Prevalence Of Fragile X Mental Retardation 1 Premutation (Fmr1) In Young Infertile Women With Diminished Ovarian Reserve. Implications In Clinical Practice

Abstract Study question Are young infertile patients with diminished ovarian reserve (DOR) elegible to perform the FMR1 premutation study? Summary answer Study of the FMR1 premutation should be considered in infertile young patients with DOR in order to give them an adequate genetic counselling. What is known already FMR1 gene may have some reproductive implications. Most notable is that FMR1 premutation expansions are associated with premature ovarian insufficiency (POI), diagnosed by amenorrhea or oligomenorrhea and FSH hormonal levels >25U/L before 40 years old. Presence of FMR1 premutation implies a risk of develop POI up to 24% and having an offspring with fragile X syndrome. The frequency of FMR1 premutation in general population is estimated in 0.3-0.7%. The role of FMR1 premutation expansions in diminished ovarian reserve (DOR) patients is not clearly established and could be considered as a previous step to POI that may be related to sterility. Study design, size, duration Retrospective review of the FMR1 gene study requested in patients of an Assisted Reproduction Unit of a tertiary Hospital in Barcelone from January-2016 to December-2019. A total of 307 cases were evaluated to determine the number of CGG repeat and AGG interruptions to assess the FMR1 gene status. Participants/materials, setting, methods A total of 307 samples were assessed. Clinical and reproductive data were collected. The FMR1 status was requested on patients who present: a) POI (n = 60); b) Family history of the FMR1 mutation (n = 11); c) Infertile normo-ovulatory and young (≤35 years old) women with DOR defined as antral follicle count (AFC) < 7 and antimüllerian hormone <0.8ng/ml (n = 71); d) Miscellaneous (n = 29) FMR1 was studied in 136 oocyte donors (screened by protocol), this was considered control group. Main results and the role of chance Mean age (±SD) of infertile DOR group was 32.7 +/- 2.1 years old (range 26-35) and showed altered ovarian reserve markers: AMH 0.43 ng/ml (SD ± 0.28) and AFC 4.27 (SD ± 2.1) follicles. In this group, 4 FMR1 premutation cases were found. Mean age (±SD) in control group was 26.28 +/- 5.2 years old and presented normal AMH and AFC values. One FRM1 premutation carrier was detected among 136 patients, prevalence comparable to the non-sterile population. The prevalence of FRM1 premutation was significantly higher in the DOR infertile group 5,6% vs 0,73% in the donors’ group (p = 0.02). Significant differences were observed also in terms of age and ovarian reserve markers between both groups. Very few cases of POI patients or family history of Fragile X Syndrome have been evaluated, due to the fact we are not a reference of these kind of patients. Among patients with a family history, 1 case from 11 (9.1%) was detected. In the POI group, three cases of premutation out of 60 (5%) were found. Limitations, reasons for caution This is a retrospective study with limited determinations of FMR1 studies. Donor screening and young infertile patients with significant low ovarian reserve are the main indications to request FMR1 status gene, so may lead to a selection bias. Wider implications of the findings These results should be confirmed prospectively in a higher population of infertile young patients with DOR, in order to identify the profile of infertile patient with diminished ovarian reserve who are elegible to perfom FMR1 gene premutation to give them an adequate clinical and genetic counselling. Trial registration number not apllicable