Abstract
Primary ovarian insufficiency (POI) is one of the major causes of female infertility associated with the premature loss of ovarian function in about 3.7% of women before the age of 40. This disorder is highly heterogeneous and can manifest with a wide range of clinical phenotypes, ranging from ovarian dysgenesis and primary amenorrhea to post-pubertal secondary amenorrhea, with elevated serum gonadotropins and hypoestrogenism. The ovarian defect still remains idiopathic in some cases; however, a strong genetic component has been demonstrated by the next-generation sequencing (NGS) approach of familiar and sporadic POI cases. As recent evidence suggested an oligogenic architecture for POI, we developed a target NGS panel with 295 genes including known candidates and novel genetic determinants potentially involved in POI pathogenesis. Sixty-four patients with early onset POI (range: 10–25 years) of our cohort have been screened with 90% of target coverage at 50×. Here, we report 48 analyzed patients with at least one genetic variant (75%) in the selected candidate genes. In particular, we found the following: 11/64 patients (17%) with two variants, 9/64 (14%) with three variants, 9/64 (14%) with four variants, 3/64 (5%) with five variants, and 2/64 (3%) with six variants. The most severe phenotypes were associated with either the major number of variations or a worse prediction in pathogenicity of variants. Bioinformatic gene ontology analysis identified the following major pathways likely affected by gene variants: 1) cell cycle, meiosis, and DNA repair; 2) extracellular matrix remodeling; 3) reproduction; 4) cell metabolism; 5) cell proliferation; 6) calcium homeostasis; 7) NOTCH signaling; 8) signal transduction; 9) WNT signaling; 10) cell death; and 11) ubiquitin modifications. Consistently, the identified pathways have been described in other studies dissecting the mechanisms of folliculogenesis in animal models of altered fertility. In conclusion, our results contribute to define POI as an oligogenic disease and suggest novel candidates to be investigated in patients with POI.
Highlights
Female factors account for one-third of all causes of infertility
We report a total of 114 rare variants in 78 different genes (Figure 1A, Table S2) in 64 patients
We propose novel candidate gene-disease variants likely causative or conferring susceptibility to primary ovarian insufficiency (POI) onset
Summary
Female factors account for one-third of all causes of infertility. Besides tubal disease and endometrial pathology, the dysregulation of any essential step involved in the ovulation of a competent oocyte may cause primary ovarian insufficiency (POI), a clinical syndrome defined by the premature loss of ovarian function. The consequent long-standing estrogen deficiency exposes these women to an increased risk of complications such as cardiovascular diseases, reduced bone mineral density, and cognitive impairment [2] This disorder is highly heterogeneous in its etiology and several causes have been reported, mainly genetic, associated with chromosomal abnormalities (especially including X chromosome, such as in Turner syndrome), and autoimmune, infectious, or iatrogenic. The remarkable point that emerged from recent NGS studies is the occurrence of oligogenic defects [6, 23] From this perspective, various interacting genes might affect several mechanisms and pathways, and the synergistic and/or cumulative effect of several variants may contribute to POI phenotype. The NGS results in 64 patients with PA or early onset SA based on our panel of 295 POI candidate genes presented here aims to contribute to expand the list of potentially causative candidate genes and to support a genetically heterogeneous architecture of POI, resulting from defects in multiple complementary pathways
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