Justine Bouilly1, Isabelle Beau1, Sara Barraud1, Valérie Bernard1, Kemal Azibi1, Jérôme Fagart1, Anne Fèvre1, Anne Laure Todeschini1, Reiner A Veitia1, Chérif Beldjord1, Brigitte Delemer1, Catherine Dodé1, Jacques Young1, Nadine Binart1. 1. Inserm 1185 (J.B., I.B., S.B., J.F., J.Y., N.B.), Le Kremlin-Bicêtre, Université Paris-Saclay, Faculté de Médecine Paris Sud, 94270 Le Kremlin-Bicêtre, France; Service de Biochimie et Génétique Moléculaire (K.A., C.B., C.D.), Hôpital Cochin, AP-HP, Université Paris-Descartes, 75004 Paris, France; Service d'Endocrinologie-Diabète-Nutrition (A.F., B.D.), CHU de Reims-Hôpital Robert-Debré, 51100 Reims, France; Institut Jacques Monod (A.L.T., R.A.V.), Université Paris Diderot-PARIS 7/CNRS UMR7592, 75013 Paris, France; and Service d'Endocrinologie et des Maladies de la Reproduction (J.Y.), APHP, Hôpital de Bicêtre, 94270 Le Kremlin-Bicêtre, France.
Abstract
CONTEXT: Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility. POI affects 1% of women before age 40 years, and several genetic causes have been reported. To date, POI has been considered a monogenic disorder. OBJECTIVE: The aim of this study was to identify novel gene variations and to investigate if individuals with POI harbor mutation in multiple loci. PATIENTS AND METHODS: One hundred well-phenotyped POI patients were systematically screened for variants in 19 known POI loci (and potential candidate genes) using next-generation sequencing. RESULTS: At least one rare protein-altering gene variant was identified in 19 patients, including missense mutations in new candidate genes, namely SMC1β and REC8 (involved in the cohesin complex) and LHX8, a gene encoding a transcription factor. Novel or recurrent deleterious mutations were also detected in the known POI candidate genes NOBOX, FOXL2, SOHLH1, FIGLA, GDF9, BMP15, and GALT. Seven patients harbor mutations in two loci, and this digenicity seems to influence the age of symptom onset. CONCLUSIONS: Genetic anomalies in women with POI are more frequent than previously believed. Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic effect of several mutations may underlie the POI phenotype.
CONTEXT: Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility. POI affects 1% of women before age 40 years, and several genetic causes have been reported. To date, POI has been considered a monogenic disorder. OBJECTIVE: The aim of this study was to identify novel gene variations and to investigate if individuals with POI harbor mutation in multiple loci. PATIENTS AND METHODS: One hundred well-phenotyped POI patients were systematically screened for variants in 19 known POI loci (and potential candidate genes) using next-generation sequencing. RESULTS: At least one rare protein-altering gene variant was identified in 19 patients, including missense mutations in new candidate genes, namely SMC1β and REC8 (involved in the cohesin complex) and LHX8, a gene encoding a transcription factor. Novel or recurrent deleterious mutations were also detected in the known POI candidate genes NOBOX, FOXL2, SOHLH1, FIGLA, GDF9, BMP15, and GALT. Seven patients harbor mutations in two loci, and this digenicity seems to influence the age of symptom onset. CONCLUSIONS: Genetic anomalies in women with POI are more frequent than previously believed. Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic effect of several mutations may underlie the POI phenotype.
Authors: Aaron M Moore; Zongli Xu; Ramya T Kolli; Alexandra J White; Dale P Sandler; Jack A Taylor Journal: Epigenetics Date: 2019-03-28 Impact factor: 4.528
Authors: Bushra Gorsi; Edgar Hernandez; Marvin Barry Moore; Mika Moriwaki; Clement Y Chow; Emily Coelho; Elaine Taylor; Claire Lu; Amanda Walker; Philippe Touraine; Lawrence M Nelson; Amber R Cooper; Elaine R Mardis; Aleksander Rajkovic; Mark Yandell; Corrine K Welt Journal: J Clin Endocrinol Metab Date: 2022-02-17 Impact factor: 5.958
Authors: Sarah Eskenazi; Anne Bachelot; Justine Hugon-Rodin; Genevieve Plu-Bureau; Anne Gompel; Sophie Catteau-Jonard; Denise Molina-Gomes; Didier Dewailly; Catherine Dodé; Sophie Christin-Maitre; Philippe Touraine Journal: J Endocr Soc Date: 2021-03-01