Homozygosity for pericentric inversions of chromosome 9. Prenatal diagnosis of two cases

The finding of homozygosity for a pericentric inversion of chromosome 9 [inv(9)] is rare, and previously has not been reported at prenatal diagnosis. We describe two unrelated cases of homozygosity for inv(9) identified in amniocytes. In each case, both parents were heterozygotes for the inv(9); 46,XX,inv(9)(p11q13) and 46,XY,inv(9) (p11q13). Case 1 resulted in a normal term infant who at age 5 years was phenotypically and developmentally normal. Case 2 was referred for severe intrauterine growth retardation (IUGR) and oligohydramnios, and subsequently expired in utero. Even though inv(9) is a normal chromosome variant with a frequency of 1 to 3% in the general population, the finding of homozygosity for inv(9) and IUGR in this fetus suggested the possibility of uniparental disomy (UPD). Molecular studies confirmed the presence of both parental inv(9) chromosomes, excluding the possibility of chromosome 9 UPD as the cause of IUGR in this fetus. Presumably, inv(9) homozygosity results from the high frequency of inv(9) heterozygosity, and is a normal variant. However, until the effects of UPD for chromosome 9 are established, parental karyo types and, where appropriate, molecular studies should be performed to exclude UPD. In addition, more reports of inv(9) homozygosity detected prenatally are needed to assess its frequency and outcome.     

Part of the RBM gene cluster is located distally to the DAZ gene cluster in human Yq11.23

Normal human Y and inverted Y chromosomes were chosen for physical fluorescence in situ hybridization (FISH) mapping of RBM and DAZ probes for the relative positioning of the RBM and DAZ gene clusters in interval 6 of the human Y chromosome. The inversion breakpoint in Yq11.23 turned out to be distal to the DAZ gene cluster, as the entire DAZ signal appears in the short arm of the inv(Y) chromosome. On the contrary, this inversion breakpoint in Yq11.23 divides the RBM signal cluster, leaving a weaker signal on the long arm while bringing the main RBM signal to the short arm of the inv(Y) chromosome. Thus, it can be concluded that, in contrast to previous claims, part of the RBM gene cluster is located distally to the DAZ gene cluster in deletion interval 6 of the human Y chromosome.     

Not para-, not peri-, but centric inversion of chromosome 12

A 39 year old male with primary infertility was diagnosed as having Klinefelter syndrome by conventional cytogenetic analysis, which also showed an abnormal chromosome 12. Fluorescence in situ hybridisation (FISH) analysis of the aberrant chromosome using a 12 specific centromeric probe showed a break in the alphoid repeats followed by an inversion within the short arm, resulting in a pseudodicentric chromosome. Further FISH analyses using telomeric and subtelomeric probes showed that the other breakpoint was in the subtelomeric region of the short arm. The karyotype is designated 47,XXY,inv(12)(p10p13.3). To our knowledge this is the first report of a case of "centric inversion".     

West's syndrome associated with inversion duplication of chromosome 15

We describe a five year old boy with inversion duplication of chromosome 15 (inv dup (15)) who, at the age of six months had started to develop West's syndrome. He later developed cryptogenic myoclonic epilepsy which was resistant to medication. On examination there was dysmorphia, overall hypotonia and diffuse pyramidalism. On starting ACTH the crises of flexion spasms were reduced but these were soon followed by myoclonic crises, both tonic and atonic, which did not respond to the various anticonvulsive treatments given. We comment on the changes in chromosome 15 linked to convulsions, and particularly the phenotypes of the inv dup (15) which depend on the size and genetic composition of the anomaly. This is the third case described in the literature of a patient with West's syndrome associated with supernumerary inversion duplication of chromosome 15. It is suggested that the karyotype be included when studying convulsive encephalopathies and cryptogenic refractory epilepsy, especially in infantile spasms.     

Maternal origin of inv dup(15) chromosomes in infantile autism

Six male patients with infantile autism and an extra inverted duplicated chromosome 15[inv dup(15)] were reported in a previous study. These patients had four copies of the chromosome region 15pter-q13, or an inv dup(15)(pter-->q13; q13-->pter). In this new study, DNA from the families of four of the patients were analysed using Southern based RFLPs and microsatellite polymorphisms from the region. In all four cases the inv dup(15) chromosome was of maternal origin. Furthermore, the data suggests that it originated in the maternal meiotic process rather than in an early mitosis in the developmental process of the embryo. The extra chromosome contained material from both of the maternally derived 15-chromosomes. Based on the molecular data presented here, a model for the origin of chromosome markers of this type is proposed.     

Veterinary medicine comment on camel medicine in Fan-mu tsuan yen-fang]

A small supernumerary chromosome was observed in two Prader-Willi syndrome (PWS) patients. The clinical diagnosis of PWS was confirmed by the ascertainment of the deletion of region 15q11-13 in one case and uniparental disomy (UPD) of the same region in the other. The markers were negative for dystamycinA/DAPI banding, did not contain NOR-positive satellites, and had an appearance consistent with a very small ring chromosome. Fluorescent in situ hybridization (FISH) analysis with the "all human centromere" probe indicated the presence of centromeric sequences in both markers. Chromosomal in situ suppression hybridization with chromosome specific libraries demonstrated that the small markers in the deleted and UPD patient originated from chromosome 15 and X, respectively. To the best of our knowledge these are the only PWS patients reported with a supernumerary marker chromosome other than inv dup(15) characterized by FISH.     

A duplication of distal Xp associated with hypogonadotrophic hypogonadism, hypoplastic external genitalia, mental retardation, and multiple congenital abnormalities

An unusual familial case of three sibs with a partial duplication of distal Xp sequences is described. The proband, an 18 year old boy, showed mental retardation, severe dysmorphic features, hypogonadotrophic hypogonadism (HHG), and hypoplastic external genitalia. His karyotype was 46,Y,inv dup(X) (p22.11-->p 22.32). The proband has two sisters each with the same inv dup(Xp) chromosome. Both sisters presented with short stature but were otherwise phenotypically normal. The abnormal X chromosome was inactive in the majority of cells examined. Southern blot dosage analysis indicated a duplication of distal Xp sequences. The proximal breakpoint is located between DXS28 and DXS41, and is therefore at least 2 Mb distal to the DSS locus. The relationship between the phenotype and the Xp duplication is discussed.     

Constitutional mosaicism for a chromosome 9 inversion resulting in recombinant aneusomy in an offspring

We report on a case of constitutional mosaicism for a large pericentric inversion of chromosome 9 in a man whose daughter had recombinant aneusomy resulting in partial 9q duplication and partial 9p deletion. At age 6 months, the girl was evaluated because of congenital anomalies [corrected] and developmental delay. Chromosomal analysis on this infant showed a derivative chromosome 9 which was later determined to be a recombinant chromosome with trisomy of 9q34.1-->qter and monosomy of pter-->9p24. Chromosomal analysis in her father showed the presence of two cell lines; 75% of lymphocytes had a 46,XY pattern, and 25% had a 46,XY,inv(9)(p24q34.1) karyotype. The infant's physical findings represent a composite of the reported cases of both trisomy 9q34.1-->qter and monosomy pter-->9p24. The infant's father was phenotypically and cognitively normal. This case broadens the spectrum of reported cases of mosaicism for an autosomal structural rearrangement generating unbalanced gametes, and further supports the tenet that constitutional mosaicism has clinical relevance for genetic counseling.     

X-linked mental retardation with a fragile site in Xq and an inversion of chromosome no. 9

The second black male with X-linked mental retardation and a fragile site at Xq27 was ascertained by screening for macroorchidism. GTG banding revealed the presence of an inv(9)(p13q21). This inversion is thought to be a chance occurrence and is probably of no clinical significance. More cases having a marker Xq and a chromosome abnormality are expected; some of these abnormalities will be clinically significant.     

Mosaicism for a small supernumerary ring X chromosome in a dysmorphic, growth-retarded male: mos47,XXY/48,XXY, +r(X)

Supernumerary ring X [r(X)] chromosomes are often found in patients with Turner syndrome. The phenotypic effects of the r(X) chromosome are variable, and largely depend on the presence or absence of the X inactivation (XIST) locus. Ring(X) chromosomes in males are rare and have been previously reported in only four cases, with 47,XY, + r(X) or mos47,XY, +r(X)/46,XY karyotypes. These patients all had developmental delay and dysmorphic features. We describe a 2.5-year-old male patient with facial dysmorphia, growth retardation, microcephaly, global developmental delay, and microphallus. Cytogenetic analysis from peripheral blood lymphocytes and fibroblasts identified mosaicism for two cell lines: mos48,XXY, + r(?X)/47,XXY. Fluorescence in situ hybridization (FISH) with an X chromosome paint showed the ring chromosome to be X chromosome derived. This is the first case of an r(X) chromosome described in a 47,XXY patient. FISH analysis of the r(X) chromosome with an XIST probe showed that the XIST locus was absent. Functional disomy of genes in the r(X) chromosome most likely accounts for the abnormal phenotype in the proband.     

The pericentromeric inversion, inv (6)(p25q13), is a novel diagnostic marker in chondromyxoid fibroma

Chondromyxoid fibroma is a benign bone tumor that arises most commonly in the metaphysis of long bones in young adults. The cytogenetic features of this tumor are not well known. In this study, four chondromyxoid fibromas were karyotyped after short-term cell culture. All of the tumors contained clonal rearrangements of chromosome 6, and each of these rearrangements involved band 6q13. Two tumors contained a pericentromeric inversion, inv (6)(p25q13), which was described recently in chondromyxoid fibroma. 6q13 rearrangements are not associated with other types of bone and soft tissue tumors, and the inv (6)(p25q13) is reported only in chondromyxoid fibroma. Hence, this cytogenetic marker might be helpful in distinguishing chondromyxoid fibroma from chondrosarcoma and other histologic mimics. The consistent occurrence of 6q13 rearrangements suggests a specific oncogenic mechanism in chondromyxoid fibroma, most likely involving oncogene activation.     

Cloning of inv, a gene that controls left/right asymmetry and kidney development

Most vertebrate internal organs show a distinctive left/right asymmetry. The inv (inversion of embryonic turning) mutation in mice was created previously by random insertional mutagenesis; it produces both a constant reversal of left/right polarity (situs inversus) and cyst formation in the kidneys. Asymmetric expression patterns of the genes nodal and lefty are reversed in the inv mutant, indicating that inv may act early in left/right determination. Here we identify a new gene located at the inv locus. The encoded protein contains 15 consecutive repeats of an Ank/Swi6 motif at its amino terminus. Expression of the gene is the highest in the kidneys and liver among adult tissues, and is seen in presomite-stage embryos. Analysis of the transgenic genome and the structure of the candidate gene indicate that the candidate gene is the only gene that is disrupted in inv mutants. Transgenic introduction of a minigene encoding the candidate protein restores normal left/right asymmetry and kidney development in the inv mutant, confirming the identity of the candidate gene.     

Reevaluation of the virulence phenotype of the inv yadA double mutants of Yersinia pseudotuberculosis

Yersinia pseudotuberculosis and Yersinia enterocolitica are closely related human pathogens causing gastroenteritis. Invasin and YadA are two of the most extensively studied virulence factors of the Yersinia genus. Invasin is the primary invasion factor encoded by the inv gene on the chromosome and is required for the penetration of the epithelial cells. YadA is encoded by the yadA gene on the 70-kb virulence plasmid and has multiple functions. Previous studies indicate that an inv yadA double mutant of Y. enterocolitica is avirulent while an inv yadA mutant of Y. pseudotuberculosis is hypervirulent. In this study, we investigated this unexpected difference. New constructs of the inv yadA mutants of Y. pseudotuberculosis were made and tested in mice. These new constructs were not hypervirulent; rather, they maintained the same virulence as the wild-type strain. Further examination of the inv mutant used for the previous study revealed that it carries an aberrant inv phenotype and has an altered outer membrane profile and an altered colony morphology. Therefore, the mutants used previously were not isogenic to the parental wild-type strain, which may in part account for the difference in the results obtained.     

Structural abnormalities of the X chromosome in non-Hodgkin's lymphoma

It has recently been reported that additional X chromosomes occur in over 30% of B-cell non-Hodgkin's lymphomas (NHL), and that monosomy of the X chromosome occurs in 38% of female patients with T-cell leukaemia or lymphoma. These observations have suggested a possible role for the X chromosome in the evolution of NHL. We have now examined 280 cases of NHL, and have identified 19 examples of structurally altered X chromosomes in the malignant cells from 17 of these cases. These abnormalities were mainly characterized by either a translocation involving Xp22, or a translocation/deletion involving Xq28. The relevance of these observations is discussed with respect to other published reports, and together they suggest that lymphoma-associated oncogenes may exist on the X chromosome at bands p22 or q28.     

Inversion (X)(p11.4q22) associated with Norrie disease in a four generation family

We report on a 4-generation family in which Norrie disease occurs together with a pericentric inversion of the X chromosome in all affected males and carrier females. The breakpoint in the short arm of the X chromosome appears to be at the purported location of the Norrie disease gene. This is the second report of an association between Norrie disease and a chromosome aberration involving Xp11, and the first report of a specific gene disruption, thus physical gene location, due to a pericentric chromosome inversion.     

Increased frequency of chromosome abnormalities in fibroblasts from hairy cell leukemia patients

A hereditary component is implicated in many different cancers, including hairy cell leukemia (HCL), and may involve an instability of the genome. We have previously documented recurrent clonal and non-clonal chromosomal abnormalities in hairy cells. To ascertain whether this instability of the genome is restricted to the malignant cells or if it might also include normal cells we performed cytogenetic investigations on skin fibroblasts and hairy cells from eight HCL patients and skin fibroblasts from eight referents. The frequency of chromosome abnormalities, regardless of clonality, was significantly increased in the fibroblasts from patients compared to referents. Also, five patients compared to one referent showed clonal abnormalities in their fibroblasts. Immunohistochemical investigations excluded the possibility that the fibroblast cultures were contaminated with hairy cells. Two patients had constitutional abnormalities, inv(5)(p13.1q13.3) and t(13;14), and one additional patient, possibly mosaic, showed the same abnormality, inv(9)(p21-22q22), in both fibroblasts (17/30) and blood (5/21) cells. Aberrations in patient fibroblasts also included sporadic inv(5), del(6)q, inv(19), and del(20)q, abnormalities previously shown to occur in hairy cells. A clonal expansion with trisomy 7 occurred in vitro as documented by fluorescence in situ hybridization (FISH). The only clonal abnormality occurring in a referent was -Y/-Y,+15 in an elderly male. In conclusion, a constitutional chromosomal instability may precede chromosome abnormalities and be of importance in the development of hairy cell leukemia.     

The structure of the capsular polysaccharide from Klebsiella type 52, using the computerised approach CASPER and NMR spectroscopy

In swine, distinct centromeric satellite DNA families have been described that correspond to either all the metacentric chromosomes except the Y (Mc1) or all the acrocentric chromosomes (Ac2). Using primed in situ (PRINS) labeling, we show here that primers derived from various sequences specifically label the centromeres of different subgroups of chromosomes. Among five primers derived from centromeric sequences of acrocentric chromosomes reported to be very homogeneous, four recognize all the acrocentric chromosomes, whereas one labels prominently chromosome 17. For the metacentric chromosomes, six primers have been derived from several divergent sequences. Among these primers, two recognize all the metacentric chromosomes except 5, 10, and 12. Three other primers label small subsets of metacentric chromosomes, including the X and one or two additional chromosomes. The last primer is specific to chromosome 1. These preliminary results suggest that it should be possible to define specific primers for almost every swine chromosome. Already, some of the primers reported here permit a distinction between swine chromosomes difficult to differentiate without banding, such as the X chromosome and chromosome 9. Therefore, the PRINS technique using centromeric motifs constitutes an additional tool for cytogenetic studies in swine.     

Prenatal exclusion of segmental trisomy in familial chromosome 21 pericentric inversion by fluorescence in situ hybridization

We report the prenatal exclusion of partial trisomy in a family with maternal pericentric inversion of chromosome 21 by fluorescence in situ hybridization (FISH). After determining the structural rearrangement in the mother and her affected son with 46,XY,rec(21)dup(21q)inv(21)(p11q22) resulting in Down syndrome (DS), a chorionic villus sample from the current pregnancy was analysed for the copy number of the DS critical region with a cosmid contig. The signal distribution was normal and the cytogenetic analysis revealed that the fetus had inherited the inverted chromosome 21 in a balanced form. FISH probes specific for the DS region are of great value in supporting cytogenetic results, regardless of the structural status of chromosome 21.