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Case Reports
. 2025 Mar;197(3):e63924.
doi: 10.1002/ajmg.a.63924. Epub 2024 Nov 4.

Identification and Characterization of Novel FSHR Copy Number Variations Causing Premature Ovarian Insufficiency

Anna Lokchine  1   2 , Anne Bergougnoux  3   4 , Nadège Servant  3 , Linda Akloul  5 , Erika Launay  2 , Laura Mary  2 , Laurence Cluzeau  2 , Mathieu Philippe  2 , Mathilde Domin-Bernhard  6 , Solène Duros  6 , Sylvie Odent  5   7 , Elena Tucker  8   9 , Françoise Paris  3   10   11 , Marc-Antoine Belaud-Rotureau  1   2 , Sylvie Jaillard  1   2
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Free article
Case Reports

Identification and Characterization of Novel FSHR Copy Number Variations Causing Premature Ovarian Insufficiency

Anna Lokchine et al. Am J Med Genet A. 2025 Mar.
Free article

Abstract

Follicle stimulating hormone (FSH) is a key pituitary gonadotropic hormone implicated in human fertility and is crucial for folliculogenesis and recruitment of new antral follicles. Variations in its receptor, FSHR, can lead to diverse reproductive phenotypes including ovarian hyperstimulation syndrome (OHSS) and premature ovarian insufficiency (POI). This study reports a novel case of FSHR-related ovarian insufficiency in a patient with primary amenorrhea, subnormal AMH levels, and delayed puberty. Genetic exploration revealed two compound heterozygous intragenic deletions of FSHR. Specifically, the patient inherited a maternally derived deletion spanning exons 5-10 and a paternally derived deletion involving exons 3-6. Through chromosomal microarray analysis (CMA), exome sequencing, long-range PCR, and Sanger sequencing, we characterized the breakpoints and confirmed the compound heterozygous deletions. The findings reveal a complete loss of function of both FSHR alleles, contributing to the patient's POI phenotype. This case emphasizes the complexity of genotype-phenotype correlations in FSHR-related disorders and the role of CNVs in POI phenotypes. Although these events are rare, our results advocate for the inclusion of CNV detection in the diagnostic workup of POI to ensure accurate diagnosis and better patient management.

Keywords: FSHR; copy number variation; infertility; premature ovarian insufficiency.

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References

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