Abstract
Purpose
Women carriers of FMR1 premutation are at increased risk of early ovarian dysfunction and even premature ovarian insufficiency. The aim of this study was to examine a possible association between FMR1 permutation and numeric sex chromosome variations.
Methods
A retrospective case-control study conducted in the reproductive center of a university-affiliated medical center. The primary outcome measure was the rate of sex chromosomal numerical aberrations, as demonstrated by haplotype analyses, in FMR1 premutation carriers compared to X-linked preimplantation genetic testing for monogenic/single gene defect (PGT-M) cycles for other indications that do not affect the ovarian follicles and oocytes.
Results
A total of 2790 embryos with a final genetic analysis from 577 IVF PGT-M cycles were included in the final analysis. Mean age was similar between the groups, however, FMR1 carriers required more gonadotropins, and more women were poor responders with three or less oocytes collected. The ratio of embryos carrying a numeric sex chromosome variation was similar: 8.3% (138/1668) of embryos in the FMR1 group compared to 7.1% (80/1122) in the controls. A subgroup analysis based on age and response to stimulation has not demonstrated a significant difference either.
Conclusions
Although carriers of FMR1 premutation exhibit signs of reduced ovarian response, it does not seem to affect the rate of numeric sex chromosomal variation compared to women undergoing PGT-M for other indications. This suggests that the mechanism for chromosomal number aberrations in women at advanced maternal age are different to those FMR1 premutation carriers with poor ovarian reserve.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10815-023-02730-1.
Keywords: Sex chromosome aneuploidies, Ovarian reserve, FMR-1, Aneuploidy, PGT-M
Introduction
Fragile X syndrome is the most common cause of inherited developmental delay, intellectual disability, and autistic spectrum disorder. It affects 1:4000–5000 males and 1:2500–8000 females [1]. The syndrome is caused by an expansion of CGG trinucleotide repeats in the 5' untranslated region of FMR1 gene (fragile X mental retardation), localized on the X chromosome. The normal range of CGG repeats is 5–44, intermediate: 45–54 repeats, premutation 55–200 repeats and an expansion to more than 200 repeats will cause a silencing of the FMR1 gene and result in fragile X syndrome [2]. The absence of the FMR1 protein (FMRP) leads to the unique pathologic features of the disease [3].
Women with 55–200 CGG repeats are pre-mutation carriers and the prevalence of pre-mutation in women is estimated to be 1:130–256 [1]. The pre-mutation state leads to increased transcription of FMR1 mRNA while the FMRP is translated in a low to normal quantity [4]. Elizur et al. suggested a nonlinear association between the number of CGG repeats and the level of FMR1 mRNA in the granulosa cells, with the highest accumulation observed in the mid-range of 80–120 repeats [5]. Female carriers of the pre-mutation are at risk of reduced ovarian reserve and premature ovarian insufficiency (POI), depletion of ovarian follicles with cessation of menses, and serum FSH level in the menopausal range before the age of 40. It is estimated that up to 26% of pre-mutation carriers can develop POI [6].
The mechanism behind ovarian damage in FMR1 pre-mutation carriers is unknown. To date, two main molecular mechanisms have been suggested. Firstly, accumulation of FMR1 mRNA, which is toxic to the ovary and follicles, causes either accelerated follicle atresia or decreased initial follicle reserve. Secondly, protein toxicity caused by the production of a polyglycine peptide through CGG repeat-associated non-AUG initiated translation can be toxic to the cells [5, 7]. Other pathogenic mechanisms include aberrant mitochondria and lower mitochondrial mass, R Loop induced DNA damage, and epigenetic modulation have also been suggested [8–10] .
Sex chromosome abnormality is a common chromosomal aberration both at prenatal diagnosis, with an overall incidence of 1 in 250–300, and postnatal (1 in 400 newborns) [11]. Aneuploidy of autosomal or sex chromosomes is associated with advanced maternal age or reduced ovarian reserve [12–14]. Sex chromosomal aneuploidy (e.g., 45XO) is one of the common chromosomal-number aberrations that is identified both in early miscarriages and embryos [15]. In a study of chromosome abnormalities in normally developing embryos from older females, sex chromosome aneuploidies were the most common event with a XXY trisomy and two X-monosomies [16]. FMR1 pre-mutation carriers are at a significantly higher risk of reduced ovarian reserve and POI traits, and it can be hypothesized that they are also susceptible to sex chromosomal number variation. This study aimed to explore a possible correlation between poor oocyte quality, as reflected by an increase in rate of sex chromosome number variations in FMR1 pre-mutation carriers, compared to women undergoing preimplantation genetic testing for monogenic/single gene defects (PGT-M) for other indications that do not affect the ovarian follicles and oocytes.
Materials and methods
Study population and design
This was a retrospective cohort study. All patients were recruited from the reproductive center of a university-affiliated medical center. We searched the medical records of women undergoing IVF-PGT-M cycles for X-linked disorders and social sex selection between 2010–2020. Cycle parameters of FMR1 pre-mutation carriers with 70–200 CGG repeats (study group) were compared to cycles of women undergoing PGT-M for whom the genetic analyses included haplotyping of the sex chromosome and therefore numeric changes involving absent or addition of haplotypes could be identified: carriers of other X-linked diseases (e.g., Duchenne), paternal X-linked inheritance or sex selection for autism spectrum disorder (ASD) and social sex selection. All patients were referred for PGT-M at our center following a comprehensive genetic consultation. A mutation carrier status was diagnosed by pregestational screening or a family history genetic disease. In accordance with the ministry of health guidelines in our country, PGT-M is offered to FMR-1 premutation carriers with 70 or more CGG repeats, since the risk for expansion to a full mutation in those with less than 70 repeats is very low and they undergo antenatal testing.
Cycles with no oocytes collected were excluded.
PGT-M is covered by the public health system in Israel; however, preimplantation genetic testing for aneuploidy (PGT-A) is not covered and is not routinely carried out, thus the prevalence of numeric sex chromosome variations can be studied mainly in PGT-M or PGT-structural rearrangement (SR) cycles that include haplotyping of the sex chromosomes.
Controlled ovarian hyperstimulation, fertilization, and PGT-M
Ovarian stimulation was performed by means of one of the following protocols: short gonadotropin-releasing hormone (GnRH) agonist protocol, fixed GnRH antagonist protocol, and mid-luteal long GnRH agonist protocol. Ideally, when two follicles attained a mean diameter of 17 mm, 250 mg of human recombinant chorionic gonadotropin was administered. Oocyte retrieval by an ultrasound-guided transvaginal approach was scheduled 36 to 38 h later. Oocytes were denuded of cumulus cells for prevention of maternal contamination, using hyaluronidase and a fine hand-drawn glass pipette. Fertilization was always performed by intracytoplasmic sperm injection (ICSI) for prevention of paternal contamination. The embryo biopsy was performed 3 days following fertilization for each embryo that was composed of six cells or more and had less than 30% fragmentation. For biopsy, a micromanipulator mounted on an inverted microscope was used. Perforation of the zona pellucida was performed using an in-contact laser apparatus. A single blastomere is sufficient to obtain a reliable and accurate diagnosis of FMR1 [17].
A multiplex nested PCR was developed for the simultaneous amplification of the FMR1 CGG repeats containing region, the three markers on the X and Y chromosome, and the eight or more FMR1 flanking informative polymorphic markers. This was followed by haplotype analysis and detection of chromosomal number variation (CNV) as described previously by our group [17]. During PGT-M, monosomy or trisomy of the X and Y chromosomes is demonstrated by the characterization of several informative polymorphic markers. The absence or the addition of parental haplotypes hints at monosomy and trisomy, respectively. Concerning monosomy, all cases can be identified using haplotype analysis; however, only about a third of trisomy errors can be identified using this method. This limitation is due to the fact that trisomy events originate from the same parental chromosome and carry the same polymorphic markers and will be mistakenly shown as having a normal chromosomal constitution. This issue was discussed previously by our group [18].
In all other PGT-M cycles, aimed at diagnosing monogenic X-linked disorders, a multiplex nested PCR protocol was developed and personally optimized for each patient. For this purpose, the familial mutation and the informativity of the polymorphic markers were taken into consideration. Each protocol for X-linked mutation included an amplification of the familial mutation, three markers for gender determination, and amplification of at least six markers flanking the tested gene from both sides. Similar to the diagnosis of FMR1 mutated allele. In several cases included in this study, the causative mutation was unknown. In these PGT-M cycles, only a gender determination was required, and six polymorphic markers localized on X chromosome and five other markers localized on Y chromosomes were analyzed.
Statistical analysis
The differences between categorical variables were assessed by the χ2 test and Fisher’s exact test and variation between continuous variables was assessed by the t test and Mann-Whitney U test for normal or skewed distribution, respectively. A generalized linear model (GLM) repeated measurement was developed to analyze the rate of sex chromosomal aberrations in each group. This model includes repeated measurement of numerous embryos for each subject and can control for both between-subjects factors and within-subjects factors.
A two-sided P value of < 0.05 was indicated as statistically significant.
Ethical approval
This retrospective study was approved by the Tel Aviv Sourasky Medical Center Helsinki Committee (Approval number: 0149-20-TLV).
Results
Two thousand seven hundred ninety embryos with a complete genetic analysis from 577 IVF PGT-M cycles were included in the final analysis. Three hundred ninety four cycles of 92 FMR1 pre-mutation carriers (study group) with a mean number of 127.5 (± 53.3) CGG repeats were compared to 183 cycles in 72 women undergoing PGT-M cycles for other X-linked disorders in the controls (the indications and the tested genes for PGT-M included in the control group are presented in Supplemental Table 1).
Mean age was similar between the groups; however, FMR1 carriers required more gonadotropins, and more women were found to be poor responders with three or less oocytes collected (based on the Bologna criteria for ovarian stimulation cycle outcome) (Table 1). As expected, the diminished response to stimulation in the FMR1 group affected the number of oocytes collected, embryos undergoing biopsy and eventually the number of embryos available for transfer (Table 2).
Table 1.
Demographic and cycle parameters
| FMR1 | Controls | P value | |
|---|---|---|---|
| Age at cycle start | 33.34 ± 4.08 | 34.65 ± 6.19 | 0.01 |
| BMI | 23.70 ± 4.58 | 24.70 ± 5.44 | 0.1 |
| Baseline FSH | 8.90 ± 4.53 | 7.43 ± 2.53 | 0.001 |
| Length of stimulation (days) | 11.78 ± 2.63 | 11.60 ± 1.99 | 0.18 |
| Total gonadotropin dose (IU) | 3415.78 ± 1576.1 | 2618.52 ± 1380.97 | < 0.001 |
| Maximal E2 (pg/ml) | 2264.95 ± 1748.5 | 2522.99 ± 1660.99 | 0.09 |
| No. of oocytes collected | 10.12 ± 7.39 | 13.8 ± 7.21 | < 0.001 |
| Poor responders* | 54 (14.1%) | 6 (3.3%) | < 0.001 |
Data is presented as mean ± std. deviation or as count (percent). FSH = follicle stimulating hormone, E2 = estradiol. CGG = trinucleotide repeat in FMR1 mutation carriers. No. = number
*Poor responders:1–3 oocytes aspirated (Bologna criteria)
Table 2.
IVF Lab parameters and embryonic outcomes per cycle
| FMR1 | Controls | P value | |
|---|---|---|---|
| Lab parameters | |||
| No. of oocytes injected | 8.98 ± 7.02 | 12.25 ± 7.19 | < 0.001 |
| Fertilization rate % | 60.6% 2350/3878 | 58.2% 1470/2526 | 0.057 |
| No. of embryos biopsied | 4.86 ± 3.59 | 6.67 ± 4.22 | < 0.001 |
| Biopsy rate % | 79.2% 1862/2350 | 83.1% 1221/1470 | 0.004 |
| Embryonic outcomes | |||
| No. of healthy embryos | 2 ± 1.78 | 2.77 ± 2.45 | < 0.001 |
| No. of embryos that inherited the mutated allele | 2.05 ± 1.86 | 2.92 ± 2.06 | < 0.001 |
| No. of undiagnosed embryos | 0.4 ± 0.78 | 0.51 ± 0.75 | 0.137 |
| No. of frozen embryos | 0.54 ± 1.72 | 1.34 ± 3.73 | 0.007 |
| No. of embryos transferred | 1.43 ± 1.17 | 1.6 ± 1.21 | 0.117 |
Data is presented as mean ± std. deviation or as rate (%); No. = number
The mean number of embryos undergoing biopsy per patient was 20.92 ± 20.36 and 16.96 ± 14.48 for FMR1 and controls, respectively, p = 0.152
Predictably, 46.2% of the embryos in the FMR1 group inherited the pre-mutated allele (771/1668) as compared to the 50% expected proportion. The ratio of numeric sex chromosome variations was comparable: 8.3% of embryos in the FMR1 group (138/1668) compared to 7.1% in the controls (80/1122, p = 0.281) (Table 3). One hundred two cycles in the FMR1 group had at least one embryo with numeric sex chromosome variation (29.9%) compared to 57 cycles (31.7%) in the control group (p = 0.69). Furthermore, a GLM which controls for within and between subjects' effects was developed to analyze the rate of sex chromosomal aberrations in each group: no differences were found between the groups (p = 0.74). The number of CGG repeats was not associated with the proportion of embryos carrying a numeric sex chromosome variation: 7.9% (15/190), 8.6% (57/665), and 6.7% (66/981), p = 0.371 for carriers with 70–80, 80–120, and 120–200 CGG repeats, respectively.
Table 3.
Numeric sex chromosome variations
| FMR1 | Controls | P value | |
|---|---|---|---|
| All numeric sex chromosome variations | 138/1668 (8.3%) | 80/1122 (7.1%) | 0.281 |
| Monosomy | 108/138(78.3%) | 65/80 (81.3%) | 0.729 |
| Trisomy | 30/138 (21.7%) | 15/80(18.8%) | 0.728 |
| Sex chromosomes aberrations in women < 40 years of age | |||
| All numeric sex chromosome variations | 131/1552 (8.4%) | 61/872 (7.0%) | 0.211 |
| Monosomy | 104/131 (79.4%) | 53/61(86.9%) | 0.235 |
| Trisomy | 27/131 (20.6%) | 8/61 (13.1%) | 0.235 |
Embryos of women at advanced age (> 40 years old) are at a higher risk for aneuploidy; therefore, to eliminate a possible bias, a subgroup analysis of women younger than 40 years was performed (Table 3). No differences in the rate of numeric sex chromosome variations were found between study and control in this age group. Next, we searched for a possible association between poor oocyte quality in women with poor ovarian response (three or less oocytes) and higher risk of chromosomal aberrations. No significant difference was found in poor responders compared to normal responders (8.1% 222/2736 vs. 5.1% 3/59, p = 0.625, for good responders vs. poor responders, respectively).
Discussion
As anticipated more women carriers of FMR-1 premutation in this cohort exhibited signs of reduced ovarian reserve and poor response to ovarian stimulation; nevertheless, the prevalence of numeric sex chromosome variations was comparable between the groups. After further analysis, with sub-divisions based on age and the number of oocytes aspirated, no statistically significant difference was demonstrated.
The rate of numeric sex chromosome variations found in FMR1 premutation carriers and the controls was higher than that reported by Fragouli et al. 4.73% and 6.88% in cleavage stage embryos and blastocysts, respectively [19]. This difference cannot be explained by age as the mean age in their study group was older. It is possible that the larger cohort of 2790 embryos analyzed in this study compared to only 754 in their study, can explain the difference.
The association between female ageing and chromosomal aneuploidy is well known. Prolonged arrest at the prophase of the first meiotic division of oocyte in women at advanced maternal age could expose the oocyte to errors in chromosome segregation and aneuploidy. Possible molecular mechanisms include recombination failure that alters the connection between homologous chromosomes before segregation, loss of cohesion between sister chromatids that effects microtubule attachment, altered histones that cause incorrect attachment of the meiotic spindle, and mitochondrial dysfunction that results in low cell energy and an increased level of reactive oxygen species (ROS) [20]. The increased risk for chromosome aneuploidies with advanced maternal age is well documented. Forty-four percent of embryos are aneuploid at a maternal age of 22 compared to more than 75% after 42 years of age [12]. More specifically, the incidence of sex chromosome aneuploidies (e.g., 45,X0 and 47,XXY ) in amniotic fluid specimens was 8.77% and it increased with maternal age [14].
What is the effect of reduced ovarian reserve on oocyte quality and ultimately aneuploidy? Although the correlation between ovarian ageing on chromosomal number abnormalities has been comprehensively described, the effect of diminished ovarian reserve and poor oocyte quality and the rate of embryo aneuploidy are debatable. Katz-Jaffe et al. found a higher percentage of aneuploid embryos in women with diminished ovarian reserve [13]. However, Morin et al. found similar blastulation, aneuploidy, and live birth rates in women with reduced ovarian reserve compared to normal responders. The aneuploidy rate was around 30% [21]. The result of this study suggests that the mechanism for chromosomal number aberrations in women at advanced maternal age are different to those responsible for poor ovarian reserve.
This study analyzed numeric sex chromosome variations in day 3 embryos; however, it should be noted that the level of aneuploidy differs according to the developmental stage of the embryo and later at the stage of pregnancy due to selection and preference of normal and viable cells. Aneuploidy events are most common in cleavage stage embryos compared to blastocyst (83% vs. 58%, respectively), compared to an aneuploidy rate of 74% in oocytes [19]. In genetic analysis of early spontaneous miscarriage, the most common abnormality is sex chromosome monosomy (45 X0) followed by trisomies 16, 21, and 22 [15]. Among newborns the most common aneuploidy is trisomy 21 followed by sex chromosome trisomies [15].
To the best of our knowledge this is the first study analyzing the prevalence of numeric sex chromosomal variations in day-three embryos of FMR1 premutation carriers undergoing PGT-M. The strengths of this study are a relatively large cohort of FMR1 premutation carriers undergoing PGT-M and that by using a GLM analysis it was possible to control for within and between subjects’ effects. This study is, however, limited by its retrospective design, and that aneuploidy in autosomal chromosomes could not be assessed and only monosomies were fully diagnosed. PGT-A is not covered by the public health system in our country; nevertheless, sex chromosome monosomy or trisomy is one of the common aneuploidies described in embryos [22]. Therefore, even with this limitation the large cohort of 2790 tested embryos in our study can still detect slightly higher aneuploidy rates in embryos of FMR-1 premutation carriers. The prevalence of numeric sex chromosomes variations in day five of embryo development could be addressed by future research.
In conclusion, although carriers of FMR1 premutation exhibit signs of reduced ovarian response, it does not appear to affect the rate of numeric sex chromosomal variations compared to women undergoing PGT-M for other indications.
Supplementary information
Indication for PGT-M in the control group (DOCX 30.2 kb)
Funding
No funding was received for conducting this study.
Declarations
Ethics approval and consent to participate
The institution review board (IRB) of Tel Aviv Sourasky Medical Center approved the study (Approval number: 0149-20-TLV).
Conflicts of interest
The authors declare that they have no conflicts of interest.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Mira Malcov and Ophir Blickstein equally contributed to this work.
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Associated Data
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Supplementary Materials
Indication for PGT-M in the control group (DOCX 30.2 kb)