Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing

Abstract

Premature ovarian failure (POF) is a frequent pathology affecting 1-1.5% of women under 40 years old. Despite advances in diagnosing and treating human infertility, POF is still classified as being idiopathic in 50-80% of cases, strongly suggesting a genetic origin for the disease. Different types of autosomal and X-linked genetic anomalies can originate the phenotype in syndromic and non-syndromic POF cases. Particular interest has been focused on research into non-syndromic POF causative coding variants during the past two decades. This has been based on the assumption that amino acid substitutions might modify the intrinsic physicochemical properties of functional proteins, thereby inducing pathological phenotypes. In this case, a restricted number of mutations might originate the disease. However, like other complex pathologies, POF might result from synergistic/compensatory effects caused by several low-to-mildly drastic mutations which have frequently been classified as non-functional SNPs. Indeed, reproductive phenotypes can be considered as quantitative traits resulting from the subtle interaction of many genes. Although numerous sequencing projects have involved candidate genes, only a few coding mutations explaining a low percentage of cases have been described. Such apparent failure to identify aetiological coding sequence variations might have been due to the inherent molecular complexity of mammalian reproduction and to the difficulty of simultaneously analysing large genomic regions by Sanger sequencing. The purpose of this review is to present the molecular and cellular effects caused by non-synonymous mutations which have been formally associated, by functional tests, with the aetiology of hypergonadotropic non-syndromic POF. Considerations have also been included regarding the polygenic nature of reproduction and POF, as well as future approaches for identifying novel aetiological genes based on next generation sequencing (NGS).

Xenogeneic Decellularized Scaffold: A Novel Platform for Ovary Regeneration

“…However, 1.0-1.5% of women younger than 40 years face early menopause because of premature ovarian failure (POF). 1,2 Ovarian hormones play crucial roles in breast development, vasculoprotective action, anti-inflammatory processes, bone formation, and even mental health. [3][4][5][6] Therefore, women with POF often experience more severe menopausal symptoms than nature menopausal ones, as infertility, osteoporosis, cardiovascular disease, autoimmune disorders, and depression.…”

Primary Ovarian Insufficiency

“…It could be used in the near future regarding a variety of ovarian dysfunctions for diagnostic and predictive purposes. 19 Moreover, many genes that currently appear isolated in function actually may be interrelated within yet to be defined pathways. It is logical to stratify by gene function in ostensibly distinct systems: endocrine, folliculogenesis, cell cycle, meiosis, mitochondrial, as examples.…”

Primary ovarian insufficiency associated with autosomal abnormalities: from chromosome to genome-wide and beyond

“…93 Three NGS main formats, depending on the length of the genome region being analyzed, are normally used: whole-genome sequencing (WGS), whole-exome sequencing (WES), and custom target sequencing microarrays (TSM). 94 The major limitation of NGS is replication error, which might yield a false-positive result. To decrease the replication error, the second confirmation assay using Sanger sequencing or a second round of the same assay is recommended.…”

“…To decrease the replication error, the second confirmation assay using Sanger sequencing or a second round of the same assay is recommended. 94,95 During recent years, only a few studies applied NGS technology to analyze women with POI. Fonseca et al 37 designed a TSM-NGS study with Sanger sequencing confirmation in 12 Colombian nonsyndromic POI women and 521 controls.…”