and genital abnormalities, which are among malformations specific for del(l 8p) syndrome, were not observed. Supraorbital flatness, depressed nasal bridge, flared nostrils and low set ears were observed as dysmorphic findings, however, confident determination in fetuses is difficult. …

Journal ArticleDOI
TL;DR: This is the first case of de novo ring chromosome 16 diagnosed prenatally with a new phenotypic pattern and also reinforces the importance of offering amniocentesis with a-CGH if fetal anomalies are detected.
Abstract: A fetus with de novo ring chromosome 16 is presented. At 20 weeks' gestation, ultrasound examination demonstrated bilateral clubfoot, bilateral renal pyelectasis, hypoplasia of the corpus callosum, and transposition of the great vessel. Amniocentesis was performed. Chromosome analysis identified a ring chromosome 16 [47,XY,r(16)] and array comparative genomic hybridization (a-CGH) demonstrated that the ring included the euchromatic portion 16p11.2. Postmortem examination confirmed prenatal findings. This is the first case of de novo ring chromosome 16 diagnosed prenatally with a new phenotypic pattern and also reinforces the importance of offering amniocentesis with a-CGH if fetal anomalies are detected.

Journal ArticleDOI
TL;DR: The presence of euchromatic material from chromosome 1 in the ring suggests that the relationship between the cytogenetic findings and the clinical manifestation is likely causative, and might indicate different mitotic vulnerability of certain chromosome abnormalities at early postzygotic stages versus later during development.