Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families.

Thierry Brue, Sophie Christin-Maitre, Philippe Touraine, Jean-Pierre Siffroi, Esther Kott, Tabassome Simon, Alexandra Rousseau, Sandra Chantot-Bastaraud, Anne Bachelot, Catherine Pienkowski, Alexandre Rouen, Virginie Grouthier, Anne-Marie Guedj, Isabelle Cedrin, Anne Gompel, Yves Reznik, Sophie Catteau-Jonard, Brigitte Delemer, Véronique Kerlan, Eli Rogers

Journal: Fertility and sterility 2022;117(4):843-853

PMID: 35115167

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Abstract

OBJECTIVE

To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI).

DESIGN

Cross-sectional study.

SETTING

Endocrinology and reproductive medicine teaching hospital departments.

PATIENTS

Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects.

INTERVENTIONS

None.

MAIN OUTCOME MEASURES

The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES.

RESULTS

A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4).

CONCLUSIONS

The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways.

CLINICAL TRIAL REGISTRATION NUMBER

NCT 01177891.

Address: Département de Génétique Médicale, Unité INSERM U933, Hôpital Armand-Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: [email protected].; Département de Génétique Médicale, Unité INSERM U933, Hôpital Armand-Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France.; Service d'Endocrinologie, Centre Hospitalier Universitaire de Brest, Brest, France.; Service d'Endocrinologie, Diabète, Nutrition, Centre Hospitalier Universitaire de Reims, Reims, France.; Service de Médecine de la Reproduction, Hôpital Lille, France.; Service d'Endocrinologie, Hôpital Caen, France.; Université de Paris, Unité de Gynécologie Médicale, Hôpital Port-Royal, France.; Service de Médecine de la Reproduction, Hôpital Jean Verdier, France.; Service d'Endocrinologie, Nîmes, France.; Service d'Endocrinologie, Bordeaux, France.; Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l'Hypophyse, Marseille, France, and Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale, Marseille Medical Genetics, Institut Marseille Maladies Rares, Marseille, France.; Service d'Endocrinologie Pédiatrique, Hôpital de Toulouse, France.; Service d'Endocrinologie et Médecine de la Reproduction, Centre Constitutif des Maladies Endocriniennes Rares de la Croissance et du Développement, Centre Constitutif du Centre des Pathologies Gynécologiques Rares, Sorbonne Université, Hôpital de la Pitié-Salpétrière, Paris, France; Sorbonne Université, Paris, France.; Unité de Recherche Clinique de l'Est Parisien, Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris, France.; Département de Génétique Médicale, Unité INSERM U933, Hôpital Armand-Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France; Sorbonne Université, Paris, France.; Département de Génétique Médicale, Unité INSERM U933, Hôpital Armand-Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France; Sorbonne Université, Paris, France; Service d'Endocrinologie, Diabétologie et Médecine de la Reproduction, Centre Constitutif des Maladies Endocriniennes Rares de la Croissance et du Développement, Sorbonne Université, Hôpital Saint-Antoine, Paris, France.

DOI: 10.1016/j.fertnstert.2021.12.023

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MeSH Terms: Cohort Studies, Cross-Sectional Studies, Female, Fragile X Mental Retardation Protein, Humans, Menopause, Premature, Primary Ovarian Insufficiency, Exome Sequencing