Hum. Reprod. Advance Access originally published online on November 1, 2007
Human Reproduction 2008 23(1):222-226; doi:10.1093/humrep/dem358
Cryptic Xp duplication including the SHOX gene in a woman with 46,X, del(X)(q21.31) and premature ovarian failure
1 Service de Biologie et Génétique de la Reproduction, Inserm U782, Université Paris 11, Hôpital A Béclère, Clamart, France 2 Laboratoire de Cytogénétique, Hôpital R. Debré, Paris, France 3 Laboratoire de Cytogénétique, Université Pierre et Marie Curie, Assistance-Publique Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France 4 UPRES 1533, Université Pierre et Marie Curie, Service d’Endocrinologie de la Reproduction, Assistance-Publique Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France 5 URC-EST Hôpital, Saint-Antoine, France 6 ATL R and D, Reproductive Biology and Genetics Laboratory, La Verriere, France
7 Correspondence address. Reproductive Endocrine Unit, Hôpital Saint-Antoine, EA 1533, 184 rue du faubourg Saint-Antoine, 75012 Paris, France. Tel: +33-1-49282400; Fax: +33-1-49283195; E-mail: sophie.christin-maitre{at}sat.aphp.fr
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Abstract |
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BACKGROUND: Premature ovarian failure (POF) is defined as amenorrhoea for >6 months, occurring before the age of 40, with an FSH serum level in the menopausal range. Although Xq deletions have been known for a long time to be associated with POF, the mechanisms involved in X deletions in order to explain ovarian failure remain unknown. In order to look for potentially cryptic chromosomal imbalance, we used high-resolution genomic analysis to characterize X chromosome deletions associated with POF.
METHODS: Three patients with POF presenting terminal Xq deletions detected by conventional cytogenetics were included in the study. Genome wide microarray comparative genomic hybridization (CGH) at a resolution of 1 Mb and fluorescence in situ hybridization (FISH) was performed.
RESULTS: Microarray CGH and FISH studies characterized the three deletions as del(X)(q21.2), del(X)(q21.31) and del(X)(q22.33). Microarray CGH showed that the del(X)(q21.31) was also associated with a Xpter duplication including the SHOX gene. In these patients with POF, deletions or duplications of autosomes have been excluded.
CONCLUSION: This study is the first one using microarray in patients with POF. It demonstrates that putative X chromosome deletions can be associated with other chromosomal imbalances such as duplications, and therefore illustrates the use of microarray CGH to screen chromosomal abnormalities in patients with POF.
Key words: deletion/duplication/microarray CGH/premature ovarian failure/X chromosome
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Introduction |
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Premature ovarian failure (POF), more accurately termed primary ovarian insufficiency (POI) (Albright et al., 1942
), is defined as amenorrhoea of >6 months’ duration in the presence of raised gonadotropins, i.e. follicle-stimulating hormone (FSH) serum levels in the menopausal range, occurring before the age of 40 (Coulam et al., 1986; Vegetti et al., 2000; Goswami and Conway, 2005). Different abnormalities of the X chromosome have been reported in patients with POF, apart from Turner syndrome. Two implicated chromosomal regions have been located on the long arm of the X chromosome, at Xq13–21 (Powell et al., 1994) and at Xq26–27 (Krauss et al., 1987). In those regions, several critical loci have been identified: OMIM #211360 (POF1 Xq26–28 containing FMR1), #300511 (POF2A containing DIAPH) and #300604 (POF2B containing the POF1B gene).
In clinical cytogenetics, the precise identification of a chromosomal abnormality is a key factor when considering genotype–phenotype correlation. Our working hypothesis was that in patients with POF, a routine conventional karyotype might miss subtle chromosomal abnormalities. Indeed, in recent years, microarray comparative genomic hybridization (CGH) technology has been applied to constitutional chromosomal abnormalities in order to detect submicroscopic chromosomal aberrations and has demonstrated a high sensitivity (Schoumans et al., 2004; Shaw-Smith et al., 2004). With the advent of the human genome project, an ordered set of sequenced DNA elements for each of the human chromosomes is now available. The deposition and immobilization of these DNA elements in an array format (‘genomic microarrays’) recreates human chromosomes on a glass slide and provides a template against which the whole genome may be analysed (Solinas-Toldo et al., 1997). This technology can therefore be applied to reveal chromosomal imbalances with a higher resolution (Veltman et al., 2004). Recently, patients presenting developmental anomalies, associated with chromosomal abnormalities diagnosed by conventional cytogenetic methods, have been studied using microarray CGH. In those patients, additional subtle chromosomal rearrangements unrelated to their previously known chromosomal abnormalities have been identified, thanks to CGH (Ciccone et al., 2005; Gribble et al., 2005).
Therefore, we have used CGH array in order to analyse three patients with terminal Xq chromosome deletions. We have identified in one of them, an unknown cryptic Xp duplication.
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Patients
Women were recruited from Hôpital Saint-Antoine, Paris, and Hôpital Antoine Béclère, Clamart. Inclusion criteria were primary amenorrhoea or secondary amenorrhoea for >6 months, occurring before the age of 40, with an FSH serum level higher than 40 mIU/ml. FSH was measured in duplicate using an immunofluorescent assay (Immulite, Siemens). The study was approved by the institutional review board of Saint-Antoine Hospital, and all participants gave their written informed consent. None of the three patients had a personal or familial history of autoimmunity. These three patients exhibited no stigmata of Turner syndrome. No history of mental retardation was reported in boys among the three families. None of the patients had a history of pelvic surgery, blepharophimosis or hearing loss. The three patients belong to a prospective cohort of patients with POF. They were selected because they presented an Xq deletion on a standard karyotype. X chromosome mosaicism was excluded after studying 200 cells.
Clinical and biological data
Case 1: Her menarche occurred at the age of 16. Her menses were regular up to the age of 28 when she presented severe oligomenorrhoea, with an average of two cycles per year. At the age of 24, a benign functional ovarian cyst was removed during laparoscopy. The ovaries appeared normal. She became pregnant at the age of 26 but had an early spontaneous abortion. At the age of 33, she had secondary amenorrhoea. Her FSH, LH and estradiol (E2) levels were, respectively, 87, 41 and 15 pg/ml. Conventional cytogenetic analysis showed a 46,X, del(X)(q21.3) karyotype. The mode of inheritance of the Xq deletion was not identified, because of non-availability of parental karyotypes. Her height was 158 cm, and her weight 52 kg and her body mass index (BMI) 21.
Case 2: Her menarche was at 12, with regular menses every 28 days up to the age of 15. She was on the pill for 4 years and had secondary amenorrhoea when she stopped the pill. She never became pregnant. Her FSH and LH levels were, respectively, 124 and 28 mUI/ml with an E2 level below 15 pg/ml. Conventional cytogenetic analysis showed a 46,X,del(X)(q21.2) karyotype. The Xq21.2-qter deletion occurred de novo, as the karyotypes of the parents were normal. Her weight was 49 kg, her height 156 cm giving a BMI of 20. Her mother’s height was 160 cm and her father’s height was 198 cm.
Case 3: Her first menses occurred at the age of 12, and she had regular menses until the age of 26. She took the pill up to the age of 32 and stopped her contraception in order to become pregnant. She has never been able to start a pregnancy. After stopping the pill, she had secondary amenorrhoea. Her FSH, LH and E2 levels were, respectively, 97, 63 and 39 pg/ml. Conventional cytogenetic analysis showed a 46,X,del(X)(q22.3) karyotype. The Xq22.3-qter deletion occurred de novo, as the karyotypes of the parents were normal. Clinically, her height was 148 cm, her weight 56 kg giving a BMI of 25. In her past history, she only had hypertension at the age of 28, treated by beta-blockers. Her mother and sister’s heights were respectively 156 and 155 cm. Her mother’s menopause occurred at the age of 56.
Microarray CGH analysis
Microarray CGH was performed according to the manufacturer’s protocol on a genomic DNA array containing 2500 bacterial artificial clones (BAC) and P1-derived artificial chromosome (PAC) clones spotted in duplicate (Spectral GenomicsTM, Houston, TX, USA). This microarray provides an average resolution of 1 Mb for detection of chromosomal imbalances throughout the genome.
Genomic DNA from the three patients (test DNA) and reference genomic DNA (a sample with no known chromosomal imbalances) were digested with EcoR1 for 16 h at 37°C and re-purified by Zymo Research’s Clean and ConcentratorTM (Orange, CA, USA). The reference and test DNAs were labelled with Cy3 and Cy5 by Invitrogen’s BioPrime random labelling kit. The labelled reference DNA and labelled test DNA samples were combined with 50 µg of human Cot-1 DNA and 30 µg of sheared salmon sperm DNA. The labelled DNAs were denatured at 72°C for 10 min followed by incubation at 37°C for 30 min to block repetitive sequences. Hybridization was performed for 48 h, at 37°C. Slides were washed at room temperature in 2x SSC for 3–5 min then washed at 50°C for 25 min in 50% formamide/2x SSC. Hybridized microarray slides were scanned with GenePix 4000B scanner (Axon Instruments Inc., Union City, CA, USA). The data obtained were normalized and analysed using the Spectralware 1.0 software (Spectral Genomics).
Fluorescence in situ hybridization
Fluorescence in situ hybridization (FISH) analysis was performed using the whole X chromosome painting probe (Vysis Inc., Downers Grove, IL, USA), several X chromosome locus specific probes at subtelomeric Xq and Xp chromosomal regions, the SHOX gene locus (Xp22.33), the KAL1 gene locus (Xp22.32), a centromeric X chromosome DXZ1-alpha satellite probe (Vysis Inc.) for detecting X chromosome mosaicism, and BAC and PAC clones, as probes, selected from Genome Database Ensembl August 2006 (www.ensembl.org/index.html), spanning the Xq13–q22 region (from the Wellcome Trust Sanger Institute, Great Britain and M.Rocchi, University of Bari, Italy). Clones were plated and propagated and glycerol stocks were prepared. Isolation and purification of DNA were performed using the QIAGEN plasmid Maxi Kit (QUIAGEN SA, Courtaboeuf, France), according to the manufacturer’s instructions. FISH probes were created using purified BAC and PAC DNA by nick translation with Spectrum Green or Spectrum Red dUTP (Vysis Inc.) or dig-dUTP (Roche Diagnostic, IN, USA). The labelled DNA probes were applied to interphase and metaphase cells from the patients. For each probe, 10 metaphases were analysed.
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Microarray CGH analysis
The array-CGH profiles for X chromosomes in the three different cases showed loss of Xq, confirming the deletions observed with conventional cytogenetic methods. No deletion and no duplication were identified on autosomes in any of the three cases. However, in Case 1, the X chromosome’s profile showed a gain of the Xp22.33 region corresponding to a duplication, undetected by conventional karyotype (Fig. 1A). The size of this Xp duplication was 2.14 Mb.
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FISH analysis
FISH analysis with the X-specific centromeric probe (DXZ1) showed two positive signals in the total of 50 metaphases counted and in at least 97% of the 200 interphase nuclei analysed. This indicates that the Xq deletions concerned every cell studied and therefore were non-mosaic.
FISH using the whole X chromosome painting probe confirmed complete hybridization on normal and deleted X chromosomes, thus excluding any translocation between the X chromosome and an autosome in all three patients. A hybridization signal with the Xqter probe was only present on the normal X chromosome confirming Xq terminal deletions in all cases. In Case 1, the Xp telomere region and SHOX gene locus were duplicated (Fig. 1B). Furthermore, the KAL1 gene locus was normally hybridized, confirming the small cryptic chromosomal duplication identified by the array CGH analysis. This small chromosomal Xp duplication was localized on the Xq breakpoint.
A study of Xq proximal breakpoint, in Xq21.2 (Case 2), showed that it contains part of the CHM gene for choroideremia and a CpG island (Genome Database Ensembl August 2006). The Xq breakpoints of the other deletions were more distal, as they mapped in Xq21.31 and Xq22.33.
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Discussion |
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In this study, we have characterized Xq deletions involving Xq21-qter, in three patients with POF, using a genome wide microarray CGH. Although Xq deletions have long been known to be associated with POF, the mechanisms involved in X deletions to explain ovarian failure remain unknown. In order to look for potentially cryptic chromosomal imbalances, we used array-based CGH. In our study, at a resolution of 1 Mb, the array-based CGH confirmed the deletions of X chromosomes in all three cases. Interestingly, this study ruled out any other chromosome deletion or duplication in Cases 2 and 3. However, in Case 1, an Xpter duplication was identified. This result suggests that unusual X chromosome rearrangements can be misinterpreted when using a conventional karyotype. A diagnosis of simple terminal Xq deletions, as reported previously in the literature (Ogata et al., 2001
), may underestimate the degree of chromosomal rearrangements.
Microarray CGH technology has recently been applied to constitutional chromosomal abnormalities demonstrating its high sensitivity in diseases other than POF (Schoumans et al., 2004; Shaw-Smith et al., 2004; Veltman et al., 2004). Different groups have recently reported additional cryptic deletions and duplications in patients who have mental retardation and dysmorphic features with known translocations or inversions (Ciccone et al., 2005; Gribble et al., 2005). Using an X chromosome BAC array, Veltman et al. (2004) investigated nine patients with X linked diseases, other than POF. Among these nine patients, with previously known X chromosome rearrangements, they found three cases with an additional unidentified X chromosome deletion or duplication (Veltman et al., 2004). Therefore, additional cryptic chromosomal abnormalities may be more frequent than previously considered.
Using the microarray analysis approach, among our three patients, we identified a previously undetected cryptic partial Xp duplication in Case 1. Using FISH analysis with X chromosome probes, Ogata et al. (2001) reported two cases of complex rearranged X chromosomes, in five patients with POF initially diagnosed with simple terminal Xq deletions. The first one was an interstitial Xq deletion. The second one was a der(X) chromosome with partial Xq deletion and partial Xp duplication. To our knowledge, only three cases of der(X) with partial Xq deletion and Xp duplication have been reported so far, in the literature (Leppig et al., 1993; Ogata et al., 2001; Adamson et al., 2002). The first two patients, reported by Leppig et al. (1993) and Ogata et al. (2001), had de novo recombinant X-chromosomes with a roughly distal half of Xp duplication (Xp21.2-pter). These two duplications were attached to proximal Xq, with a deletion of all but the proximal portion of Xq. The breakpoints of the recombinant X-chromosome encompassing the Xp duplication and the Xq deletions are similar between the two cases. Finally, Adamson et al. (2002) reported a duplication of the X chromosome, Xp11.2-pter, resulting from a meiotic recombination of maternal X chromosomal pericentric inversion (inv(X)(p11.22q21.2)). In our der(X) case (Case 1), the associated Xp duplication corresponded to the Xp22.32-Xpter region. The breakpoints were localized between the SHOX and KAL genes. Therefore, this is the smallest Xp duplication (2.14 Mb) described so far as being associated with an Xq deletion. We believe that this duplication may be involved in the mechanisms of POF, as suggested by 47,XXX women who have an entire X chromosome duplication and a higher risk of ovarian insufficiency than 46,XX women (Spear et al., 1988). Furthermore, this Xp duplication located at the telomeric Xq region may alter pairing of X chromosomes during meiosis and therefore induce oocyte depletion.
Considering the phenotype, two of the three previously reported cases with Xp duplication, were tall, both measuring 172 cm (Leppig et al., 1993; Ogata et al., 2001). The patient we report, as well as Adamson’s et al. (2002) were not tall. This suggests that SHOX duplication does not always lead to increased stature. Ogata et al. (2002) suggested that a complex interaction may exist between SHOX protein levels and sex steroids in determining stature.
In patients with POF, deletions of the X chromosome have suggested two main critical regions located in Xq13.3–q22 (Powell et al., 1994) and Xq26–q28 (Tharapel et al., 1993). Marozzi et al. (2000) reported that the second region is limited from Xq26.2 to Xq28 in a series of six patients. Recently, Eggermann et al. (2005) have narrowed the distal region after a case report of a woman with a small deletion spanning from Xq27.2/Xq27.3 to Xq28 in a familial case of POF with secondary amenorrhoea. Very few cases of familial POF, associated with different-sized Xq interstitial and terminal deletions have been reported (Krauss et al., 1987; Maraschio et al., 1996; Rizzolio et al., 2006). It has been found that members of the same family carrying del(X) from q27 to qter showed a variable degree of gonadal dysgenesis (Maraschio et al., 1996). Cases 2 and 3 are sporadic cases of Xq deletions. The mode of transmission for Case 1 is unknown as the parents’ karyotypes were not available. Rossetti et al. (2004) have reported an interstitial and distal deletion of the X chromosome in two affected women and their fertile mother. However, the majority of patients with Xq deletions have oligomenorrhoea, followed by secondary amenorrhoea or premature ovarian failure, irrespective of the size of the deletion (Therman et al., 1990). Our three patients presented with secondary amenorrhoea, at the age of 33, 19 and 32, respectively, for Cases 1, 2 and 3. The age of 33 is the latest age reported so far in a woman with a large Xq deletion. This result implies that a karyotype should be performed when investigating a woman with POF, even after the age of 30.
A search for genes interrupted by the breakpoints in balanced X-autosome translocations has identified several candidate genes interrupted by the translocations, out of >40 balanced translocations mapped: DIAPH2 in Xq22, XPNPEP2 in Xq25, POF1B, DACH2 and CHM in Xq21.2. The relevance of these genes in the etiology of POF is yet unknown as mutations and expression analysis have failed to demonstrate a role in ovarian failure. Other translocations reported in the literature fall into very poorly transcribed regions (Toniolo, 2006; Portnoï et al., 2006). In Cases 1 and 3, the breakpoints located respectively at Xq21.3 and Xq22.3 fell into a region poor in predicted genes (Genome Database Ensembl April 2007). In Case 2, the breakpoint was located at Xq21.2, interrupting the CHM gene, mapped to Xq21.2. Choroideremia (CHM) is an X-linked recessive ophthalmic disease characterized by a progressive degeneration of the choroid and the pigmented epithelium of the retina. Our patient was not affected so far with choroideremia. Garcia-Hoyos et al. (2005) described a female patient with choroideremia carrying a 46,X,t(X;4)(q21.2;p16.3) translocation. The breakpoint in the X chromosome lies in the locus of CHM gene. Their analysis confirmed that the CHM gene was disrupted in the X chromosome involved in the translocation. In our case, the study of the DNA replication pattern of the X chromosomes showed that the deleted X was inactivated, explaining why our patient was not affected with choroideremia.
In summary, we report the first genomewide microarray analysis in women with POF. This study performed in women with Xq deletions, has increased our sensitivity as we were able to detect an Xp duplication. Furthermore, in these women, deletions or duplications of autosomes have been excluded. This result suggests that a conventional karyotype may miss some chromosomal abnormalities in patients with POF. Further studies need to be performed in a larger cohort of women with POF, in particular in women with normal conventional karyotypes. Those studies should increase our knowledge on the mechanisms involved in premature ovarian failure.
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This study was supported by the Direction de la Recherche Clinique, Assistance Publique Hôpitaux de Paris (PHRC AOR016).
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Submitted on July 26, 2007; resubmitted on October 5, 2007; accepted on October 9, 2007.
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