P-714 Clinical utility of FMR1 screening: risk factor or monogenic cause for POI
Authors: Okutman Ö , Van A , Kelen Der , Viville S , Verpoest W 
Published: June 2023

Abstract

Study question
Is there a risk factor association or a monogenic relationship between FMR1 premutation and developing Fragile X-associated primary ovarian insufficiency (FXPOI)?

Summary answer
There is an association between FMR1 premutation and FXPOI rather than a monogenic relationship, which is highly dependent on ethnicity.

What is known already
Among the 40 genes involved in primary ovarian insufficiency (POI), identified in our recent systematic review (Van Der Kelen et al., 2022), the FMR1 premutation is considered as the most common cause of POI. A premutation in the FMR1 gene is defined as a CGG trinucleotide repeat length between 55 and 200 in the 5′ untranslated region. The term FXPOI is used for women with premutation in FMR1 who have a loss of normal function of the ovaries before the age of 40. There is conflicting evidence about the relationship between POI and length of premutation FMR1 alleles.

Study design, size, duration
Curated publications identified in PubMed and Web of Science on genetics of human female infertility and sex development by using the MESH terms, key words and inclusion/exclusion criteria described in our comprehensive systematic review were subjected to screening for “FMR1 gene.” The articles included cover a period from 1988 to the 1st of November 2021.

Participants/materials, setting, methods
A total of 161 publications in PubMed and 61 unique publications in Web of Science were identified, and subsequently screened for triplet expansion, primary ovarian insufficiency, and/or early menopause. Of these, 56 papers were selected, excluding publications exclusively on males as well as studies on non-human species, pediatric cases, reviews, and expression studies. The study and control groups repeat numbers, ethnicity, and conclusions in the article are listed.

Main results and the role of chance
Expansion in CGG trinucleotide repeat length happens at female meiosis and the risk for expansion increases with an increasing number of CGG repeats. There is an intermediate zone between 45 and 55 CGG repeats when the allele may be stable or unstable. Among 56 publications, 54 describing FMR1 triplet repeat size in women with POI, 34 were studying only the women with POI (observational) while 20 were including also control group (comparative). 2 publications were meta-analyses in which 13 and 11 case control studies were included respectively, 5 studies being in common.
POI-associated premutations showed a wide range of repeat sizes. Women carrying midsize range repeats (&gt;70-&lt;100) potentially have a higher risk for POI compared to the general population. In recent decades, population-based screenings have indicated that FMR1 premutations are not as prevalent in women with ovarian insufficiency as previous estimates have suggested, but they still represent a substantial cause of POI. When present, the number of AGG interruptions and the size of uninterrupted CGG repeats are directly correlated with the ovarian reserve. No increased risk of POI associated with a premutation was reported among populations of non-European descent, such as the Han Chinese, Indian, and Jordan populations.

Limitations, reasons for caution
Available reports are difficult to compare because the ethnicity and number of patients analyzed, availability of clinical data and the quality of results are different in each study. Additionally, an effect of X-inactivation in POI women with premutation was not studied.

Wider implications of the findings
Owing to the low penetrance and a molecular mechanism that has not yet been fully elucidated, the clinical utility of FMR1 screening in women with reduced ovarian reserve needs further investigation before clinical implication.

Trial registration number
N/A