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NOBOX gene variants in premature ovarian insufficiency: ethnicity-dependent insights

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Premature ovarian insufficiency (POI) affects approximately 1% of women before the age of 40. Genetic contribution is a significant component of POI. The NOBOX gene was considered one of the major genetic causes of POI. However, the pathogenicity and the penetrance of NOBOX variants remain unclear.

Methods

We studied the whole coding region of the NOBOX gene by next generation sequencing in a cohort of 810 patients with POI, and we compared the frequency of each identified NOBOX variant to the general population taking into account the ethnicity of each individual.

Results

Screening of the whole coding region of the NOBOX gene allowed us to identify 35 different variants, including 5 loss-of-function variants. In total, 171 patients with POI (25%) carried out at least one NOBOX variant. Regarding missense variants, we observed a significant overrepresentation of the most frequent ones in our 810 POI patients as compared to the general, except for p.(Arg117Trp). However, taking into account the ethnic origin of the individuals, we observed no significant OR difference for p.(Arg44Leu) and p.(Arg117Trp) in African subgroup and for p.(Asp452Asn) in European subgroup.

Conclusion

This population study suggests that the p.(Arg44Leu) variant could be considered benign variant and that the p.(Asp452Asn) and p.(Arg117Trp) variants could be considered moderate risk pathogenic variants with probably partial and very low penetrance and/or expressivity. In contrast, p.(Gly91Trp) and p.(Gly152Arg) variants could be considered pathogenic variants with a moderate functional impact.

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Data availability

The data that support the findings of the study are available from the corresponding author and the first author upon reasonable request.

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Author information

Author notes

  1. Laila El Khattabi

    Present address: Département de Génétique Médicale, Unité Fonctionnelle de Génomique Chromosomique, APHP. Sorbonne Université, Hôpital Armand Trousseau, 75012, Paris, France

  2. Pénélope Jordan, Camille Verebi, Laila El Khattabi, and Thierry Bienvenu contributed equally to this work.

Authors and Affiliations

  1. Service de Médecine Génomique Des Maladies de Système Et d’Organe, Hôpital Cochin, APHP, Centre Université de Paris Cité, 123 Boulevard de Port-Royal, 75014, Paris, France

    Pénélope Jordan, Camille Verebi, Corinne Fouveaut, Jean Michel Dupont, Laila El Khattabi & Thierry Bienvenu

  2. Unité de Gynécologie Médicale, APHP, Centre Université de Paris Cité Cité, Hôpital Cochin Port-Royal, 75014, Paris, France

    Sandrine Perol, Sarah Grotto & Geneviève PLU-Bureau

  3. Service d’endocrinologie, Diabétologie Et Médecine de La Reproduction, APHP, Sorbonne Université, Hôpital Saint-Antoine, 75012, Paris, France

    Sophie Christin-Maitre

  4. Service d’Endocrinologie, de Diabétologie Et Des Maladies Métaboliques A, Hospices Civiles de Lyon, 69000, Lyon, France

    Aude Brac de la Perrière

  5. Service de Gynécologie Médicale, CHU de Bordeaux, 33000, Bordeaux, France

    Virginie Grouthier

  6. Département d’assistance Médicale À La Procréation, Hôpital Jeanne de Flandre, 59000, Lille, France

    Sophie Jonard-Catteau

  7. Département d’Endocrinologie Et Médecine de La Reproduction, APHP. Sorbonne Université, Pitié-Salpêtrière Hospital, Center for Rare Endocrine and Gynecological Disorders, ERN-HCP, Paris, France

    Philippe Touraine

Authors
  1. Pénélope Jordan
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  2. Camille Verebi
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  3. Sandrine Perol
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  4. Sarah Grotto
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  9. Sophie Jonard-Catteau
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  10. Philippe Touraine
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  11. Geneviève PLU-Bureau
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  13. Laila El Khattabi
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  14. Thierry Bienvenu
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Contributions

LEK and TB co-conceptualized and designed the study. SP, PJ, DMG, EP, SJC, PT, SCM, and GPB reviewed medical records and collected patient data. CF performed molecular analysis and provided data analysis, tables, and figures. PJ, TB, CV, JMD, and LEK have written content toward the first draft of the manuscript. All authors reviewed and revised the manuscript and approved the final version as submitted and agree to be accountable for all aspects of the work. All authors are responsible for the accuracy and integrity of the work.

Corresponding author

Correspondence to Thierry Bienvenu.

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Jordan, P., Verebi, C., Perol, S. et al. NOBOX gene variants in premature ovarian insufficiency: ethnicity-dependent insights. J Assist Reprod Genet 41, 135–146 (2024). https://doi.org/10.1007/s10815-023-02981-y

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