ESPE Abstracts

Background: Primary ovarian insufficiency (POI), characterized by amenorrhea with elevated gonadotropin concentrations, includes a spectrum ranging from 46, XX gonadal dysgenesis to premature menopause. There is increased evidence that it has a strong genetic basis in its etiology, however, since its rarity and special condition that does not permit the definition of families with this disorder, the molecular diagnosis remains elusive in most of these patients.

Methods: In this study, using karyotyping, chromosomal microarray, and next-generation sequencing (NGS) methods, we investigated the molecular genetic etiology in non-Turner syndrome girls diagnosed with POI in childhood or adolescence in a university hospital. Thirty-four girls from 31 families aged 3-18 years who were diagnosed with POI based on clinical and laboratory findings were included in the study. All the patients were evaluated by both a pediatric endocrinologist and a pediatric geneticist. Exome sequencing performed by the NGS method targeted with the DNBSEQ-400 platform exome panel was analyzed for 65 genes known to be associated with POI in all patients. The variants were then categorized according to the American College of Medical Genetics recommendations. Suspected deletions detected by NGS were confirmed by chromosomal microarray analysis.

Results: All the patients presented before 18 years of age. Eighteen of 34 cases were either syndromic or had at least one significant associated congenital abnormality. Five patients had chromosomal anomalies other than Turner’s syndrome (one 47 XXX, one 48 XXXX, one Xp partial deletion, one derivative chromosome 9, and two large deletions in chromosome 8 and chromosome 16). Homozygous likely pathogenic variants in the genes RMND1, FSHR, ERCC6, HSD17B4, PMM2, and HOXA13 were detected in 7 patients. Heterozygous variants of unknown significance (VUOS) for conditions known to be autosomal dominantly inherited (AD) were detected in the genes FOXL2, MCM9, BMPR1B, and SALL4 in 5 patients. In 12 of 32 patients who had NGS analysis, more than one variant (pathogenic, likely pathogenic, or VOUS) was detected. In three patients, no genetic etiology could be found.

Conclusion: The genetic etiology of POI is complex and heterogeneous. Chromosomal abnormalities are an important cause of POI in even apparently non-syndromic cases. Oligogenic inheritance might be noteworthy in the molecular genetic etiology of early-onset POI.