An analysis of Xq deletions

We characterized by fluorescence in situ hybridization and Southern blotting 14 partial Xq monosomies, 11 due to terminal deletions and 3 secondary to X/autosome translocations. Three cases were mosaics with a XO cell line. In view of the possible role played by telomeres in chromosome segregation, we hypothesize a relationship between the loss of telomeric sequences in terminal deletions and the presence of 45,X cells. A correlation between phenotype and extent of deletion revealed that there is no correspondence between the size of the deletion and impairment of gonadal function. Turner stigmata are absent in patients without an XO cell line, when the breakpoint is distal to Xg24. A low birthweight is present whenever the breakpoint is at q22 or more proximal.     

Turner's syndrome--correlation between karyotype and phenotype

Turner's syndrome is defined as a congenital disease determining by quantitative and/or structural aberrations of one from two X chromosomes with frequent presence of mosaicism. Clinically it is characterized by growth and body proportion abnormalities, gonadal dysgenesis resulting in sexual infantilism, primary amenorrhoea, infertility, characteristic stigmata, anomalies of heart, renal and bones and the presence of some diseases like Hashimoto thyroiditis with hypothyroidism, diabetes mellitus type 2, osteoporosis, hypertension. Turner's syndrome occurs in 1:2000 to 1:2500 female livebirth. The most frequent X chromosome aberrations in patients with phenotype of Turner syndrome are as follows: X monosomy - 45,X; mosaicism (50-75%), including 45,X/46,XX (10-15%), 45,X/46,XY (2-6%), 45,X/46,X,i(Xq), 45,X/46,X,del(Xp), 45,X/46,XX/47,XXX; aberration of X structure: total or partial deletion of short arm of X chromosome (46,X,del(Xp)) isochromosom of long arm of X chromosome (46,X,(i(Xq)), ring chromosome (46, X,r(X)), marker chromosome (46,X+m). Searching of X chromosome and mapping and sequencing of genes located at this chromosome (such as SHOX, ODG2, VSPA, SOX 3) have made possible to look for linkage between phenotypes and adequate genes or regions of X chromosome. In this paper current data concerning correlation between phenotype and karyotype in patients with TS have been presented.     

De novo duplication xq22-q23 in a girl with short stature and gonadal dysgenesis

A female of 20 years of age with short stature, gonadal dysgenesis and Turner stigmata with a de novo dup Xq22-q23 was studied. The maternal cytogenetic study was normal. This case represents the smallest Xq duplication in an abnormal female. We discuss the possibility of a maternal imprinting.     

Recombinant chromosome as a result of pericentric inversion of X chromosome

Summary A structural X chromosome abnormality was found in the karyotype of a tall patient with gonadal dysgenesis and with no extragenital anomalies. Based on her mother's karyotype, which showed a pericentric inversion of the X chromosome: 46,X,inv(X)(p22q24), as well as from G and R banding, we concluded that the abnormal X chromosome of our patient was a recombinant chromosome that had originated as a result of one crossing over in the inversion loop during gametogenesis in her mother. The recombinant X chromosome had a partial deletion of Xq and a partial duplication of Xp: 46,X,rec(X),dup p,inv(X)(p22q24). After BUDR incorporation, the abnormal X chromosome of the patient and that of her mother showed a late replication. The karyotype-phenotype correlation and the nonrandom inactivation of the inverted X chromosome in the mother are discussed.     

Partial deletion of the X chromosome in gonadal dysgenesis 46,X,del(X)(p22) identified by BUdR treatment

Summary In this report we describe a deletion of the short arm of the X chromosome in a 16-year-old female with gonadal dysgenesis.The breakpoint was localized by BUdR treatment and acridine orange staining in region 2, band 2.Of the examined cells, 3% showed an early replication of the deleted X chromosome.     

Deletion (X)(q26.1-->q28) in a proband and her mother: molecular characterization and phenotypic-karyotypic deductions.

During a routine prenatal diagnosis we detected a female fetus with an apparent terminal deletion of an X chromosome with a karyotype 46,X,del(X)(q25); the mother, who later underwent premature ovarian failure, had the same Xq deletion. To further delineate this familial X deletion and to determine whether the deletion was truly terminal or, rather, interstitial (retaining a portion of the terminal Xq28), we used a combination of fluorescence in situ hybridization (FISH) and Southern analyses. RFLP analyses and dosage estimation by densitometry were performed with a panel of nine probes (DXS3, DXS17, DXS11, DXS42, DXS86, DXS144E, DXS105, DXS304, and DXS52) that span the region Xq21 to subtelomeric Xq28. We detected a deletion involving the five probes spanning Xq26-Xq28. FISH with a cosmid probe (CLH 128) that defined Xq28 provided further evidence of a deletion in that region. Analysis with the X chromosome-specific cocktail probes spanning Xpter-qter showed hybridization signal all along the abnormal X, excluding the possibility of a cryptic translocation. However, sequential FISH with the X alpha-satellite probe DXZ1 and a probe for total human telomeres showed the presence of telomeres on both the normal and deleted X chromosomes. From the molecular and FISH analyses we interpret the deletion in this family as 46,X,del(X) (pter-->q26::qter). In light of previous phenotypic-karyotypic correlations, it can be deduced that this region contains a locus responsible for ovarian maintenance.     

A possible exception to the critical region hypothesis.

Cytogenetic studies were done on a 5-year-old female with multiple congenital anomalies and mental retardation, revealing an unbalanced X/11 translocation. Her mother and phenotypically normal sister carry the balanced form of the translocation, while her brother has a normal 46,XY karyotype. Banding studies showed the breakpoints to be Xq22 and 11q13. These are remarkable for the following reasons: (1) the X breakpoint is within the critical region of the X chromosome, yet the balanced carrier does not manifest gonadal dysgenesis; and (2) the proband was trisomic for most of the long arm of chromosome 11. Late-replication studies of cells from the two balanced carriers showed inactivation of the normal X.     

The similarity of phenotypic effects caused by Xp and Xq deletions in the human female: a hypothesis

Summary We have collected from the literature adult nonmosaic women with the following aberrant X chromosomes: Xp- (52), Xq- (67), idic(Xp-)(10), idic(Xq-)(9), and interstitial deletions (12). Lack of Xp, and especially Xcen-Xp11 (b region), may cause full-blown Turner syndrome. However, individual Turner symptoms, including gonadal dysgenesis, otherwise seem to be randomly distributed with respect to the different Xp and Xq deletions, although breakpoints distal to Xq25 do not give rise to any phenotypic anomalies except in a few cases of secondary amenorrhea or premature menopause. Of the carriers of an Xp- or Xq- chromosome, 65% and 93%, respectively, suffer from ovarian dysgenesis, whereas all idic(Xp-) and idic(Xq-) chromosomes cause primary or secondary amenorrhea. Xq deletions do not induce specific symptoms different from those caused by Xp deletions. Lack of the tip of Xp has led in 46/52 cases to short stature, but 43% of the Xq- carriers are also short. To explain these observations, we propose the following hypothesis. Since deletions of truly inactivated regions do not seem to cause any symptoms, we assume that the b region (Xcen-p11) always stays active in a normal inactive X, but is inactivated in deleted X chromosomes, especially in Xq- chromosomes. In some cases, inactivation may spread to the tip of Xp; this would explain the apparently variable behavior of the Xg and STS genes, and the short stature of some Xq- carriers. Full chromosome pairing seems to be a prerequisite for the viability of oocytes and thus for gonadal development. Deleted X chromosomes necessarily leave a portion of the normal X unpaired and isodicentrics probably interfere with pairing, resulting in atresia of oocytes. The role played by the critical region (Xq13–q24) in ovarian development is still unclear.     

Ovarian dysgenesis due to an idic(X)(q2803)

A 17-year-old female patient with gonadal dysgenesis but no other turnerian features was found to have a 46,X,idic(X)(pter----q2803:q2803----pter) karyotype in her lymphocytes. Replication of the rearranged X was consistently late and symmetrical. It is postulated that the ovarian dysgenesis usually seen in nonmosaic carriers of Xq;Xq terminal rearrangements may be secondary to a nonreactivation of the abnormal chromosome before meiosis.     

Short-arm deletion of an X chromosome (45,XO/46,XX p-)

Summary A 31-year-old female patient with short stature, signs of gonadal dysgenesis, and slight Turner signs is described with a mosaic 45,XO/46,XX del (X) (qterp11) determined with trypsin Giemsa-banding and C-staining. BUdR incorporation indicated the deleted X to be late replicating.     

Molecular definition of Xq common-deleted region in patients affected by premature ovarian failure

High-resolution cytogenetic analysis of a large number of women with premature ovarian failure (POF) identified six patients carrying different Xq chromosome rearrangements. The patients (one familial and five sporadic cases) were negative for Turner's stigmata and experienced a variable onset of menopause. Microsatellite analysis and fluorescent in situ hybridization (FISH) were used to define the origin and precise extension of the Xq anomalies. All of the patients had a Xq chromosome deletion as the common chromosomal abnormality, which was the only event in three cases and was associated with partial Xp or 9p trisomies in the remaining three. Two of the Xq chromosome deletions were terminal with breakpoints at Xq26.2 and Xq21.2, and one interstitial with breakpoints at Xq23 and Xq28. In all three cases, the del(X)s retained Xp and Xq specific telomeric sequences. One patient carries a psu dic(X) with the deletion at Xq22.2 or Xq22.3; the other two [carrying (X;X) and (X;9) unbalanced translocations, respectively] showed terminal deletions with the breakpoint at Xq22 within the DIAPH2 gene. Furthermore, the rearranged X chromosomes were almost totally inactivated, and the extent of the Xq deletions did not correlate with the timing of POF. In agreement with previous results, these findings suggest that the deletion of a restricted Xq region may be responsible for the POF phenotype. Our analysis indicates that this region extends from approximately Xq26.2 (between markers DXS8074 and HIGMI) to Xq28 (between markers DXS 1113 and ALD) and covers approximately 22 Mb of DNA. These data may provide a starting point for the identification of the gene(s) responsible for ovarian development and folliculogenesis.     

Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern

This paper describes a female infant with microphthalmia with linear skin defects syndrome (MLS) and monosomy for the Xp22 region. Her clinical features included right microphthalmia and sclerocornea, left corneal opacity, linear red rash and scar-like skin lesion on the nose and cheeks, and absence of the corpus callosum. Cytogenetic studies revealed a 45,X[18]/46,X,r(X)(p22q21) [24]/46,X,del(X)(p22)[58] karyotype. Fluorescence in situ hybridization analysis showed that the ring X chromosome was positive for DXZ1 and XIST and negative for the Xp and Xq telomeric regions, whereas the deleted X chromosome was positive for DXZ1, XIST, and the Xq telomeric region and negative for the Xp telomeric region. Microsatellite analysis for 19 loci at the X-differential region of Xp22 disclosed monosomy for Xp22 involving the critical region for the MLS gene, with the breakpoint between DXS1053 and DXS418. X-inactivation analysis for the methylation status of the PGK gene indicated the presence of inactive normal X chromosomes. The Xp22 deletion of our patient is the largest in MLS patients with molecularly defined Xp22 monosomy. Nevertheless, the result of X-inactivation analysis implies that the normal X chromosomes in the 46,X,del(X)(p22) cell lineage were more or less subject to X-inactivation, because normal X chromosomes in the 45,X and 46,X,r(X)(p22q21) cell lineages are unlikely to undergo X-inactivation. This supports the notion that functional absence of the MLS gene caused by inactivation of the normal X chromosome plays a pivotal role in the development of MLS in patients with Xp22 monosomy. Received: 16 December 1997 / Accepted: 25 February 1998     

The critical region on the human Xq

Summary Adult female carriers of balanced X; autosome translocations (118 cases) and of balanced X inversions (31 cases) have been collected from the literature. Forty-five of the 118 translocation carriers in whom the break was in the critical region (Xq13–q22, Xq22–q26, separated by a narrow region within Xq22) showed gonadal dysgenesis. Seven of the 31 inversion carriers in whom the break was in the same region also had gonadal dysgenesis, whereas the remaining 24 were normal in this respect. The critical region consists mainly of Q-bright material, and is the fifth brightest segment in the human genome. The region contains relatively few genes. It is possible that meiotic crossing-over, rarely, if ever, takes place in it. The critical region may therefore consist of two supergenes whose integrity must be maintained to allow normal ovarian development. The effect exerted by this region differs from other known position effects, in that it is independent of the break-point within the region and of the chromosome bands to which the broken ends are attached. One possible mechanism causing this effect might be a change in the replication order of the chromosome bands, which, in turn, might affect their function.     

X-X translocation in a patient with gonadal dysgenesis and the problem of phenotype-karyotype correlations

Summary A sex-chromatin-positive woman without stunted growth, but with primary amenorrhea, and some stigmas of pure gonadal dysgenesis had the chromosome constitution 45,X/46,Xt(X;X)(q27;q27). The abnormal chromosome formed a large Barr body and was late-labeling. The chromosome consisted of two X chromosomes attached by their long arms (end-to-end), both apparently having the partial distal deletion. Both centromeric regions showed C-staining but only one constriction. The chromosome is interpreted as an isodicentric with only one centromere functioning. Some problems of phenotype-karyotype correlations are discussed.     

Prenatal and postnatal characterization of a de novo Xq22.1 terminal deletion

We present a case of a de novo Xq22.1 chromosomal terminal deletion discovered prenatally by conventional cytogenetics. The pregnancy resulted in the birth of a normal girl. Preferential inactivation of the abnormal X was demonstrated postnatally. Fluorescence in situ hybridization (FISH) demonstrated a terminal Xq deletion spanning Xq22.1 -->qter. An X painting probe ruled out a translocation. The deleted X chromosome was determined to be of paternal origin. The girl is now 4 years old with normal physical and psychomotor development. X chromosomal deletions are infrequent findings in prenatal diagnosis and present a difficult counseling challenge when they occur. Prenatal X-inactivation studies provide an opportunity for more informative genetic counseling when a de novo X chromosome deletion is detected.     

X-autosome translocation with a breakpoint in Xq22 in a fertile woman and her 47,XXX infertile daughter

Summary An unusual case is presented of a fertile woman heterozygous for a balanced X-autosome translocation t(X;12) (q22;p12) with a break-point (Xq22) in the critical region of the X chromosome. The karyotypes of her daughter, who is infertile, and one of her two sons are 47,XXX,t(X;12)(q22;p12) and 46,XY,t(X;12)(q22;p12) respectively. The literature on balanced X-autosome translocations in males and females involving both arms of the X chromosome is reviewed. All 23 of the 36 cases of females with balanced Xq-autosome translocation, that exhibited gonadal failure have a break-point between bands Xq13 and Xq26.     

Structural abnormalities of the Y chromosome and abnormal external genitals

Summary Three infants with different types of Y-chromosome abnomalies, including short- and/or long-arm deletion and mosaicism, are reported. The karyotypes of these patients were: 45,X/46,X,del(Y)/47,X,del(Y), del(Y) on peripheral lymphocytes and 45,X/46,X, del(Y) on gonadal tissue (case 1), 45,X/46,X,del(Y) (case 2), and 45,X/46,X,r(Y) (case 3). In case 1 the euchromatic segment on the deleted Y was distinctly larger than that of the father's Y.The three infants had no gross phenotypic anomalies except ambiguous genitals and low birth weight, and they were small for date. The histologic diagnosis in two of them was mixed gonodal dysgenesis (cases 1 and 2).The relationship between structural abnormalities of the Y chromosome and ambiguous genitals as well as male-determining factors is discussed.     

Multiorgan autoimmunity in a Turner syndrome patient with partial monosomy 2q and trisomy 10p

Turner syndrome is a condition caused by numeric and structural abnormalities of the X chromosome, and is characterized by a series of clinical features, the most common being short stature and gonadal dysgenesis. An increased frequency of autoimmune diseases as well as an elevated incidence of autoantibodies has been observed in Turner patients.     

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.     

Molecular analysis of 46,XY females and regional assignment of a new Y-chromosome-specific probe

Summary The relationship between Y-chromosome abnormalities and gonadal differentiation was investigated in six phenotypic females with a 46,XY karyotype and one patient with ambiguous genitalia secondary to apparently nonmosaic 46,XY mixed gonadal dysgenesis. No alterations were found in the Y chromosomes of six of these individuals by the use of either cytogenetic or molecular techniques. Cytogenetic analysis with high-resolution G-banding and Q-banding revealed a small deletion in the short arm of the Y chromosome in one female patient with some features of Turner syndrome. Southern hybridization with Y-specific probes showed a loss of DNA within deletion intervals 1, 2, and 3 of the Y chromosome. A new Y-chromosome-specific DNA probe that hybridizes to deletion interval 3 is described.