Resolution of breakpoints in a complex rearrangement by use of multiple staining techniques: confirmation of suspected 12p12.3 intraband by deletion dosage effect of LDHB

A complex de novo translocation was found in leukocytes and fibroblasts from a boy with mental retardation and minor abnormalities. The 45,XY chromosome constitution found in all cells was initially interpreted from routine G- and Q-banding techniques as a balanced translocation of part of the short arm of 12 to the short arm of 15 and of the long arm of 21 to the short arm of 12. With additional staining techniques and use of prometaphase chromosome preparations, it was determined that the distal portion of band 12.3 of the short arm of chromosome 12 was missing from the 12/15 and the 12/21 translocation chromosomes. This interpretation was confirmed by a decreased concentration of the LDH-B subunit in lactate dehydrogenase isozymes of the patient's fibroblasts, consistent with his being hemizygous for the LDHB locus.     

A 14q+ chromosome in a malignant lymphoma in a patient with Down's syndrome

A 17-year-old Japanese boy with Down's syndrome developed leukemic lymphosarcoma; histology of a lymph node biopsy revealed a malignant lymphoma, of the poorly differentiated lymphocytic (ML-PDL) or possibly lymphoblastic type (ML-LB). The Giemsa-banding technique for chromosome analysis revealed the karyotype of the lymphoma cells to be 47,XY,+21,14q+. A chromosome study of PHA-stimulated lymphocytes showed a 21-trisomic pattern, i.e., 47,XY,+21. The 14q+ marker was a product of a translocation in which the long arm of chromosome No. 8 (probable break at band q11) was translocated to the long arm of a No. 14 at band q32, which is a region usually affected in various types of lymphomas. Two normal No. 8 chromosomes were present. Thus, the lymphoma cells were partially trisomic for chromosome No. 8.     

Partial trisomy 8 (trisomy 8q2106 leads to 8qter).

A case of trisomy for part of the long arm of chromosome 8, confirmed by G-banding analysis, in a white male infant is described. The mother carried a reciprocal translocation between chromosome 8 and chromosome 13 (46,XX,t(8;13),(q21:q34). The patient had inherited the translocated chromosome 13 and was thus trisomic for the distal half of the long arm of chromosome 8. He had many of the clinical features of the full trisomy 8 syndrome. As compared with previously reported cases with trisomy of the distal end of chromosome 8, he was more dysmorphic and showed greater developmental retardation.     

Partial trisomy 21

Five patients showing several stigmata of Down's syndrome and a partial trisomy of chromosome 21 are reported. Three patients with only a moderate degree of mental retardation had an additional deleted chromosome 21; the characteristic dark G-band region of the long arm of 21 was missing. In another patient with a typical Down's syndrome the G-band region and the distal portion of the long arm of 21 were present in excess and were translocated onto the short arm of 15. Clinical features suggestive of Down's syndrome were also seen in a mildly retarded girl with a mosaic chromosome constitution (one cell line had an isochromosome for the long arm of chromosome 21 and the other had a deletion of the short arm of chromosome 21).
By correlating clinical and cytogenetic data on these patients, an attempt was made to analyse the phenotypic effects caused by the presence of excess amounts of different segments of chromosome 21.     

Partial trisomy 15 and temporal lobe syndrome in a retarded girl without gross malformations

A supernumerary small bisatellited chromosome was found in a girl with stunted growth and psychomotor retardation. The extra chromosome was identified as a deleted 15, del(15)(q21), with C-band positive heterochromatin and satellite-like appendages to the distal end of the long arm. This chromosome was the product of a translocation between a chromosome 15 and some other acrocentric chromosome, as shown by G-, C- and Q-banding and silver staining of the nucleolus organizer regions.
The proposita had no gross phenotypic malformations. She had a small head, a high forehead, oblique palpebral fissures, bilateral enophthalmus, clinodactyly and simple dermatoglyphic patterns. She was autistic and suffered from epileptic seizures and expressive aphasia. The waking electroencephalogram revealed diffuse abnormalities; sleep recording showed focal spikes and sharp waves anteriorly on the left side. The pneumoencephalogram showed microventriculy, an enlarged left temporal horn and some enlarged sulci in the right frontotemporal cortex.
The prenatal influence of the chromosome anomaly is interpreted as being the primary cause of these disorders, neonatal asphyxia being a secondary contributing factor.     

De novo subtelomeric deletion of 15q associated with satellite translocation in a child with developmental delay and severe growth retardation

We report on a case of satellited 15q with subtelomeric deletion in a girl with delayed development and severe growth retardation. The patient also has a triangular face, downturned angles of the mouth, micrognathia, and minor limb malformations including mild talipes equinovarus, genu recurvatum, and increased dorsiflexion of both limbs. Cytogenetic analysis using standard GTG banding showed a female karyotype with a satellited-like structure at the distal long arm of one chromosome 15. Silver staining of the nucleolar organizing region (AgNOR) confirmed the presence of a satellite DNA translocation at the lesion. Analysis using fluorescent in situ hybridization (FISH) detected a subtelomeric deletion of the terminal 15q. Additional molecular analysis using microsatellite markers along the long arm of chromosome 15 defined a maximally deleted region at approximately 4.7 Mb. Haploinsufficiency of the IGF1R gene expression is thought to be the cause of growth delay in all 15q terminal deletion including our patient.     

A de novo complex chromosomal rearrangement with nine breakpoints characterised by FISH in a boy with mild mental retardation, developmental delay, short stature and microcephaly

A de novo complex chromosome rearrangement (CCR) involving chromosomes 1, 6, 7, 15 and Y was detected in a boy with mental retardation, short stature, and microcephaly. Fluorescence in situ hybridisation (FISH) with whole chromosome painting libraries, band-specific cosmids and telomeric probes was essential for the characterisation of the rearrangement. The CCR was shown to be the result of at least nine chromosomal breaks and involved the alternating insertion of two segments of the short arm of chromosome 1 and two segments of the long arm of chromosome 6 into a novel derived chromosome 7. A non-reciprocal translocation between the distal short arm of the same chromosome 7 and the distal long arm of the Y chromosome was also found, together with a paracentric inversion of the long arm of chromosome 15. The only detectable imbalance was a deletion of the heterochromatic Yq telomeric region. FISH investigations in this case have revealed an additional complexity in this CCR, which has implications for reproductive risk assessment and genetic counselling.     

Maternal uniparental disomy of chromosome 16 in a case of spontaneous abortion

To investigate the involvement of uniparental disomies (UPDs) in spontaneous abortions, we analyzed in detail the polymorphism of microsatellites on each chromosome in cases of abortion. Of the 52 spontaneous abortions investigated, 25 had a normal karyotype. The polymorphic analysis of these cases revealed that, in the villi from 24 of the 25 cases, biparental patterns were present in informative microsatellites in all autosomes. In the remaining case with a 46,XX karyotype (case 18), however, the informative patterns of the microsatellites of chromosome 16 appeared to be both of maternal origin. The results also showed that the region from the distal end of the short arm to near the middle point of the long arm of chromosome 16 (pter to D16S3107) were heterozygous, and those of the remaining region of the long arm (D16S3018 to qter) were homozygous. That is, this fetus had maternal isodisomy and heterodisomy of chromosome 16, originating from a maternal, meiosis I non-disjunction of dyad 16 that accompanied a crossover at near the middle point of the long arm. The present finding suggests that some UPDs may become a cause for spontaneous abortions.     

Breakpoint within the nucleolus organizer region resulting in a reciprocal translocation t (4;14)(q21;p12)

Reciprocal translocations involving a break in the nucleolus organizer region (NOR) are rare. A balanced translocation in a mother and her fetus with breakpoints in the NOR at 14p12 and on the long arm of a chromosome 4 at band 4q21 is described. The rearrangement was characterized by Ag-NOR staining, multiplex fluorescence in situ hybridization (M-FISH), and FISH with rDNA probes. This and other cases with breakpoints within NORs are discussed.     

Nonmosaic tetrasomy 15q25.2 → qter identified with SNP microarray in a patient with characteristic facial appearance and review of the literature

Tetrasomy for the distal chromosome 15q is rare, and only 22 patients (including 6 cases without detailed information) have been described to date in the literature. Here we report on another patient with nonmosaic tetrasomy 15q25.2-qter resulted from an inverted duplication of distal chromosome 15. This patient presents with features of development delay, arachnodactyly, joint contractures and typical facial dysmorphism including frontal bossing, short palpebral fissures, long philtrum, low-set ears, high-arched palate and retrognathia. Unlike most of the related patients, abdominal ultrasound test and brain MRI showed normal. Karyotyping analysis revealed a supernumerary marker chromosome presented in all metaphase cells examined. Parental karyotyping analysis was normal, indicating a de novo chromosome aberration of the patient. SNP microarray analysis found a two copy gain of 17.7 Mb from the distal long arm of chromosome 15 (15q25.2-qter). Further FISH analysis using SureFISH 15q26.3 IGF1R probe proved an inverted duplication of distal long arm of chromosome 15. The segmental duplications which lie in the hotspots of 15q24-26 might increase the susceptibility of chromosome rearrangement. Compared with the George-Abraham' study [2012], ADAMTSL3 might be more related to the cardiac disorders in tetrasomy 15q patients. Considering all patients reported in the literature, different mosaic degrees and segmental sizes don't correlate to the severity of phenotypes. A clear delineation on tetrasomy for distal chromosome 15q could still be investigated.     

Mirror-symmetric duplicated chromosome 21q with minor proximal deletion, and with neocentromere in a child without the classical Down syndrome phenotype

We report on a mentally retarded child with multiple minor anomalies and an unusually rearranged chromosome 21. This der(21) chromosome has a deletion of 21p and of proximal 21q, whereas the main portion of 21q is duplicated leading to a mirror-symmetric appearance with the mirror axis at the breakpoint. The centromere is only characterized by a secondary constriction (with a centromeric index of a G chromosome) at an unexpected distal position, but fluorescence in situ hybridization (FISH) with either chromosome specific or with all human centromeres alpha satellite DNA shows no cross hybridization. Thus, the marker chromosome represents a further example of an "analphoid marker with neocentromere." Molecular analysis using polymorphic markers on chromosome 21 verified a very small monosomic segment of the proximal long arm of chromosome 21, and additionally trisomy of the remaining distal segment. Although trisomic for almost the entire 21q arm, our patient shows no classical Down syndrome phenotype, but only a few minor anomalies found in trisomy 21 and in monosomy of proximal 21q, respectively.     

Cytogenetic analysis of spontaneous and 2-cyanoethylene oxide-induced tk-/- mutants in TK6 human lymphoblastoid cultures

Two phenotypic classes of selectable tk-/- mutants have been isolated from the TK6 human lymphoblast cell line; one has a normal growth rate (tkn) relative to the parental cell line; the other has a slow growth rate (tks). Complete karyotypes of metaphase chromosomes were prepared and analyzed from 16 tks mutants (eight spontaneous and eight 2-cyanoethylene oxide [CNEtO]-induced), two spontaneous tkn mutants, and the parental TK6 cell line. Southern blot analysis of these tk-/- mutants indicated that all had lost a 14.8 kb polymorphic band corresponding to the active tk allele. No chromosome abnormalities with respect to the parental cell line TK6 were observed in eight spontaneous tks mutants. Chromosome abnormalities that may have been related to CNEtO treatment were observed in four of eight CNEtO mutants. However, chromosome 17, containing the tk locus in man, was cytologically normal with respect to the parental TK6 cell line in 15 of 16 tks mutants. A visible abnormality of chromosome 17 was present in one CNEtO-induced tks mutant. The abnormality was a duplication of the long arm of the chromosome 17, with break points at q11 and q21. The latter break point is close to the site of the tk locus, suggesting that the aberration observed may be associated with tk-/- phenotype. These observations contrast with the relatively high incidence (greater than or equal to 59%) of chromosome 11 abnormalities reported in tks (small colony) mouse lymphoma L5178Y/TK +/- mutants.     

Meiotic exchange event within the stalk region of an inverted chromosome 22 results in a recombinant chromosome with duplication of the distal long arm

Meiotic recombination occurs between homologous euchromatic regions of human chromosomes in early meiosis. However, such exchanges have been thought not to occur in the stalk regions of acrocentric chromosomes. We describe a child whose chromosome analysis suggests that crossovers do occur in homologous stalk regions. The proband, initially seen as a term female infant, was born to a 28-year-old mother. Dysmorphic features included wide metopic sutures, low anterior hairline, hypertelorism, external ear malformations, and cleft lip and palate. Blood chromosomes of the proband and parents were studied by G-banding, Q-banding, R-banding, and silver staining. The infant karyotype showed a sub-metacentric chromosome 22; that of the mother showed a pericentric inversion of chromosome 22. Chromosomes of the father were normal. In the infant, the abnormal chromosome 22 long arm appeared normal, but with additional long arm material attached to the distal short arm. In the mother, the distal long arm of the abnormal chromosome 22 was translocated to the distal short arm. The abnormal chromosome stalk in the child was intermediate in size to the stalk size of the abnormal and normal chromosomes 22 in the mother. Fluorescent in situ hybridization (FISH) analysis using chromosome 22 paint and ARSA gene probe confirmed that the duplicated material in the proband was of chromosome 22 origin; the karyotype interpretation is: 46,XX,rec(22)dup(22q)inv(22)(p13q13.1)mat. This abnormal karyotype is most likely due to a crossover event within the inversion loop during meiosis. The stalk length discrepancy suggests that the crossover site occurred in the stalk region.     

Familial cryptic translocation (2;17) ascertained through recurrent spontaneous abortions

We report a young woman who presented with a reproductive history of three recurrent spontaneous abortions (RSA) and two neonatal deaths. Comparative genomic hybridization (CGH) was used to determine the chromosomal composition of the patient's last miscarriage. It showed the presence of monosomy for the distal end of chromosome 2 long arm (segment 2q37.2 to qter) and trisomy for the distal end of chromosome 17 long arm (segment 17q25 to qter). The mother was found to be a carrier for a cryptic translocation between chromosomes 2 and 17 long arms by fluorescence in situ hybridization using a subtelomeric probe for 17q. Retrospective CGH analysis on one baby who died neonatally showed that he had inherited the maternal translocation in the same unbalanced state as the last pregnancy loss. His detailed postmortem examination is reported.     

Dic(21;21) in a Down''s syndrome child with an unusual chromosome 9 variant in the mother.

A child with characteristic clinical features of Down's syndrome and raised red cell SOD-1 activity was found to have, in addition to a single chromosome 21, a reverse dicentric tandem translocation of two No 21s with dual NORs and C band regions. The breakpoints on the chromosomes involved in the translocation were at the most distal end of the long arms (21q223). The phenotypically normal mother carried a rare variant of a chromosome 9.     

Mirror‐symmetric duplicated chromosome 21q with minor proximal deletion,and with neocentromere in a child without the classical Down syndrome phenotype

We report on a mentally retarded child with multiple minor anomalies and an unusually rearranged chromosome 21. This der(21) chromosome has a deletion of 21p and of proximal 21q, whereas the main portion of 21q is duplicated leading to a mirror‐symmetric appearance with the mirror axis at the breakpoint. The centromere is only characterized by a secondary constriction (with a centromeric index of a G chromosome) at an unexpected distal position, but fluorescence in situ hybridization (FISH) with either chromosome specific or with all human centromeres alpha satellite DNA shows no cross hybridization. Thus, the marker chromosome represents a further example of an “analphoid marker with neocentromere.” Molecular analysis using polymorphic markers on chromosome 21 verified a very small monosomic segment of the proximal long arm of chromosome 21, and additionally trisomy of the remaining distal segment. Although trisomic for almost the entire 21q arm, our patient shows no classical Down syndrome phenotype, but only a few minor anomalies found in trisomy 21 and in monosomy of proximal 21q, respectively. Am. J. Med. Genet. 91:116–122, 2000. © 2000 Wiley‐Liss, Inc.     

Partial trisomy 17q22-qter and partial monosomy Xq27-qter in a girl with a de novo unbalanced translocation due to a postzygotic error: Case report and review of the literature on partial trisomy 17qter

Partial trisomy 17q22-qter is a rare but well-recognized clinical entity. We present a case of partial trisomy for the long arm of chromosome 17, which was detected in a female infant with severe psychomotor and somatic retardation, Stargardt disease, short limbs, and numerous minor anomalies. Differential chromosomal staining demonstrated an excess of genetic material on the long arm of the late replicating X chromosome. FISH and DNA polymorphism analysis showed that the extra material belonged to the distal part of the long arm of chromosome 17 and that there was a partial monosomy of the distal part of the long arm of the derivative X chromosome. The breakpoint regions of this translocation were identified by molecular analysis using polymorphic microsatellite markers on human chromosomes 17 and X. The origin of the abnormal X chromosome was found to be paternal, whereas the origin of the duplicated part of chromosome 17 was maternal. The unbalanced translocation between the paternal X and the maternal chromosome 17 is, therefore, suggested to be due to a postzygotic error. Am. J. Med. Genet. 70:87–94, 1997. © 1997 Wiley-Liss, Inc.     

Emery-Dreifuss muscular dystrophy: localisation to Xq27.3----qter confirmed by linkage to the factor VIII gene.

Two families with Emery-Dreifuss muscular dystrophy (EMD) have been studied with DNA markers mapping to Xq27.3----qter. No recombination was observed in 11 phase known meioses informative for the factor VIII gene (F8C) and eight phase known meioses informative for DXS15 (DX13), giving maximum lod scores of 3.50 and 2.50 respectively at a recombination fraction of zero. DXS52 (St14) showed one recombinant in 12 phase known meioses giving a maximum lod score of 2.62 at a recombination fraction of 0.07. These results map EMD to the distal end of the long arm of the X chromosome and are an important step in the development of tests for carrier detection and prenatal diagnosis.     

Novel chromosome 16 abnormality--der(16)del(16) (q13)t(16;21)(p11.2;q22)--associated with acute myeloid leukemia.

Inversion of chromosome 16 is a common feature of acute myeloid leukemia (AML) M4, while t(16;21), although also associated with AML, appears to be a separate entity. We present a patient with myelodysplastic syndrome (MDS) who transformed to AML-M1. The karyotype was normal at diagnosis; at 15 months, hematological evidence of transformation was present, and repeat cytogenetics showed a novel rearrangement of one chromosome 16. Two breaks had occurred; one in the short arm at 16p11, with translocation of the segment distal to this onto chromosome 21q, and the other in the long arm at 16q22 with subsequent deletion of the segment from 16q22-->qter. Fluorescence in situ hybridization (FISH) confirmed the abnormalities detected by cytogenetics and excluded involvement of the AML1 gene on 21q22. While the 16q22 breakpoint was at the usual site for the inv(16), the 16p11 was not. The patient is more characteristic of t(16;21) than inv(16), and adds to the spectrum of chromosome 16 abnormalities in AML.     

Localisation of the gene for Emery-Dreifuss muscular dystrophy to the distal long arm of the X chromosome.

The linkage relationships of the gene for Emery-Dreifuss muscular dystrophy have been analysed in a large American kindred using DNA probes from different regions of the X chromosome. Close linkage was found with the locus for factor VIII, with no recombinants in 12 opportunities (maximum lod score 4.3), and with locus DXS15 (two recombinants in 17 opportunities, maximum lod score 2.9 at 0 = 10 cM). No linkage was found with probes pERT87 and 754, which are closely linked to Duchenne and Becker muscular dystrophies at Xp21. These results confirm a separate localisation on the distal part of the long arm at q27-28 for Emery-Dreifuss muscular dystrophy and should provide the basis for prenatal diagnosis and improved carrier detection in this disorder if the linkage is confirmed to be close.