ESPE Abstracts (2015) 84 P-1-134

Co-Existing Variants of FOXE1 and BMP15 Genes in Young Females with Primary Ovarian Insufficiency: Evidence of Digenic Inheritance

Nikolaos Settasa,b, Lina Michalac, Efthimios Deligeorogloud, Dionisios Chrysise, Andreas Pampanosf, Eleni Theocharif, Olympia Vallaf, Christalena Sofocleousb, Kitsiou Sofiab, Helen Fryssirab, Emmanuel Kanavakisb, Catherine Dacou-Voutetakisa, George P Chrousosa & Antonis Voutetakisa

aFirst Department of Pediatrics, School of Medicine, Athens University, Athens, Greece; bDepartment of Medical Genetics, Athens University, Athens, Greece; cFirst Department of Obstetrics and Gynecology, Athens University, Athens, Greece; dSecond Department of Obstetrics and Gynecology, Athens University, Athens, Greece; eDepartment of Pediatrics, School of Medicine, University of Patras, Patras, Greece; fDepartment of Medical Genetics, Alexandra Hospital, Athens, Greece

Background: FOXE1 gene variants containing alterations in the alanine tract length may confer susceptibility to primary ovarian insufficiency (POI). BMP15 gene variants have also been related to POI.

Objective and hypotheses: To evaluate the contribution of FOXE1 and BMP15 variants in the pathogenesis of POI and to investigate the hypothesis of digenic inheritance in this disorder.

Method: FOXE1 and BMP15 genes were directly sequenced in 35 young females with idiopathic POI (mean age at presentation 17.7±5.91 years) and in 50 female controls from the general population.

Results: In four out of the 35 POI cases, presenting at the age of 14, 25, 24 and 14 years respectively, a shorter alanine tract of the FOXE1 gene was detected (genotypes: 8/16, 8/14, 8/8 and 12/12 respectively). Two of the patients were siblings. Thus, the frequency of FOXE1 variants was 11.4% in patients vs 2% in the controls. In two out of the four patients (8/16, 8/14), variants of the BMP15 gene (c.-9G/G, C>G), were also detected. These BMP15 variants have been previously implicated in POI. No similar BMP15 variants were present in controls. The mother of the two siblings with the shorter FOXE1 alanine tract was also affected with POI (at age <30 years), after the birth of her children (mother’s genotype 8/14).

Conclusion: Data strongly indicate that i) FOXE1 gene variants with a shorter alanine tract are causatively related to POI, ii) co-existence of variants in other POI-related genes (in this study BMP15) is possibly required in certain cases, for the clinical expression of an ovarian defect (digenic inheritance). These data are in accordance with our previous report on FOXL2 also suggesting digenic inheritance in POI.