ESPE Abstracts (2014) 82 FC6.1

Search for Genetic Defects in the Transcription Factor Genes FOXL2, FOXE1, BMP15, NOBOX, and GDF9 in Children, Adolescents and Young Adults With Premature Ovarian Insufficiency POI

Nikolaos Settasa, Margarita Anapliotoua, Euthimios Deligeorogloub, Emmanuel Kanavakisc, Eleni Fryssirac, Christina Kanaka-Gantenbeina, Lina Michalad, Catherine Dacou-Voutetakisa, George Creatsasb, George P Chrousosa & Antonis Voutetakisa


aFirst Department of Pediatrics, School of Medicine, Athens University, Athens, Greece; bSecond Department of Obstetrics and Gynecology, School of Medicine, Athens University, Athens, Greece; cDepartment of Medical Genetics, School of Medicine, Athens University, Athens, Greece; dFirst Department of Obstetrics and Gynecology, School of Medicine, Athens University, Athens, Greece


Background: Molecular defects are rarely detected in Premature ovarian insufficiency (POI) patients.

Objective and Hypotheses: We hypothesized that the frequency of causative molecular defects could be higher in cases with early onset of POI. Moreover, the analysis of multiple genes in the same POI group could disclose co-existence of more than one molecular aberration.

Method: In 25 subjects, aged 17.1±7 years at POI onset, bidirectional sequencing of the coding region of FOXL2, FOXE1, BMP15, NOBOX, and GDF9 genes was performed.

Results: In the FOXL2 gene, a novel, de novo heterozygous deletion (p.K150Rfs*121) was detected in one subject. In the FOXE1 gene, a novel aberrant alanine tract was detected (8/16 alanine residues vs the normal 14/14) in one subject, while the 16/16 type was present in 12%. In the BMP15 gene, the mutation p.Q115H/WT was detected in one subject (zero in the European population, 1000 genome project). In silico analysis of p.Q115H predicted to be damaging in 5/7 softwares. In the BMP15 gene the mutation p.A180T/WT was detected in 4% (0.5% in the European population). In silico analysis of p.A180T predicted to be damaging in 2/7 softwares. The haplotype G-G-C (c.-9C/G, and c.308A>G, c.852C>T) of the BMP15 gene was detected in 12% (Dixit et al.: 2.6% and zero in controls). 16% of our subjects were carriers of the p.D452N of the NOBOX gene (1.6% in the European population). No missense variants were detected in the GDF9 gene. In two patients co-existing aberrations in two genes were identified.

Conclusion: Genetic aberrations in POI-related genes were frequently detected in our POI group (48%). The co-existence of aberrations in two genes found in two of our subjects possibly indicates digenic inheritance.