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Background <p>Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder affecting 5–15% of women of reproductive age and is a leading cause of female infertility. It is a complex, multifactorial condition in which genetic factors play a significant role and may affect siblings within a family. Here, we present the case of two infertile sisters from an Iranian family.</p> Methods and results <p>Two sisters with treatment-resistant infertility and a history of PCOS underwent comprehensive genetic evaluation. Whole exome sequencing (WES) was performed on one of the sisters, and identified a missense variant, rs745386710, which is located in exon 5 of the <i>FSHR</i> gene, resulting in the p.L149F substitution. Sanger sequencing confirmed the presence of this variant in the other affected sister. variant interpretation was conducted in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). Structural protein analysis indicated that this variant may reduce protein-protein affinity. Importantly, we provide the first functional evidence for this variant.</p> Conclusion <p>This variant appears to significantly reduce protein stability and impair binding to follicle-stimulating hormone (FSH) and its receptor (FSHR), which may inhibit follicular maturation and contribute to the pathogenesis of PCOS.</p>

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A FSHR missense variant associated with polycystic ovary syndrome in an Iranian family with multiple affected sisters

  • 期刊论文

  • 发表日期：

    2025年10月28日

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  • Mahtab Behrafigh,
  • Mouness Rahimian,
  • Maryam Afkari,
  • Mona Khosravi-Far,
  • Navid Almadani,
  • Seyed Abolhassan Shahzadeh Fazeli

摘要

Background

Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder affecting 5–15% of women of reproductive age and is a leading cause of female infertility. It is a complex, multifactorial condition in which genetic factors play a significant role and may affect siblings within a family. Here, we present the case of two infertile sisters from an Iranian family.

Methods and results

Two sisters with treatment-resistant infertility and a history of PCOS underwent comprehensive genetic evaluation. Whole exome sequencing (WES) was performed on one of the sisters, and identified a missense variant, rs745386710, which is located in exon 5 of the FSHR gene, resulting in the p.L149F substitution. Sanger sequencing confirmed the presence of this variant in the other affected sister. variant interpretation was conducted in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). Structural protein analysis indicated that this variant may reduce protein-protein affinity. Importantly, we provide the first functional evidence for this variant.

Conclusion

This variant appears to significantly reduce protein stability and impair binding to follicle-stimulating hormone (FSH) and its receptor (FSHR), which may inhibit follicular maturation and contribute to the pathogenesis of PCOS.