Coexistence of inverted Y, chromosome 15p+ and abnormal phenotype.

In this study, we report conventional and molecular cytogenetic studies in a patient with multiple anomalies who is a carrier of a pericentric inversion on chromosome Y and a chromosome 15p+. His parents were phenotypically normal. The father is a carrier of a pericentric inversion of chromosome Y, and the mother carries a large chromosome 15p+ variant. The inverted Y chromosome was demonstrated by GTG- and CBG-banding, and DAPI-staining. The presence of extra chromosomal material on the chromosome 15p, that was C-band and DAPI positive, was demonstrated by trypsin G-banding. This suggests that the extra chromosomal material contained repetitive DNA sequences. NOR-staining indicated the presence a nuclear organizer region at the junction of the chromosome 15p+ material. Fluorescence in situ hybridization (FISH), with chromosome X and Y painting probes, alpha- and classic-satellite probes specific for chromosome Y, alpha- and beta-satellite III probes for chromosome 15 were used to elucidate the nature of both the inverted Y chromosome and chromosome 15p+. The result with chromosome X and Y painting probes, alpha-satellite, classic-satellite, and DYS59 probes specific for chromosome Y revealed the rearrangement of the Y chromosome was an inv(Y)(p11.2q11.22 or q11.23). FISH with alpha-satellite and beta-satellite III probes for chromosome 15 demonstrated that the extra chromosomal material on the chromosome 15 probably represents beta-satellite III sequences. The possible roles of the simultaneous occurrence of an inverted Y and the amplified DNA sequence on chromosome 15p in the abnormal phenotype of the proband are discussed.     

The inverted Y-chromosome polymorphism in the Gujarati Muslim Indian population of South Africa has a single origin.

Y-specific polymorphisms were studied in Gujarati Muslim Indians possessing a Y-chromosome pericentric inversion [inv(Y)] in an attempt to prove a common genetic origin for the inversion. The p49a/TaqI and p49a/PvuII haplotypes were determined for 9 normal and 8 inv(Y) Gujarati Muslim men. Men with the inversion possessed identical TaqI and PvuII profiles, as opposed to 7 different TaqI and 8 different PvuII haplotypes observed in the 9 normal men. These results provide conclusive evidence for a common genetic origin of the inverted Y chromosome observed in this Gujarati Muslim community.     

Molecular analysis of recombination in a family with Duchenne muscular dystrophy and a large pericentric X chromosome inversion.

It has been demonstrated in animal studies that, in animals heterozygous for pericentric chromosomal inversions, loop formation is greatly reduced during meiosis. This results in absence of recombination within the inverted segment, with recombination seen only outside the inversion. A recent study in yeast has shown that telomeres, rather than centromeres, lead in chromosome movement just prior to meiosis and may be involved in promoting recombination. We studied by cytogenetic analysis and DNA polymorphisms the nature of meiotic recombination in a three-generation family with a large pericentric X chromosome inversion, inv(X)(p21.1q26), in which Duchenne muscular dystrophy (DMD) was cosegregating with the inversion. On DNA analysis there was no evidence of meiotic recombination between the inverted and normal X chromosomes in the inverted segment. Recombination was seen at the telomeric regions, Xp22 and Xq27-28. No deletion or point mutation was found on analysis of the DMD gene. On the basis of the FISH results, we believe that the X inversion is the mutation responsible for DMD in this family. Our results indicate that (1) pericentric X chromosome inversions result in reduction of recombination between the normal and inverted X chromosomes; (2) meiotic X chromosome pairing in these individuals is likely initiated at the telomeres; and (3) in this family DMD is caused by the pericentric inversion.     

Familial pericentric inversion of the X chromosome [inv(X)(p11q28)]

A familial pericentric inversion of the X chromosome [46,X,inv(X)(p11q28)] and [46,inv(X)(p11q28), Y] is reported. The carriers of the inv(X) presented no clinical symptoms. Either the inverted or the normal X chromosome may be late replicating.     

Pericentric inversion in natural populations of Oligoryzomys nigripes (Rodentia: Sigmodontinae).

We analysed polymorphism for pericentric inversion in chromosome 3 of Oligoryzomys nigripes (Rodentia: Sigmodontinae) in several populations in Brazil and examined the meiotic behaviour of this chromosome in heterozygotes. We observed an orderly pairing of all chromosomes at pachytene in heterozygotes for the inverted chromosome 3. No indication of meiotic arrest and germ-cell death was found. Electron microscopy of synaptonemal complexes and conventional meiotic analysis indicated strictly nonhomologous synapsis and crossing-over suppression in the inverted region in the heterozygotes, which prevent the formation of unbalanced gametes. Thus, the pericentric inversion in chromosome 3 does not apparently result in any selective disadvantages in heterozygous carriers. In the majority of the populations studied, the frequencies of acrocentric homozygotes, metacentric homozygotes, and heterozygotes were in Hardy-Weinberg equilibrium. However, in some populations, we detected an excess of heterozygotes and a deficiency of acrocentric homozygotes.     

Familial pericentric inversion of chromosome 12

Summary A pericentric inversion in one of the chromosomes 12, found in two families living in the same region, is deseribed. This inversion was detected during routine chromosomal analysis in two separate laboratories. The breakpoints were at 12p112 and 12q13. The inverted segment represented approximately 20% of the length of chromosome 12. Twenty nine descendants of carriers of the inversion were investigated, and the inversion was present in 23 of them. The other six descendants showed a normal karyotype. After correction for sample bias with the single selection scheme, a segregation ratio of 3:1 was estimated, indicating that the inverted chromosome 12 was preferentially transmitted. All the carriers of the inversion were phenotypically normal, without noticeable fertility disturbances.     

Analysis of sperm chromosome complements from a man heterozygous for a pericentric inversion of chromosome 1

Human sperm chromosomes were studied in a man heterozygous for a pericentric inversion of chromosome (1)(p31q12). Q-banded pronuclear chromosomes were analyzed after in vitro penetration of golden hamster oocytes. A total of 159 sperm were examined: 54% bearing the inverted chromosome 1 and 46% the normal chromosome 1. These frequencies are not significantly different from the theoretical 11 ratio. There were no recombinant sperm with duplications or deficiencies, suggesting that a pairing loop failed to form or that crossing-over was suppressed. The frequency of abnormalities unrelated to the inversion was 5% for numerical, 8.8% for structural, 2.5% for numerical and structural, values not significantly different from control donors studied in our lab. The frequencies of X- and Y-bearing sperm were 46% and 54%, respectively, not significantly different from the expected value of 50%. This is the fifth pericentric inversion studied by human sperm chromosome analysis; recombinant chromosomes have been observed in two of the five cases. Some of the factors associated with an increased risk of recombinant sperm appear to be inversion size greater than 30% of the chromosome and chromosome breakpoints in G-light bands.     

Replication banding and FISH analysis reveal the origin of the Hyla femoralis karyotype and XY/XX sex chromosomes

The pine woods treefrog, Hyla femoralis, is unique among North American hylid frogs in having a metacentric chromosome 6 and heteromorphic sex chromosomes of the XY/XX type. The X chromosome is distinguished by having a nucleolar organizing region (NOR) in the short arm. The Y chromosome does not possess an NOR. Until the present study, it was not known if the NOR was not present on the Y chromosome or inactive and therefore not detectable by conventional cytogenetic methods like silver staining. Exclusive of its unique features the karyotype of H. femoralis closely resembles those of North American frogs with karyotypes like H. chrysoscelis. We used replication banding and fluorescence in situ hybridization (FISH) with a DNA probe to the 18S + 28S ribosomal genes, which are located at the NOR, to characterize the H. femoralis karyotype. Our analysis revealed that the 18S + 28S ribosomal genes are not present on the Y chromosome, and that the karyotype of H. femoralis was derived from an H. chrysoscelis-like karyotype by relocation of the NOR to the X chromosome from chromosome 6 and either a concurrent or subsequent pericentric inversion of chromosome 6.     

Chiasma studies in structural hybrids IX. Crossing-over in pericentric inversion ofScilla scilloides

InScilla scilloides (Lindle) Druce, the heterozygotes for a pericentric inversion were found to be predominant in a small natural population consisting of cytogenetic type BB (2n=18). Pericentric inversion may include about half the length of the original subtelocentric chromosome, changing it to submetacentric. The 9II were always formed in these heterozygotes as well as in normal plants at MI in PMCs. A single chiasma was formed in the shorter one of two inverted segments divided by the kinetochore at MI, while one or two inversion chiasmata were observed in the longer segment. The AI separation was always regular. Since both arms of a normal chromosome and those of an inverted one were clearly distinguishable from one another at AI and AII, two kinds of crossover chromatids could be identified. Both sides of the single inversion chiasma always opened out reductionally. The frequency of bivalent without inversion chiasma agreed statistically with that of half-bivalent at AI or chromatid structure at AII, which resulted from non crossing-over within the inverted segment. Likewise, no statistical difference was found between the frequency of a single chiasma and that of a single crossing-over product in a longer inverted segment. These findings have clearly proved that the chiasma is a consequence of genetic crossing-over. The average proportion of good pollen grains in the inversion heterozygotes, 53.6%, amounted to about half that of normal plants, 97.7%.     

The Fertility Effects of Pericentric Inversions in Drosophila Melanogaster

Heterozygotes for pericentric inversions are expected to be semisterile because recombination in the inverted region produces aneuploid gametes. Newly arising pericentric inversions should therefore be quickly eliminated from populations by natural selection. The occasional polymorphism for such inversions and their fixation among closely related species have supported the idea that genetic drift in very small populations can overcome natural selection in the wild. We studied the effect of 7 second-chromosome and 30 third-chromosome pericentric inversions on the fertility of heterokaryotypic Drosophila melanogaster females. Surprisingly, fertility was not significantly reduced in many cases, even when the inversion was quite large. This lack of underdominance is almost certainly due to suppressed recombination in inversion heterozygotes, a phenomenon previously observed in Drosophila. In the large sample of third-chromosome inversions, the degree of underdominance depends far more on the position of breakpoints than on the inversion's length. Analysis of these positions shows that this chromosome has a pair of ``sensitive sites' near cytological divisions 68 and 92: these sites appear to reduce recombination in a heterozygous inversion whose breakpoints are nearby. There may also be ``sensitive sites' near divisions 31 and 49 on the second chromosome. Such sites may be important in initiating synapsis. Because many pericentric inversions do not reduce the fertility of heterozyotes, we conclude that the observed fixation or polymorphism of such rearrangements in nature does not imply genetic drift in very small populations.     

Pericentric inversion of chromosome 12; a three family study

Summary A pericentric inversion of chromosome 12 has been followed in three large independently ascertained Danish families. Out of a total number of 52 persons examined, 25 were found to carry the inversion. The break-points in all three families were localized to p13 and q13, resulting in more than one-third of the total length of the chromosomes being inverted. However, no chromosomal aberrations arising because of meiotic crossing-over inside the inverted area have been found among the offspring of the carriers. The percentage of spontaneous abortions among carriers is found to be high, viz. 33%. The segregation rate is calculated to be 0.58, which is not significantly different from an expected segregation rate of 0.5. In family 3, an additional inversion of a chromosome 9 has been found in 4 individuals. Our results are discussed in relation to previous findings and with respect to the genetic counselling of families with pericentric inversions.     

Familial inversion of chromosome No. 8: an affected child and a carrier fetus.

An infant with multiple congenital anomalies was found to have a duplication-deficiency disorder involving chromosome No. 8. The abnormality was identified as an unbalanced recombinant inherited from the mother who was a carrier of a pericentric inversion of chromosome No. 8. The inversion was observed in several members of this family, including a fetus who was diagnosed by an amniocentesis. The inverted chromosome was demonstrated only with the use of a differential staining technique, in this case, by trypsin-Giemsa banding.     

Transposition of human immunoglobulin V kappa genes within the same chromosome and the mechanism of their amplification.

The variable, joining and constant gene segments of the human immunoglobulin kappa locus (V kappa, J kappa and C kappa) are located on the short arm of chromosome 2 at 2p11-2p12. Here we describe a cluster of 11 V kappa genes on the long arm of chromosome 2 at 2cen-q11. By pulsed-field gel electrophoresis, cosmid cloning and DNA sequencing the cluster was shown to consist of four amplified units (amplicons). The amplicons, each 110-160 kb in size, are organized within 650 kb as an array of inverted repeats with short stretches of non-amplified DNA in between. Cloning and sequencing of three different joints between amplified and non-amplified DNA revealed the existence of parts of Alu repeats at each of the analysed joints. It is suggested that during evolution a group of five V kappa genes was transposed from the short to the long arm of chromosome 2 by a pericentric inversion. Three of the five V kappa genes were then amplified in two subsequent steps to yield the structure found in the majority of the present day population. The possible relation of this structure to a pericentric inversion of chromosome 2 that is seen cytogenetically in a small fraction of today's population is discussed.     

Frequency of recombinant and nonrecombinant products of pericentric inversion of chromosome 1 in sperm nuclei of carrier: by FISH technique

Meiotic segregation products of carriers with pericentric inversion are very important for assessing the risk of unbalanced forms and appropriate genetic counseling. We investigated the incidence of recombinant and nonrecombinant products of chromosome 1 with pericentric inversion, in the sperm nuclei of the carrier by using triple color fluorescence in situ hybridization (FISH). The centromere specific and telomere specific probes for chromosome 1 were used. In the segregation analysis, 1,636 sperm nuclei were analyzed; 82.5% of the sperms were including normal or inverted chromosome 1, and the dup(p)/del(q) and del(p)/dup(q) recombinant products in sperm nuclei of our carrier were 8.7 and 7.3%, respectively. The number of recombinant products may be dependent on the formation of an inversion loop, which the number of the formation of chiasmata results in the different number of normal/balanced and recombinant products. The use of FISH, using different probe combination, in sperm nuclei has proved to be an accurate approach to determine the meiotic segregation patterns and could help to better establish a reproductive prognosis and genetic counseling.     

Inv21p12q22del21q22 and intellectual disability

Chromosomal rearrangements are common in humans. Pericentric inversions are among the most frequent aberrations (1–2%). Most inversions are balanced and do not cause problems in carriers unless one of the breakpoints disrupts important functional genes, has near submicroscopic copy number variants or hosts “cryptic” complex chromosomal rearrangements. Pericentric inversions can lead to imbalance in offspring. Less than 3% of Down syndrome patients have duplication as a result of parental pericentric inversion of chromosome 21. We report a family with an apparently balanced pericentric inversion of chromosome 21. The proband, a 23-year-old female was referred for prenatal diagnosis at 16 weeks gestation because of increased nuchal translucency. She has a familial history of Down's syndrome and moderate intellectual disability, a personal history of four spontaneous abortions and learning difficulties. Peripheral blood and amniotic fluid samples were collected to perform proband's and fetus' cytogenetic analyses. Additionally, another six family members were evaluated and cytogenetic analysis was performed. Complementary FISH and MLPA studies were carried out. An apparent balanced chromosome 21 pericentric inversion was observed in four family members, two revealed a recombinant chromosome 21 with partial trisomy, and one a full trisomy 21 with an inverted chromosome 21. Array CGH analysis was performed in the mother and the brother's proband. MLPA and aCGH studies identified a deletion of about 1.7 Mb on the long arm of inverted chromosome 21q22.11. We believe the cause of the intellectual disability/learning difficulties observed in the members with the inversion is related to this deletion. The recombinant chromosome 21 has a partial trisomy including the DSCR with no deletion. The risk for carriers of having a child with multiple malformations/intellectual disability is about 30% depending on whether and how this rearrangement interferes with meiosis.     

A new case of pericentric inversion 20

A prenatal diagnosis from a chorionic villi biopsy revealed a pericentric inversion of chromosome 20. The child's father also carries the inverted chromosome. The breakpoints p13q11.2 differ for 4 of the 5 published cases of inversion 20.     

Heterosynapsis and suppression of chiasmata within heterozygous pericentric inversions of the Sitka deer mouse

The patterns of chromosomal pairing and chiasma distribution were analyzed in male Sitka deer mice (Peromyscus sitkensis) polymorphic for terminally positioned pericentric inversions of chromosomes 6 and 7. Gand C-banding of somatic metaphases indicated that the inversions involved 30% and 40% of chromosomes 6 and 7, respectively. Analysis of silver-stained synaptonemal complexes in surface-spread zygotene and pachytene nuclei from heterozygous individuals revealed that inversion loops were not formed. The inverted segments proceeded directly to heterosynapsis without an intervening homosynaptic phase, and the heteromorphic bivalents remained straight-paired throughout pachynema. C-banded pachytene nuclei corroborated the occurrence of heterosynapsis, as the heteromorphic bivalents exhibited nonaligned centromeres. Analysis of diplonema and diakinesis indicated that crossing over had not occurred within the heterosynapsed inverted segments. The observation of chiasma suppression within the inversions indicates that pericentric inversion heterozygosity does not lead to the production of unbalanced gametes. Heterosynapsis of the inverted segments during zygonema and pachynema and the resulting chiasma suppression therefore represent a meiotic mechanism for the maintenance of pericentric inversion polymorphisms in this population of P. sitkensis.     

Correlation of the clinical phenotype with a pericentric inversion of chromosome 9]

Pericentric inversion of chromosome 9 is one of the most common structural balanced chromosomal aberrations. It is considered as a paraphysiological variant of a normal karyotype and it is possible to find it as occasional report in healthy subjects. In the last ten years different signals have appeared in literature, concerning carriers of pericentric inversion of chromosome 9, who showed different anomalies of the clinical condition. Today it is difficult, because of the rarity of the data to establish if a true correlation exists between phenotypical anomalies in the subjects studied and the pericentric inversion, or if they are only casual associations. We are trying to find possible correlations between the chromosomal rearrangements and eventual congenital defects. We describe 11 subjects with pericentric inversion of chromosome 9 examined for the presence of dysmorphic signs, mental retardation and repeated miscarriage.