Duchenne muscular dystrophy due to familial Xp21 deletion detectable by DNA analysis and flow cytometry

Summary We report two male cousins with Duchenne muscular dystrophy (DMD) in whom cytogenetic studies have shown a small interstitial deletion at Xp21. The lesion is readily detectable in patients and carriers by flow cytometry which indicates that approximately 6000 kb of DNA are deleted in each case. The DNA markers OTC, C7, and B24 are present in the deleted X chromosome but 87-8, 87-1, and 754 are absent. Despite apparently identical deletions one affected boy has profound mental handicap while the other is only mildly retarded. The results confirm the assignment of familial DMD to Xp21 and illustrate the value of flow cytometry in improving the precision of chromosome analysis. We have also undertaken flow cytometry in a cell line from a previously reported DMD patient with a de novo Xp21 deletion who had, in addition, chronic granulomatous disease, retinitis pigmentosa, and the McLeod syndrome. The results indicate that the amount of DNA deleted from the X is similar in both families despite the striking differences in phenotype.     

An Xp22 microdeletion associated with ocular albinism and ichthyosis: approximation of breakpoints and estimation of deletion size by using cloned DNA probes and flow cytometry.

Ocular albinism of the Nettleship-Falls type (OA1) and X-linked ichthyosis (XI) due to steroid sulfatase (STS) deficiency are cosegregating in three cytogenetically normal half-brothers. The mother has patchy fundal hypopigmentation consistent with random X inactivation in an OA1 carrier. Additional phenotypic abnormalities that have been observed in other STS "deletion syndromes" are not present in this family. STS is entirely deleted on Southern blot in the affected males, but the loci MIC2X, DXS31, DXS143, DXS85, DXS43, DXS9, and DXS41 are not deleted. At least part of DXS278 is retained. Flow cytometric analysis of cultured lymphoblasts from one of the XI/OA1 males and his mother detected a deletion of about 3.5 million bp or about 2% of the X chromosome. Southern blot and RFLP analysis in the XI/OA1 family support the order tel-[STS-OA1-DXS278]-DXS9-DXS41-cen. An unrelated patient with the karyotype 46,X,t(X;Y) (p22;q11) retains the DXS143 locus on the derivative X chromosome but loses DXS278, suggesting that DXS278 is the more distal locus and is close to an XI/OA1 deletion boundary. If a contiguous gene deletion is responsible for the observed XI/OA1 phenotype, it localizes OA1 to the Xp22.3 region.     

Xp21 DNA microdeletion in a patient with chronic granulomatous disease,retinitis pigmentosa,and McLeod phenotype

Summary The clinical, biochemical, and molecular analysis of a patient with chronic granulomatous disease (CGD), retinitis pigmentosa (RP), and McLeod phenotype and of his parents demonstrated the X-linked transmission of these three traits in this family and a deletion of the entire X-CGD gene of the patient DNA. All but one other DNA markers tested, including those in Xp21, were present. These findings strongly suggest that the McLeod locus and at least one XL RP gene are closely linked to the X-CGD locus in the Xp21 region of the human X chromosome.     

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.     

Exclusion mapping of the gene for X-linked neural tube defects in an Icelandic family

Various polymorphic markers with a random distribution along the X chromosome were used in a linkage analysis performed on a family with apparently Xlinked recessive inheritance of neural tube defects (NTD). The lod score values were used to generate an exclusion map of the X chromosome; this showed that the responsible gene was probably not located in the middle part of Xp or in the distal region of Xq. A further refining of these results was achieved by haplotype analysis, which indicated that the gene for X-linked NTD was located either within Xp21.1-pter, distal from the DMD locus, or in the region Xq12–q24 between DXS106 and DXS424. Multipoint linkage analysis revealed that the likelihood for gene location is highest for the region on Xp. The region Xq26–q28, which has syntenic homology with the segment of the murine X chromosome carrying the locus for bent tail (Bn), a mouse model for X-linked NTD, is excluded as the location for the gene underlying X-linked NTD in the present family. Thus, the human homologue of the Bn gene and the present defective gene are not identical, suggesting that more than one gene on the X chromosome plays a role in the development of the neural tube.     

Molecular genetic and cytogenetic characterization of a partial Xp duplication and Xq deletion in a patient with premature ovarian failure

Background

The etiology of premature ovarian failure (POF) still remains undefined. Although the majority of clinical cases are idiopathic, there are possibilities of the underestimation of the most common etiologies, probably genetic causes. By reporting a case of POF with a partial Xp duplication and Xq deletion in spite of a cytogenetically 46,XX normal karyotype, we look forward that the genetic cause of POF will be investigated more methodically.

Methods

We performed a basic and clinical study at a university hospital-affiliated fertility center. The study population was a POF patient and her family. Cytogenetic analysis, FMR1 gene analysis, multiplex ligation-dependent probe amplification (MLPA), fluorescent in situ hybridization (FISH), and oligonucleotide-array based comparative genomic hybridization (array CGH) were performed.

Results

In spite of normal cytogenetic analysis in the proband and her mother and younger sister, FMR1 gene was not detected in the proband and her younger sister. In Southern blot analysis, the mother showed a normal female band pattern, but the proband and her younger sister showed no 5.2 kb methylated band. The abnormal X chromosome of the proband and her sister was generated from the recombination of an inverted X chromosome of the mother during maternal meiosis, and the karyotype of the proband was 46,XX,rec(X)dup(Xp)inv(X)(p22.1q27.3).

Conclusion

Array CGH followed by FISH allowed precise characterization of the der(X) chromosome and the initial karyotype of the proband had been changed to 46,XX,rec(X)dup(Xp)inv(X)(p22.3q27.3)mat.arr Xp22.33p22.31(216519–8923527)x3,Xq27.3q28(144986425–154881514)x1. This study suggests that further genetic investigation may be needed in the cases of POF with a cytogenetically 46,XX normal karyotype to find out the cause and solution for these disease entities.     

Isolation of probes detecting restriction fragment length polymorphisms from X chromosome-specific libraries: potential use for diagnosis of Duchenne muscular dystrophy

Summary We have isolated 23 human X chromosome-specific DNA fragments from libraries, prepared from flow-sorted X chromosomes. To increase diagnostic potential for X-linked genetic disorders, including Duchenne muscular dystrophy (DMD), the fragments were tested for restriction fragment length polymorphisms (RFLPs) with six restriction enzymes. All fragments were regionally mapped to segments of the X chromosome with a panel of somatic cell hybrids and with human cell lines carrying unbalanced chromosomal abnormalities. Two of the isolated probes detected a high frequency RFLP. One, 754, maps between Xp11.3 and Xp21 and detects a PstI polymorphism with an allele frequency of 0.38. The other, 782, maps between Xp22.2 and Xp22.3 and reveals an EcoRI polymorphism with an allele frequency of 0.40. According to a pilot linkage study of families at risk for Duchenne muscular dystrophy, 754 gives a maximum Lod score of 7.6 at a recombination fraction of 0.03. Probe 782 lies telomeric to DMD with a maximum Lod score of 2.2 at a recombination fraction of 0.17. Using our X-chromosomal probes and a set of autosomal probes, isolated and examined in an identical way, we found a significantly lower RFLP frequency for the X chromosome as compared to the autosomes.     

The gene coding for the p68 calcium-binding protein is localised to bands q32–q34 of human chromosome 5, and to mouse chromosome 11

Summary The gene encoding a tissue inhibitor of metalloproteinases, TIMP, has previously been shown to be X-linked in both the human and mouse genomes. We have used a series of somatic cell hybrids segregating translocation and deletion X chromosomes to map the TIMP gene on the human X chromosome. In combination with previous data, the gene can be assigned to Xp11.23Xp11.4. Genetic linkage analyses demonstrate that TIMP is linked to the more distal ornithine transcarbamylase (OTC) locus at a distance of about 22 centimorgans. The data are consistent with the conclusion that TIMP maps to a conserved synteny and linkage group on the proximal short arm of the human X chromosome and on the pericentric region of the mouse X chromosome, including loci for synapsin-1, a member of the raf oncogene family, OTC, and TIMP.     

Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome

We are reporting a male patient who suffered from chronic granulomatous disease associated with cytochrome b₋₂₄₅ deficiency and McLeod red cell phenotype, Duchenne muscular dystrophy, and retinitis pigmentosa. On cytogenetic analysis, he seemed to have a very subtle interstitial deletion of part of band Xp21. Since it was impossible to know whether this material was truly deleted or inserted elsewhere in the genome, somatic cell and molecular studies were carried out. In somatic cell hybrids, the deleted X chromosome was isolated on a Chinese hamster background. Southern blot analysis with 20 single-copy probes, that had been mapped to the X short arm, led to the discovery of one (probe 754) that is missing from this patient's X chromosome and also from his total DNA. This proves that he, indeed, has a deletion rather than a balanced insertion. The results provide cytological mapping information for the X-linked phenotypes present in this patient. Furthermore, probe 754 recognizes a restriction fragment length polymorphism of high frequency that makes it the most powerful probe currently available for linkage studies with X-linked muscular dystrophy.     

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.     

A regional localisation for an X-linked suppressor gene (XS) for the Lutheran blood group

Summary Suppression of Lutheran blood group expression is usually associated with an autosomal dominant suppressor gene In(Lu) which results in the rare Lu(a-b-) phenotype. X-linked recessive suppression can also occur under the control of the XS locus with normal (XS1) and suppressor (XS2) alleles. The only known kindred with XS2 segregating was examined for polymorphic DNA markers with known regional localisations on the X chromosome. Two point linkage analysis suggested linkage of XS to DXS14 (p58.1) with =0.00, =1.96. DXS14 is situated near the centromere at Xp11. Recombinants with DXS84 (distal to DXS14 on Xp) and recombinants with DXYS1 (pDP34) (on the proximal part of Xq) suggests a localisation for XS near the centromere, between DXS84 and DXYS1 (Xp21.2-Xq21.1). Linkage to a marker on the X chromosome confirms the original assignment of XS to the X chromosome, which was based on pedigree inspection from this family.     

Cognition and the sex chromosomes: studies in Turner syndrome

Turner syndrome (TS) is a human genetic disorder involving females who lack all or part of one X chromosome. The complex phenotype includes ovarian failure, a characteristic neurocognitive profile and typical physical features. TS features are associated not only with complete monosomy X but also with partial deletions of either the short (Xp) or long (Xq) arm (partial monosomy X). Impaired visual-spatial/perceptual abilities are characteristic of TS children and adults of varying races and socioeconomic status, but global developmental delay is uncommon. The cognitive phenotype generally includes normal verbal function with relatively impaired visual-spatial ability, attention, working memory, and spatially dependent executive function. The constellation of neurocognitive deficits observed in TS is most likely multifactorial and related to a complex interaction between genetic abnormalities and hormonal deficiencies. Furthermore, other determinants, including an additional genetic mechanism, imprinting, may also contribute to cognitive deficits associated with monosomy X. As a relatively common genetic disorder with well-defined manifestations, TS presents an opportunity to investigate genetic and hormonal factors that influence female cognitive development. TS is an excellent model for such studies because of its prevalence, the well-characterized phenotype, and the wealth of molecular resources available for the X chromosome. In the current review, we summarize the hormonal and genetic factors that may contribute to the TS neurocognitive phenotype. The hormonal determinants of cognition in TS are related to estrogen and androgen deficiency. Our genetic hypothesis is that haploinsufficiency for gene/genes on the short arm of the X chromosome (Xp) is responsible for the hallmark features of the TS cognitive phenotype. Careful clinical and molecular characterization of adult subjects missing part of Xp links the TS phenotype of impaired visual spatial/perceptual ability to specific distal Xp chromosome regions. We demonstrate that small, nonmosaic deletion of the distal short arm of the X chromosome in adult women is associated with the same hallmark cognitive profile seen in adult women with TS. Future studies will elucidate the cognitive deficits and the underlying etiology. These results should allow us to begin to design cognitive interventions that might lessen those deficits in the TS population.     

DNA methylation analysis of ade novo balanced X;13 translocation in a girl with abnormal phenotype: evidence for functional duplication of the whole short arm of the X chromosome

We report on a 13-month-old girl showing dysmorphic features and a delay in psychomotor development. She was diagnosed with a balancedde novo translocation 46, X, t(X;13)(p11. 2;p13) and non-random inactivation of the X chromosome. FISH analysis, employing the X chromosome centromere andXIST-region-specific probes, showed that theXIST locus was not involved in the translocation. Selective inactivation of paternal X, which was involved in translocation, was revealed by the HUMARA assay. The pattern of methylation of 5 genes located within Xp, which are normally silenced on an inactive X chromosome, corresponded to an active (unmethylated) X chromosome. These results revealed that in our proband the X chromosome involved in translocation (Xt) was preferentially inactivated. However, genes located on the translocated Xp did not includeXIST. This resulted in functional Xp disomy, which most probably accounts for the abnormal phenotype in our patient.     

Heterozygous expression of X-linked chondrodysplasia punctata

Summary Two females showing partial expression of X-linked chondrodysplasia punctata were identified in a family. Bone dysplasia was caused by an aberrant X chromosome that had an inverse duplication of the segment Xp21.2–Xp22.2 and a deletion of Xp22.3-Xpter. To characterise the aberrant X chromosome, dosage blots were performed on genomic DNA from a carrier using a number of X-linked probes. Anonymous sequences from Xp21.2–Xp22.2 to which probes D2, 99.61, C7, pERT87-15, and 754 bind were duplicated on the aberrant X chromosome. The proposita was heterozygous for all these markers. Dosage blots also showed that the loci for steroid sulfatase and the cell surface antigen 12E7 (MIC2) were deleted as expected from the cytogenetic results. Mouse human cell hybrids were constructed that retained the normal X in the active state. Analysis of these hybrid clones for the markers from Xp21.2–Xp22.2 revealed that all the alleles of the informative markers, present in a single dosage in the genomic DNA, were carried on the normal X chromosome of the proposita. The duplicated X chromosome therefore had two identical alleles, indicating that the aberration resulted from an intrachromosomal rearrangement.     

Detection of microdeletions in the short arm of the X chromosome by chromosome stretching

The present study was focused on the resolution of "chromosome stretching". In order to determine if this method can be used for the detection of microdeletions, the p-arms of 13 normal X chromosomes were stretched as well as of those with three different deletions of known size within the DMD/BMD region in Xp21 (case A: 0.42-0.45 Mb, case B: 2.3-2.9 Mb and case C: 3.0-3.5 Mb). The process of band splitting was recorded on a video-tape and the resulting banding pattern analyzed. Stretching of the normal Xp-arms led to a splitting on a maximum band level of 1400 and showed in all cases an identical banding pattern with 13 Giemsa-dark subbands. All new Giemsa-dark and -light subbands were derived from the three initial Giemsa-dark bands at the 400 band level according to ISCN (1995): five subbands from Xp21, four subbands from Xp11.3 and Xp22.2, respectively. The origin of these subbands is partly in contrast to the high resolution ISCN (1995) ideograms: subband Xp11.22 does not originate from the Giemsa-light band Xp11.2, but from the Giemsa-dark band Xp11.3; Xp22.12 originates from Xp21; Xp22.32 from Xp22.2. Stretching of the chromosomes containing deletions showed in cases A and B no differences in banding patterns and splitting order compared to normal X chromosomes. Only in patient C was a significant difference with the normal pattern visible due to the absence of one dark subband. In this case only four Giemsa-dark subbands derived from band Xp21. Thus, at least in the DMD/BMD region, the minimal size of a deletion detected by chromosome-stretching-generated high-resolution ideograms is about 3.0-3.5 Mb.     

Random X inactivation resulting in mosaic nullisomy of region Xp21.1----p21.3 associated with heterozygosity for ornithine transcarbamylase deficiency and for chronic granulomatous disease

A young woman with normal gonadal development and mild mental retardation was found to have a small de novo interstitial deletion of most of band Xp21, karyotype designation 46,X,del(X) (pter----p21.3:: p21.1----qter). Replication studies on lymphocytes and skin fibroblasts revealed that in 45% of cells the normal X was late replicating. Somatic cell hybrids between her fibroblasts and HPRT-deficient Chinese hamster cells were obtained and selected for and against retention of the active human X chromosome. In several independent hybrids the deleted X was retained in the active state. Partial ornithine transcarbamylase (ornithine carbamoyltransferase EC 2.1.3.3) (OTC) deficiency was documented by elevated urinary orotic acid excretion and increased serum glutamine after a protein load. This confirms the mapping of the structural gene for OTC to this deletion. Testing of neutrophil function revealed heterozygosity for chronic granulomatous disease (CGD) suggesting that a gene for CGD maps within the deletion. Thus, X inactivation mosaicism is also present in hepatocytes and neutrophilic granulocytes. Random X inactivation in a female with an Xp deletion has not been previously reported. The cells from this patient and the somatic cell hybrids containing her deleted X chromosome in the absence of the normal X provide material for the precise mapping of X linked genes and DNA sequences on the short arm of the human X chromosome.     

Array-CGH characterization of a de novo t(X;Y)(p22;q11) in a female with short stature and mental retardation

We report the clinical and molecular investigations in a girl with 46,X,-X,+der(X)t(X;Y)(p22;q11) de novo karyotype who presented an intricate phenotype characterized by mental retardation and facial dysmorphisms in combination with short stature. The structure of the derivative X chromosome was studied using BAC array-CGH which disclosed the Xp22 breakpoint between the STS and the VCX3A gene and the presence of the Yq11.1qter chromosome. It is common that females with Xp;Yq translocations present only short stature and are normal in every other aspect. Thus, this would be the first case in which a girl with Xp;Yq translocation presents an unusual phenotype with intermediate male clinical features with Xp;Yq translocations. The risk of developing gonadoblastoma in females with Y chromosome material is also discussed and, to this effect, different explanations related to this apparent variation are also presented.     

正常中国人和DMD患者X染色体Xp~(21)区的RFLP研究

本文应用从人类X柒色体Xp~(21)区不同部位分离得到的9种DNA探针,分析了100名正常中国人,38名DMD患者及其母亲X柒色体Xp~(21)区的14个限制性位点多态性(RSP;又称限制性片段长度多态性,RFLP)。发现正常的X染色体与携带DMD基因的X染色体Xp~(21)区的RFLP频率没有明显差别;在38例DMD患者中有7例的X染色体有DNA片段缺失;在本文分析的24例患者母杀中有17例是DMD基因携带者,她们在Xp~(21)区的RFLP均存在杂合的多态性,因此可以应用RFLP连锁分析对这些家系进行DMD的产前诊断。     

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 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.