ESPE Abstracts

Introduction: Premature ovarian failure (POF) is defined as ovarian failure developing before the age of 40. The etiology of genetic POF is quite heterogeneous and can be due to genetic, autoimmune, environmental, viral infections or iatrogenic causes.

Objective: The aim of this study is to investigate the molecular genetic causes of non-syndromic POF cases with the gene panel based on next generation sequence analysis and to establish the relationship between genotype and phenotype.

Methods: 23 cases aged 14-40 years followed up with POF were included. Patients with a karyotype of 46, XX, primary or secondary amenorrhea before the age of 40, with elevated FSH (> 40 IU/mL) and low anti-Müllerian hormone levels (<0.03 ng/ml) were included in the study. Those with anti-cancer therapy, pelvic surgery, ovarian infection and/or autoimmune disease history were excluded. Molecular genetic analyzes were performed with Illumina Nextseq550 platform with the next generation sequence analysis method targeted with the Trusight One kit. The variants in the genes that may be related to the POF included in the panel were analyzed by filtering method. Pathogenicity of the detected variants was determined according to the criteria of “American College of Medical Genetics and Genomics” (ACMG).

Results: Median age of the cases was 17.8 (14.0-24.3) years, and 12 (52%) cases admitted before the age of 18. Fifteen (65%) of the cases had consanguineous parents. Mean weight, height and BMI SDS were -0.5 ± 1.3SD, -0.3 ± 1.7SD, -0.0 ± 1.4 SD respectively. 4 of the cases had short stature and 3 of these patients received growth hormone treatment. Mean FSH level of the cases was 82.73 ± 35.21 IU/ml. In 2 (8.6%) patients, mutations detected were in genes that have been previously proven to cause POF. One was homozygous c.339T> G (p.Tyr113Ter) in FIGLA gene and the other was homozygous c.215T> C (p.Phe72Ser) variants in PSMC3IP gene. In addition, in one (4.3%) case, heterozygous c.5420A> G (p.Asn1807Ser) variant was detected in the CHD7 gene, which was previously identified as a possible gene responsible for oligogenic inheritance in POF molecular etiology. In cases without mutation, all exome/genome sequence analysis, comparative genomic hybridization and advanced genetic analysis are ongoing.

Conclusion: Genetic panels based on next generation sequence analysis technologies can be used to determine the molecular genetic diagnosis of POF, which has a highly heterogeneous genetic basis.