Showing papers on "Ring chromosome published in 2003"

Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: cytogenetic, molecular, and clinical analyses of 32 new observations

Abstract: The terminal regions of human chromosomes are known to contain specialised DNA sequences and may be vulnerable to rearrangements causing human genetic diseases and particularly idiopathic mental impairment.1,2 During the last decade, there have been several reports of patients who are described as having a 22q13 monosomy resulting from simple terminal deletions.1,3–11 A common phenotype emerged from these reports, including variable learning difficulties with disproportionate verbal delay, generalised hypotonia, normal to accelerated growth, and minor facial dysmorphy.10 Monosomies for 22q13 have also been reported that result from unbalanced translocation with an acrocentric short arm.10,12 The acrocentric short arms only bear ribosomal genes, and their duplication or deletion is not generally thought to be phenotypically significant. Therefore such translocations can be considered as “pure” terminal 22q13 deletions. A distinct group of 22q13 monosomies has been reported that result from the formation of a ring chromosome which combines loss of some long arm material with loss of part of the short arm, with no clinical consequences. Nevertheless, although ring chromosome 22 has been described in over 50 cases,13 it remains uncertain whether the variable phenotype is caused by the loss of a variable amount of chromosomal material or by a cellular mosaicism arising from instability of the ring. Regardless of the causative rearrangement, very few cases of “pure” 22q13 monosomy have been investigated up to now by detailed molecular studies. In order to characterise this syndrome better, facilitate the diagnosis, and provide targeted health care for affected individuals, we have studied 33 patients (32 new observations) with a pure 22q13 partial monosomy, using molecular and cytogenetic methods. ### Subjects Our study involved 33 patients with a “pure” partial 22q13 monosomy, with exclusion of all rearrangements involving loss or gain of euchromatic material from any other …

Definition of a Critical Region on Chromosome 18 for Congenital Aural Atresia by ArrayCGH

Abstract: Deletions of the long arm of chromosome 18 occur in ∼1 in 10,000 live births. Congenital aural atresia (CAA), or narrow external auditory canals, occurs in ∼66% of all patients who have a terminal deletion 18q. The present report describes a series of 20 patients with CAA, of whom 18 had microscopically visible 18q deletions. The extent and nature of the chromosome-18 deletions were studied in detail by array-based comparative genomic hybridization (arrayCGH). High-resolution chromosome-18 profiles were obtained for all patients, and a critical region of 5 Mb that was deleted in all patients with CAA could be defined on 18q22.3-18q23. Therefore, this region can be considered as a candidate region for aural atresia. The array-based high-resolution copy-number screening enabled a refined cytogenetic diagnosis in 12 patients. Our approach appeared to be applicable to the detection of genetic mosaicisms and, in particular, to a detailed delineation of ring chromosomes. This study clearly demonstrates the power of the arrayCGH technology in high-resolution molecular karyotyping. Deletion and amplification mapping can now be performed at the submicroscopic level and will allow high-throughput definition of genomic regions harboring disease genes.

The giant B chromosome of the cyprinid fish Alburnus alburnus harbours a retrotransposon-derived repetitive DNA sequence.

Abstract: The cyprinid fish Alburnus alburnus possesses one of the largest supernumerary chromosomes in all vertebrates In the present study, amplified fragment length polymorphism analyses (AFLP) and fluorescence in-situ hybridization (FISH) were performed in order to characterize these extraordinary chromosomes in detail Sequence analysis of the B chromosome-specific DNA revealed a strong homology to a Drosophila Gypsy/Ty3 retrotransposon and also to a medaka (Oryzias latipes) one The sequence is highly abundant on the B chromosome but undetectable in the normal A chromosome complement It is also absent from the B chromosome of the closely related species, Rutilus rutilus, suggesting a specific spreading of the mobile element during evolution of the giant supernumerary chromosome within A alburnus Meitotic chromosomes were in-situ hybridized with the B chromosome-specific probe, documenting that the additional chromosome behaves as an autopaired ring chromosome in diakineses Our results suggest that the supernumerary chromosome of A alburnus is not derived from the normal chromosome complement but has evolved independently

Y chromosome sequences in Turner's syndrome: association with virilization and gonadoblastoma.

Abstract: UNLABELLED The presence of Y chromosome fragments in patients with Turner's syndrome is known to increase the risk of gonadoblastoma and virilization. Y chromosome material is detected in up to 6% of patients with Turner's syndrome by karyotype. By DNA analysis, Y chromosome sequences have been reported in 0-60% of patients. The putative gonadoblastoma gene has been mapped to the pericentromeric region of the Y chromosome increasing the interest in studying these sequences. AIMS 1. To determine the frequency of occult Y chromosome sequences in patients with Turner's syndrome. 2. To analyze the clinical implications of Y sequences detected by karyotype and occult Y sequences. STUDY DESIGN Cross-sectional study of 58 patients with Turner's syndrome (30 45,X; two with structural anomalies; 26 mosaic [two of whom were 45,X/46,XY]). SRY, TSPY and DYZ3 sequences were amplified by PCR using genomic DNA from peripheral blood. RESULTS All three Y chromosome sequences were found in one out of 56 patients whose karyotype was not suggestive of having Y chromosome material and in one patient with 45,X/46,Xr(X) karyotype. The patients with the ring chromosome and 45,X/46,XY karyotype underwent surgery and were found to have a gonadoblastoma and dysgerminoma. The four patients with Y chromosome material had non-virilized female genitalia. CONCLUSIONS Analysis by PCR was more sensitive in detecting Y chromosome sequences than conventional karyotype. The presence of Y material was not associated with virilization. We confirmed the association of Y fragments and gonadoblastoma at an early age.

A series of supernumerary small ring marker autosomes identified by FISH with chromosome probe arrays and literature review excluding chromosome 15.

Abstract: Seven supernumerary small ring marker autosomes were studied The pantelomere probe (Oncor) in conjunction with scoring for dicentric rings was used to confirm ring morphology The small rings were identified mainly by FISH with chromosome probe arrays (Cytocell) containing representations from all 24 chromosomes and the rings were derived from chromosomes 7, 8 (three cases), 11, 12, and 14 The effectiveness of the array methodology in identifying markers was tested Microsatellite DNA data showed biparental disomy (BPD) was present for the rings from chromosomes 7 and 14 thereby excluding UPD, both were de novo but the ring 14 was of paternal origin The literature on supernumerary small ring autosomes was reviewed excluding chromosome 15 The grade and distribution of mosaicism was invoked as the major determinant of the differences in phenotype and, in addition, variation was attributed to the possibility of different contributions from each chromosome arm There are 88 published supernumerary small ring cases in total, with phenotypic data attributable to the respective rings in 77 cases and all chromosomes being represented except chromosome 17 Of the prenatally ascertained cases, where there was adequate phenotypic data, 30% had an abnormal phenotype attributable to the ring, and there were 44% familial cases in this group Of the postnatally ascertained small rings, 75% had an abnormal phenotype attributable to the ring and there were 13% familial cases This higher abnormality rate is concordant with the considerable ascertainment bias of this latter group and the prenatal data are recommended for genetic counseling Although data are small there were some differences between the rings derived from different chromosomes Chromosomes 3 and 8 demonstrate the extremes Of the supernumerary small r(8) cases reviewed including the three presently described, 8/11 had an abnormal phenotype attributable to the marker but of the small r(3) cases, only 1/6 had an abnormal phenotype Two of the present r(8) were studied with the GATA4 probe at 8p231 The r(8) in case 2 (patient moderately retarded) was comprised mostly of an intact 8p whereas the larger r(8) in case 3 (normal phenotype) was missing 8p231 --> pter and had more of 8q contributing to the ring In other supernumerary rings postnatally ascertained, there is mostly insufficient data but there is an abnormal phenotype in 8/11 cases with multiple small rings, in 5/6 cases with r(20), and in 5/10 with r(1) A novel origin for supernumerary small rings is proposed: that they may originate from incompletely digested superfluous (haploid) pronuclei The small rings presumptively so formed may occasionally be transfected into the zygote nucleus The high proportion ( approximately 125%) of cases with multiple supernumerary small rings almost always of different centromeric origin is consistent with this concept

Two new cases of analphoid marker chromosomes.

Abstract: Supernumerary marker chromosomes (SMCs) without detectable alphoid DNA represent a rare and interesting class of rearranged marker chromosomes. These SMCs are predicted to have a neocentromere and have been referred to as neocentric marker chromosomes (NMCs). We report the molecular cytogenetic characterization of two new cases of neocentromere-containing chromosomes, one on 1q43∼44 and one on 15q26. Both cases were examined using fluorescence in situ hybridization (FISH) with various alpha-satellite DNA probes, and no alphoid DNA was detected. In case 1, the NMC originated from the distal long arm of chromosome 1 by chromosomal microdissection and reverse painting. This marker lacked detectable chromosome 1q subtelomeric sequences, and therefore appeared to be a small ring chromosome. After genetic counseling with a high risk for a MCA/MR syndrome (trisomy 1q43 q44), the family continued the pregnancy. At age 6 months, the infant demonstrated no congenital or developmental anomalies. This is the first published example of a NMC derived from chromosome 1q. The marker may be one of the smallest, if not the smallest, human NMC reported to date. In case 2, fetal ultrasonography indicated a complex heart defect (abnormal return of lower vena cava, atrial septum malformation) and bilateral hydronephrosis. Molecular cytogenetic analysis showed an inverted duplication of the distal long arm of chromosome 15 (tetrasomy 15q24 qter). The pregnancy was terminated. Autopsy demonstrated polycystic left kidney and dysplastic right kidney. Case 2 represents the ninth report of a neocentromere on distal chromosome 15q, suggesting that this region may possibly especially support the formation of neocentromeres. © 2002 Wiley-Liss, Inc.

Molecular characterization of an inherited ring (19) demonstrating ring opening.

Abstract: Ring chromosomes arise following breakage in both chromosome arms and rejoining of the centric segment at the broken ends or by end-to-end fusion of the telomeres. The phenotype of ring carriers is unpredictable, and developmental abnormalities may occur even when the ring appears to be structurally balanced. This is believed to be due to mitotic instability from abnormal segregation and sister chromatid exchange in somatic cells. Although ring chromosomes usually arise as de novo events, transmittal from mosaic carriers to offspring sometimes occurs. In such cases, offspring with ring mosaicism in combination with a normal cell line remain unexplained. In this report, we used detailed molecular and cytogenetic analyses of a prenatally detected, inherited ring (19) to observe the behavior of the ring chromosome in culture, and to investigate the mechanism of inherited ring chromosome mosaicism.

Ring chromosome 14 with localization-related epilepsy: three cases.

Abstract: Three patients showing epileptic seizures and with mosaicism of ring chromosome 14 and monosomy for chromosome 14 are described. Patients were a 17-year-old boy, karyotype 46, XY, r(14)(p12q32.33)/45, XY, -14, a 7-month-old boy, karyotype 46, XY, r(14)(p11.2q32.33)/45, XY, -14, and a 10-month-old boy, karyotype 46, XY, r(14)(p12q32.31)/45, XY, -14. Microcephaly and alopecia were observed in the first patient. However, few dysmorphic features were found typical of ring 14 chromosome. He had exhibited complex partial seizures with secondary generalization at age 3 months and had mild motor and mental retardation. Both other patients had atonic seizures followed by staring, perioral cyanosis, and respiratory arrest at age 7 or 8 months. Both also showed mild developmental delay and had a few minor anomalies compatible with ring 14 chromosome. Interictal spikes were observed in the second patient in the right occipital region, whereas an interictal encephalogram of the third patient showed sporadic spikes in the left central region. In all three cases, seizures were resistant to common antiepileptic drugs.

Ring chromosome 17: phenotype variation by deletion size.

Abstract: Ring chromosome 17 is a rare cytogenetic abnormality, with 12 previous reports in the literature. Some have a relatively mild phenotype characterized by seizures, mental retardation, skin changes and short stature. Other patients have Miller–Dieker syndrome (MDS), which includes lissencephaly, multiple dysmorphic features, severe mental retardation and shortened life expectancy. We describe two new cases of ring chromosome 17 and review the literature. Our cases and the other reports of patients without a deletion encompassing the Miller–Dieker region, delineate a fairly distinctive subgroup of individuals with ring 17, whose phenotype consists of growth and mental retardation, seizures, minor dysmorphic features, cafe-au-lait spots and retinal flecks. This classification of ring 17 into two distinct groups based on the size of the deletion and the phenotypic manifestations should facilitate clinical suspicion of this rare chromosomal abnormality.

Prenatal diagnosis of a karyotypically normal pregnancy in a mother with a supernumerary neocentric 13q21 -->13q22 chromosome and balancing reciprocal deletion.

Abstract: An adult female patient with a history of miscarriages was found to be carrying a stable supernumerary chromosome. The patient also carried a reciprocal paracentric deletion in chromosome 13q21/22. Microdissection and reverse fluorescence in situ hybridization FISH revealed that this supernumerary chromosome was derived from region 13q21 --> 13q22. The presence of a neocentromere on this supernumerary chromosome was confirmed by the absence of detectable alpha satellite DNA using FISH and the presence of centromere proteins CENP-C and CENP-A using immunofluorescence. The absence of telomere sequences suggests that the marker is a ring chromosome (r(13)). FISH using ordered BACs from the chromosome region 13q21 --> 13q31 permitted the precise positioning of the r(13) chromosome and the corresponding deletion to chromosome bands 13q21.32 --> 13q22.2. BAC 280J7 from within the r(13) was used as a FISH probe for the prenatal analysis of amniocytes at 16 weeks of gestation, which revealed a normal karyotype for the fetus. This r(13) chromosome represents the first description of chromosome 13 of the rarer class of neocentric chromosomes that are derived from interstitial deletions. It represents the first example of prenatal diagnosis in a phenotypically normal female that was ascertained to carry a neocentric marker. The presence of such a neocentric marker/deletion karyotype in a parent presents unique possible karyotypic outcomes for conceptions and unusual challenges for genetic counseling.

Ring chromosomes and low-grade gene amplification in an atypical lipomatous tumor with minimal nuclear atypia.

Abstract: Atypical lipomatous tumors (ALTs) are characterized by supernumerary ring chromosomes and/or giant marker chromosomes, which typically are composed of interspersed, amplified 12q-sequences, are C-band negative, lack a-satellite sequences, and display high copy numbers of several oncogenes, including HMGA2 (a.k.a. HMGIC) and MDM2, from the 12q13-15 region. In the present study, we report the cytogenetic and molecular genetic findings in an ALT with minimal nuclear atypia from a 16-year-old boy. At G-banding analysis, 1-3 supernumerary ring chromosomes were detected. Combined binary ratio labeling fluorescence in situ hybridization (COBRA-FISH) showed that the rings were entirely composed of material from chromosome 12, and by further FISH analysis with locus-specific probes it was revealed that they consisted of two tandemly arranged copies of the segment 12p11.2-p13.2 to 12q21.2-q23.1. Within that segment of chromosome 12, there was a small deletion including the HMGA2 locus. There was no variation in ring size and no interphase bridges could be detected, indicating that the ring chromosomes were mitotically relatively stable. The present case thus adds support to the concept that there exists a subset of ALT with limited or minimal nuclear atypia and low-level amplification of 12q sequences, further suggesting the possibility of a molecular genetic continuum between lipoma and classical examples of ALT. Furthermore, the present data strongly imply that it is the composition of the rings rather than the ring chromosome formation as such that causes the genetic instability and nuclear atypia frequently seen in ALTs. (Less)

Five new subjects with ring chromosome 22.

Abstract: Ring chromosome 22, a rare cytogenetic finding, was first described by Weleber et al. in 1968. Since then approximately 50 patients have been reported in the medical literature. We describe five previously unreported subjects with ring chromosome 22 syndrome, summarize the clinical findings of reported patients from the literature and discuss the involvement of the ring chromosome and clinical outcome. Our subjects demonstrated the prominent features of this syndrome including mental retardation, hypotonia, motor delay, lack of speech, full eyebrows, and large ears. In addition, two of our subjects had central nervous system malformations and regression. The lack of consistent physical abnormalities in our subjects further supports no consistent phenotype manifestations in this cytogenetic syndrome. The variable clinical manifestations seen in ring chromosome 22 subjects may be associated with loss of chromosome 22 sequences near the telomere or attributed to the genetic background of each subject. Similarly, recessive alleles unmasked by the deletion could also contribute to the phenotype.

Ring 21 chromosome and a satellited 1p in the same patient: novel origin for an ectopic NOR.

Abstract: Nucleolus organizer regions (NORs) are present on the satellite stalks located on the short arms of the acrocentric chromosomes. NORs present on non-acrocentric chromosomes (ectopic NORs) are rare and were reported in both phenotypically normal and abnormal individuals. We describe a patient, ascertained prenatally, with an ectopic NOR on 1p and a ring 21 chromosomes. Amniocentesis was performed at 27-weeks gestation on a 19-year-old woman after identification of intrauterine growth retardation (IUGR) by ultrasound. Cytogenetic analysis of amniocytes from the fetus showed a mos 46,XX,1ps,r(21) (p11.2q22.3)[44]/45,XX,1ps,-21[6] karyotype. Parental karyotypes were normal, indicating a de novo origin for these rearrangements in the fetus. Molecular cytogenetic characterization of the 1ps showed no loss of euchromatin and retention of the telomeric repeats. Characterization of the r(21) using array comparative genomic hybridization (CGH) identified that the deletion was approximately 5 Mb encompassing most of chromosome band 21q22.3. The ectopic NOR (1ps) was most likely derived from the acentric 21p fragment generated by the chromosome breakage event that lead to formation of the r(21) chromosome. This represents a novel mechanism for the origin of ectopic NORs. In addition, this study illustrates the importance of FISH analysis with telomeric and subtelomeric probes for characterization of chromosomes with ectopic NORs.

Prenatal diagnosis of mosaic ring chromosome 22 associated with cardiovascular abnormalities and intrauterine growth restriction.

Abstract: Objectives To present the prenatal diagnosis and perinatal findings of mosaic ring chromosome 22. Case Amniocentesis was performed at 18 gestational weeks because of an advanced maternal age. Cytogenetic analysis of the cultured amniotic fluid cells revealed mosaicism for ring chromosome 22, 45,XX,-22[6]/46,XX,r(22)(p13q13.31)[15]. Abnormal fetal sonographic findings included small for gestational age, a ventricular septal defect, and truncus arteriosus. The pregnancy was terminated. Additional phenotypic findings included hypertelorism, epicanthal folds, and abnormal ears. Cytogenetic analysis of the cord blood lymphocytes revealed a complex mosaic karyotype, 45,XX,-22[7]/46,XX,r(22)(p13q13.31)[82]/46,XX,idic r(22)(p13q13.31;p13q13.31)[11]. Cytogenetic analysis of the hepatocytes also revealed mosaic r(22) with mosaicism for idic r(22) and monosomy 22. The deletion of distal 22q and the duplication of 22q11.2 on idic r(22), and the distal 22q deletion on r(22) were demonstrated by fluorescent in situ hybridization (FISH) analysis using 22q terminal probes at 22q13 and a DiGeorge syndrome critical region probe at 22q11.2. The breakpoint on distal 22q13 and the extent of the duplication of 22q on idic r(22) was determined by examining polymorphic markers specific for chromosome 22 using quantitative fluorescent polymerase chain reaction assays. The chromosomal aberration was of maternal origin. Conclusion Molecular and FISH studies allow a better delineation of some prenatally detected aneuploidy syndromes and help elucidate the genetic pathogenesis. Fetuses having mosaic r(22) with a low level mosaicism for r(22) duplication/deletion may present cardiovascular abnormalities and intrauterine growth restriction on prenatal ultrasound. Copyright © 2002 John Wiley & Sons, Ltd.

Prenatal diagnosis of a small supernumerary, XIST-negative, mosaic ring X chromosome identified by fluorescence in situ hybridization in an abnormal male fetus

Abstract: Marker or ring X [r(X)] chromosomes of varying size are often found in patients with Turner syndrome. Patients with very small r(X) chromosomes that did not include the X-inactivation locus (XIST) have been described with a more severe phenotype. Small r(X) chromosomes are rare in males and there are only five previous reports of such cases. We report the identification of a small supernumerary X chromosome in an abnormal male fetus. Cytogenetic analysis from chorionic villus sampling was performed because of fetal nuchal translucency thickness and it showed mosaicism 46,XY/47,XY,+r(X)/48,XY,+r(X),+r(X). Fluorescence in situ hybridizations (FISH) showed the marker to be of X-chromosome origin and not to contain the XIST locus. Additional specific probes showed that the r(X) included a euchromatic region in proximal Xq. At 20 weeks gestation, a second ultrasound examination revealed cerebral abnormalities. After genetic counselling, the pregnancy was terminated. The fetus we describe is the first male with a mosaic XIST-negative r(X) chromosome identified at prenatal diagnosis. The phenotype we observed was probably the result of functional disomy of the genes in the r(X) chromosome, secondary to loss of the XIST locus.

Chromosome 18 replaced by two ring chromosomes of chromosome 18 origin.

Abstract: We here describe the first example of the replacement of an autosome by two ring chromosomes originating from the missing chromosome, presented in a patient with a single chromosome 18 and two additional ring chromosomes. Detailed fluorescence in situ hybridization (FISH) analysis revealed the chromosome 18 origin of both ring chromosomes and characterized the small and the large ring chromosome as derivatives of the short and long arm of chromosome 18, respectively. The loss of subtelomeric regions of the short and the long arm of chromosome 18 in the ring chromosomes was confirmed by FISH studies. Molecular studies showed the exclusive presence of the paternal alleles for microsatellite markers located distal to the short and long arm loci D18S843 and D18S474, respectively. This indicates the maternal origin of both rings and provides evidence for substantial deletions of the distal parts of both arms of chromosome 18 in the ring chromosomes. The dysmorphic features of the patient can be explained by these deletions in both chromosome arms, as the clinical findings partly overlap with observations in 18p- and 18q-syndrome and are similar to some cases of ring chromosome 18. Centromere misdivision is suggested as one mechanism involved in the formation of the ring chromosomes.

Characterization of a supernumerary ring chromosome 1 mosaicism in two cell systems by molecular cytogenetic techniques and review of the literature.

Abstract: We report on a 4-year-old boy with developmental delay and microcephaly with an additional small marker chromosome derived from chromosome 1 and detected in 14% of T-lymphocytes by conventional cytogenetics and in 9% of buccal smear cells by interphase FISH. Using molecular cytogenetic techniques, the marker chromosome was characterized as an extra ring chromosome consisting of euchromatic material from the proximal short arm of chromosome 1. We compare the cytogenetic data and the phenotype of our patient to those previously described cases with marker chromosome 1 mosaicism. We conclude that in addition to the straightforward molecular cytogenetic characterization of the euchromatic content of the ring chromosome, the investigation of a second cell system gives additional information about the tissue specific distribution of the supernumerary marker chromosome (SMC) and provides more reliable data for further karyotype/phenotype correlations and the prediction of the phenotypic outcome in prenatal cases.

SKY assessment of two karyotypes with 0-6 supernumerary marker/ring chromosomes and review of previously reported cases with two or more markers.

Abstract: A 7-month-old boy with developmental delay and congenital abnormalities and a 58-year-old man with mental retardation, impaired speech, and dysmorphic features were referred for cytogenetic studies. The peripheral blood chromosome studies of Patient 1 had a de novo mosaic karyotype with 2-6 supernumerary marker chromosomes. Patient 2 had a mosaic karyotype with 1-5 supernumerary marker chromosomes and normal cells. All markers appeared to have a centromere by C-banding and also by fluorescence in situ hybridization (FISH) using all centromere probe for Patient 1. The majority of the markers appeared like rings. Except for one marker in Patient 1 and 2-3 markers in Patient 2 with discernible >5 Mb euchromatin, the rest of the markers were minute and some appeared to have barely discernible euchromatin in C-banding or FISH. Spectral karyotyping (SKY) was attempted to determine the origin of the marker chromosomes. Because some markers had barely any euchromatin, their classification was not clear cut and they were identified as derived from more than one chromosome. The SKY classification of the markers in Patient 1 was 1, 3, 5, 7, 11, 15, and 22 and in Patient 2 was 1, 5, 6, or 7. Patient 2 was lost to further follow-up studies. To confirm the recurring SKY classifications in Patient 1, centromere probes for chromosomes 1, 3, 5, 7, 11, 15, and 22 were used. The markers were negative for 1, 3, and 11 but positive for 7, 15, and 22 and probably 5. Since 5 centromere probe cross hybridizes with 1 and 19, the weak signal on the marker/s in successive hybridization did not give a definitive answer. Also, the 5 paint probe was not conclusive because of the minute size of the marker. In some metaphases, two markers were derived from 5 or 22. For clinical considerations, the marker derived from 7, although variable in size, appeared to consistently have euchromatin, followed by 15, while 22 and 5 markers were mostly centromeric heterochromatin. The elastin gene probe that maps to 7q11.23, SNRPN gene that maps to 15q11.2, and TUPLE gene that maps to 22q11.2 did not give a signal on the markers. As expected for a majority of ring chromosomes, the pan telomere probe did not hybridize to any of the markers. This highly unusual karyotype was confirmed in the buccal epithelium using a mix of centromere 7 and 15 probes and the combination 14/22 probe. The ratio of additional FISH signals in the buccal mucosal cells was comparable to the ratios observed in the peripheral blood. In this study, we have attempted to consolidate the data on >/=2 marker cases to understand the analysis constraints, the range of clinical abnormalities, and the mechanisms involved. The literature was surveyed for multiple markers cases. A majority of the reported cases had two markers, either derived from the same chromosome or from two different chromosomes or two cell lines with different markers derived from the same chromosome. Cases with three or more markers were rare. The nature and extent of euchromatin content of the multiple markers appears to determine the phenotype. Frequently, multiple marker cases had small to minute markers. The clinical presentation varied from mild to severe. While two bisatellited markers may be associated with infertility, the phenotype in other cases ranged from borderline intelligence and mild dysmorphism to developmental delay, mental retardation, and congenital abnormalities.

Small supernumerary marker chromosome derived from proximal p-arm of chromosome 2: identification by fluorescent in situ hybridization.

Abstract: Conventional cytogenetics detected an interstitial deletion of proximal region of p-arm of chromosome 2 in a 6-month-old boy with a phenotype slightly resembling Down's syndrome. The deletion was inherited from the father, whose karyotype revealed a small ring-shaped marker chromosome, in addition to interstitial deletion. Fluorescence in situ hybridization identified the marker, which consisted of the proximal region of the p-arm of chromosome 2, including a part of its centromere. This case shows that molecular cytogenetic analysis can reveal the mechanism of the formation of the marker chromosome.

Characterization of the first supernumerary tricentric ring chromosome 1 mosaicism by conventional and molecular cytogenetic techniques.

Abstract: We report on the conventional cytogenetic and fluorescence in situ hybridization (FISH) results obtained for a 3.5-year-old girl with developmental and language delay and a supernumerary ring chromosome mosaicism in 8% of T-lymphocytes analyzed. Using different conventional and molecular cytogenetic techniques as YAC hybridization and comparative genomic hybridization, we could show that the extra tricentric ring chromosome consists of three heterochromatic blocks with inserted euchromatic material. Additionally, chromosome microdissection followed by FISH analysis demonstrated that the small tricentric ring chromosome consisted of material from the pericentromeric region of chromosome 1q21. Thus, the patient has a mosaic of normal cells and cells with partial pentasomy of the pericentromeric region of chromosome 1. So far, 19 cases with single supernumerary marker chromosome 1 have been published, but no tricentric ring chromosome 1 is, to our knowledge, reviewed in the literature. In this study, we compare the clinical features of our patient with cytogenetically comparable cases described in the literature. We introduce a hypothesis for the formation of a tricentric ring chromosome: starting with a monocentric ring, sister chromatid exchange leading to the formation of a tetracentric ring, which underwent intrastrand recombination generating the tricentric ring.

Muellerian aplasia associated with ring chromosome 8p12q12 mosaicism

Abstract: We report on a woman with Muellerian aplasia, renal and skeletal anomalies, and minor dysmorphic signs. Conventional cytogenetic analysis revealed mosaicism for a small supernumerary, undefinable ring chromosome. Chromosome microdissection and reverse painting demonstrated that this marker contained pericentric material from chromosome 8 (8p12q12). Thus, we identified a Muellerian aplasia phenotype with partial trisomy 8 mosaicism.

Multiple supernumerary ring chromosomes of different origin in a patient: A clinical report and review of the literature

Abstract: We describe a patient with multiple congenital abnormalities exhibiting 2-5 supernumerary chromosomes per cells. A variety of FISH techniques were used to demonstrate that the markers are probably rings, lack detectable telomere sequences, and originate from different non-acrocentric chromosomes, namely 6, 7, 10, 12, and 19. Such cases are extremely rare and this is only the 8th published report of an individual presenting three or more supernumerary chromosomes. We reviewed all available cases of multiple supernumerary chromosomes and the collective data indicate that multiple markers seem always to be rings of different origin. These results provide evidence that such multiple ring markers cannot possibly represent duplication or recurrence of an original structural rearrangement but must be derived with a common causality from different chromosomes. Possible mechanisms for the simultaneous production of multiple rings from different chromosomes are proposed, including the breakdown and rearrangement of a haploid complement shortly after fertilization in a triploid zygote.

A girl with cutaneous hyperpigmentation, café au lait spots and ring chromosome 15 without significant deletion.

Abstract: Ring chromosome 15 [r(15)] syndrome is characterised by specific facial features, cafe au lait spots, failure to thrive, mental retardation and typically with a terminal deletion of the long arm of chromosome 15. We report a 2.5 year old girl showing normal growth and development, large hyperpigmented skin changes showing hypopigmentated areas inside, multiple cafe au lait spots and premature graying-like hypopigmentation of scalp hair. She had a karyotype of r(15) in peripheral lymphocytes and fibroblasts. By FISH analysis the breakpoint was located distal to locus D15S936 (15q26.3) and within 300 kb of the end of the chromosome, indicating no deletion of functional genes on 15q. Hyperpigmentation and cafe au lait spots are rare signs in ring chromosome syndromes, but with r(15) syndrome, cafe au lait spots have been described in about 30% of patients and have been considered to result from the deletion of gene(s) on distal 15q. Based on the frequent observation of patchy hyperpigmentation with the r(15) syndrome, absent hyperpigmentation in cases of distal 15q deletion without a ring chromosome, and the telomeric breakpoint location in our patient indicating no significant deletion, we propose that the cutaneous hyperpigmentation and cafe au lait spots in our proband represent effects of the r(15) chromosome but are not caused by the deletion of specific gene(s) on distal 15q. Patchy skin hypopigmentation is a well known nonspecific sign in cytogenetic mosaicism which is commonly seen in ring syndrome.

CGH and direct diagnosis of mosaic structural chromosomal abnormalities: description of a mosaic ring chromosome 17 and review of the literature

Abstract: We report the characterisation of a de novo supernumerary chromosome marker in a mosaic state (50%) by comparative genomic hybridisation (CGH) in an 8-year-old child with hypotonia, dysmorphia and mild-to-moderate mental retardation. We describe the combined use of CGH and fluorescence in situ hybridisation (FISH) to identify the origin of the additional chromosomal material. Visual analysis of 10 CGH-metaphase spreads revealed a gain of green fluorescent signal on pericentromeric region of chromosome 17. The CGH finding was confirmed by FISH analysis using a whole chromosome 17 paint, a chromosome 17 centromeric probe and the probe coding for the Smith-Magenis locus in 17p11.2. These results show that performing both CGH and FISH in combination with classical karyotyping will certainly allow the identification of imbalanced chromosome rearrangements and, by the way, allow the identification of genes involved in mental retardation and/or malformative pathology.

Ring chromosome 12 with variable phenotypic features: Clinical report and review of the literature

Abstract: A ring chromosome 12 (p13; q2433) was observed in all cells analyzed from peripheral blood lymphocytes of a 15-year-old female referred for academic difficulties and growth delay In addition to clinical manifestations generally observed with ring chromosome 12 such as growth retardation, mental deficiency, microcephaly, the patient had bilateral pseudocamptodactyly of little fingers, mild hirsutism, exaggerated lumbar lordosis, and ostium secundum atrial septal defect (ASD) The clinical features of reported cases are analyzed The only consistent features were growth retardation and mental deficiency Breakpoint in all the cases has been at the telomeric region with minimal deletion of chromosomal material An account of complex changes at mitosis and meiosis in ring chromosome has been given Examination of 200 metaphases demonstrated 2% cell line was showing 45,XX, -12 Serum lactate dehydrogenase (LDH) level was normal ruling out overlapping monosomy 12 syndrome

Chromosomal changes detected by fluorescence in situ hybridization in patients with acute lymphoblastic leukemia.

Abstract: Objectives To investigate patients with acute lymphoblastic leukemia (ALL) for TEL/AML1 fusion, BCR/ABL fusion, MLL gene rearrangements, and numerical changes of chromosomes 4, 10, 17 and 21 by fluorescence in situ hybridization (FISH) and to determine the relationship and the significance of those findings Methods Fifty-one American patients (34 men and 17 women) were included in this study Of them there were 41 patients with pro-B cell type ALL, 9 with B cell type ALL and 1 with T cell type ALL Chromosome metaphases of each sample were prepared according to standard protocols Fluorescence in situ hybridization was performed using commercially available DNA probes, including whole chromosome painting probes, locus specific probes, specific chromosome centromere probes and dual color/multiple color translocation fusion probes The digital image analysis was carried out using Cytovision and Quips FISH programs Results An overall incidence of chromosomal anomalies, including t (9;22), MLL gene rearrangements, t (12;21), and numerical chromosomal anomalies of chromosomes 4, 10, 17 and 21 was found in 33 patients (65%) Thirty-one of them were pediatric patients and two adults The t (12;21) was the commonest chromosomal anomaly detected in this population; 14 out of the 45 pediatric patients (31%) were positive for TEL/AML1 fusion, among which three had an additional derivative 21 [t (12;21)], four had a deletion of 12p and two had an extra copy of chromosome 21 All 14 patients with positive TEL/AML1 fusion had ALL pre-B cell or B-cell lineage according to standard immunotyping The percentage of cells with fusion signals ranged from 20% to 80% All fourteen patients positive for TEL/AML1 gene fusion were mosaic Three out of the 14 patients positive for the TEL/AML1 gene fusion were originally reported to be culture failures and none of the remaining eleven samples had been found to have chromosome 12 abnormalities by conventional cytogenetic techniques All pediatric patients with pre-T or T cell lineage and the six adults were negative for TEL/AML1 fusion One patient had double Philadelphia chromosomes, three had a rearrangement or a deletion of the MLL gene, one had t (4;11) and two had a deletion of the MLL One of the patients with an MLL deletion also had a large ring of chromosome 21, and r (21) was caused by AML1 gene tandemly duplicated at least five times The second case with the MLL deletion was also unique, the patient had a t (12;21) as well A total of 20 patients had numerical changes (gain or loss) of chromosomes 4, 10, 17 and 21 Eight patients were found to have trisomies of three or four different chromosomes Interestingly, seven of these patients did not have TEL/AML1, BCR/ABL or the MLL gene rearrangement; one did have the TEL/AML1 gene fusion Eleven patients with pro-B cell or B cell type ALL (9 children with ALL, 2 adults with ALL) had numerical changes of chromosome 21 (gain 1 or 2 chromosome 21), among them, 10 patients had no structural alteration of chromosome 21, and one was combined by t (12; 21) Four patients had a monosomy of chromosome 17 and three out of these patients with monosomy 17 also had a fusion signal of TEL/AML1 Conclusions FISH plays an important role in detecting chromosome changes, especially in some cryptic chromosome translocations and patients with culture failures This study found a trend towards a division between patients who had structural changes such as t (12;21) or a ring chromosome 21 and those who had numerical changes of chromosome 21 as well as the patients with TEL/AML1 fusion and patients with the coexistence of numerical chromosomal changes of chromosomes 4, 10 and 17 In our opinion there are two separate mechanisms which lead to the development or progression of leukemia

Ring chromosome 10 (p15q26) in a patient with unipolar affective disorder, multiple minor anomalies, and mental retardation.

Abstract: For several psychiatric diseases such as schizophrenia andautism, an involvement of genes in genesis of the illness has been suggested. Many studies have reported an association between chromosomal abnormalities and psychiatric disorders [Schreppers-Tijdink et al., 1988; Lewis et al., 1995; Hong et al., 1999]. Recently linkage studies have been conducted in families with mood disorders and although no gene has yet been identified, regions of interest of several chromosomes have been identified [Craddock and Jones, 2001]. We report on a patient with ring chromosome 10 (p15q26) presenting with mild dysmorphic features, moderate mental retardation, and an unipolar affective disorder. Extensive fluorescence in situ hybridization (FISH) experiments were performed to locate the breakpoints on ring chromosome 10. This study suggests the possibility of a correlation between a mood disorder and deletion on chromosome 10 q26. This casewasascertainedwhena sister of theproband sought preconceptional genetic counselling. The male patientwasfifth child of healthy, unrelatedparents. The family history, pregnancy, anddeliverywere unremarkable. At birth the mother and father were 32and 36year-old, respectively. During childhood, there were severe feeding difficulties with progressive growth retardation. Psychomotor and developmental delay associated with behavioural abnormalities were reported during infancy. Bilateral cryptorchidism was surgically corrected at the age of 13 years. Physical examination at the age of 32 years demonstrated aweight of 40 kg (<5th centile), a length of 149 cm (<5th centile), head circumference of 51 cm (<5th centile), triangular face, pectus excavatum, micropenis, and normal secondary sexual development (Fig. 1). Mental retardation and a severe behavioural disturbance were observed. The cognitive evaluation (Terman–Merrill) showed moderate mental retardation. The questionnaire for the evaluation of the personality profile (IPDE, International Personality Disorder Examination) showed depressive/dependent, anxious, and obsessive traits. The psychiatric examination showed limited willingness to talk, never fluent conversation, often monotonous, poor memory, no alterations of sensory-perceptional level associatedwith aimless movements, reduced insight and affectivity.