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The Genetics of Non-Syndromic Primary Ovarian Insufficiency: A Systematic Review.

ABSTRACT: Several causes for primary ovarian insufficiency (POI) have been described, including iatrogenic and environmental factor, viral infections, chronic disease as well as genetic alterations. The aim of this review was to collect all the genetic mutations associated with non-syndromic POI. All studies, including gene screening, genome-wide study and assessing genetic mutations associated with POI, were included and analyzed in this systematic review. Syndromic POI and chromosomal abnormalities were not evaluated. Single gene perturbations, including genes on the X chromosome (such as BMP15, PGRMC1 and FMR1) and genes on autosomal chromosomes (such as GDF9, FIGLA, NOBOX, ESR1, FSHR and NANOS3) have a positive correlation with non-syndromic POI. Future strategies include linkage analysis of families with multiple affected members, array comparative genomic hybridization (CGH) for analysis of copy number variations, next generation sequencing technology and genome-wide data analysis. This review showed variability of the genetic factors associated with POI. These findings may help future genetic screening studies on large cohort of women.

SUBMITTER: Venturella R

PROVIDER: S-EPMC6642427 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The Genetics of Non-Syndromic Primary Ovarian Insufficiency: A Systematic Review.

Venturella Roberta R De Vivo Valentino V Carlea Annunziata A D'Alessandro Pietro P Saccone Gabriele G Arduino Bruno B Improda Francesco Paolo FP Lico Daniela D Rania Erika E De Marco Carmela C Viglietto Giuseppe G Zullo Fulvio F

International journal of fertility & sterility 20190714 3

Several causes for primary ovarian insufficiency (POI) have been described, including iatrogenic and environmental factor, viral infections, chronic disease as well as genetic alterations. The aim of this review was to collect all the genetic mutations associated with non-syndromic POI. All studies, including gene screening, genome-wide study and assessing genetic mutations associated with POI, were included and analyzed in this systematic review. Syndromic POI and chromosomal abnormalities were ...[more]

PMID: 31310068

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Project description:Primary ovarian insufficiency (POI) is characterized by marked heterogeneity, but with a significant genetic contribution. Identifying exact causative genes has been challenging, with many discoveries not replicated. It is timely to take stock of the field, outlining the progress made, framing the controversies and anticipating future directions in elucidating the genetics of POI.A search for original articles published up to May 2015 was performed using PubMed and Google Scholar, identifying studies on the genetic etiology of POI. Studies were included if chromosomal analysis, candidate gene screening and a genome-wide study were conducted. Articles identified were restricted to English language full-text papers.Chromosomal abnormalities have long been recognized as a frequent cause of POI, with a currently estimated prevalence of 10-13%. Using the traditional karyotype methodology, monosomy X, mosaicism, X chromosome deletions and rearrangements, X-autosome translocations, and isochromosomes have been detected. Based on candidate gene studies, single gene perturbations unequivocally having a deleterious effect in at least one population include Bone morphogenetic protein 15 (BMP15), Progesterone receptor membrane component 1 (PGRMC1), and Fragile X mental retardation 1 (FMR1) premutation on the X chromosome; Growth differentiation factor 9 (GDF9), Folliculogenesis specific bHLH transcription factor (FIGLA), Newborn ovary homeobox gene (NOBOX), Nuclear receptor subfamily 5, group A, member 1 (NR5A1) and Nanos homolog 3 (NANOS3) seem likely as well, but mostly being found in no more than 1-2% of a single population studied. Whole genome approaches have utilized genome-wide association studies (GWAS) to reveal loci not predicted on the basis of a candidate gene, but it remains difficult to locate causative genes and susceptible loci were not always replicated. Cytogenomic methods (array CGH) have identified other regions of interest but studies have not shown consistent results, the resolution of arrays has varied and replication is uncommon. Whole-exome sequencing in non-syndromic POI kindreds has only recently begun, revealing mutations in the Stromal antigen 3 (STAG3), Synaptonemal complex central element 1 (SYCE1), minichromosome maintenance complex component 8 and 9 (MCM8, MCM9) and ATP-dependent DNA helicase homolog (HFM1) genes. Given the slow progress in candidate-gene analysis and relatively small sample sizes available for GWAS, family-based whole exome and whole genome sequencing appear to be the most promising approaches for detecting potential genes responsible for POI.Taken together, the cytogenetic, cytogenomic (array CGH) and exome sequencing approaches have revealed a genetic causation in ?20-25% of POI cases. Uncovering the remainder of the causative genes will be facilitated not only by whole genome approaches involving larger cohorts in multiple populations but also incorporating environmental exposures and exploring signaling pathways in intragenic and intergenic regions that point to perturbations in regulatory genes and networks.

Project description:BackgroundPremature ovarian insufficiency (POI) is a severe disorder of female infertility, characterized by 4-6 months of amenorrhea before the age of 40 years, with elevated follicle stimulating hormone (FSH) levels (> 25 IU/L). Although several genes have been reported to contribute to the genetic basis of POI, the molecular mechanism of POI remains unclear.MethodsWhole-exome sequencing (WES) was performed. Sanger sequencing was carried out to validate the variant in the proband and her mother. In silico algorithms were used to analyze the mutational effect of the variant. Protein 3D structural modeling was used for predicting mutated protein structures. Vector construction and plasmids transfection were performed, and subsequently RNA-sequencing (RNA-seq) was carried out in each group to dissect the differentially expressed genes in wild-type (WT) and D1853H NOTCH2 mutant expressing groups. Gene Ontology analysis was also used to analyze the enriched biological processes or pathways among the differentially expressed genes.ResultsWe report two non-syndromic POI patients from a Chinese pedigree. The FSH level of the proband (the daughter) was 46 IU/L at the age of 22. Her menarche was at the age of 12, but she was amenorrhea at the age of 20. By WES, a rare heterozygous variant (c.5557G > C;p.D1853H) in the NOTCH2 gene was identified. In silico analysis suggested that p.D1853H was a pathogenic allele. Protein 3D structural modeling suggested that D1853H may enhance or weaken the electrostatic surface potential. By molecular analysis, we found that cells expressing the D1853H NOTCH2 mutant had similar effect in activating the NOTCH signaling pathway downstream target genes. However, 106 protein-coding genes were differentially expressed between D1853H expressing cells and WT NOTCH2 expressing cells, and these genes were enriched for collagen degradation, NCAM1 interactions and HDACs deacetylate histones, revealing a unknown underlying mechanism of the pathology that leads to POI.ConclusionsWe conclude that the rare heterozygous variant in NOTCH2 may be associated with POI. This finding provides researchers and clinicians with a better understanding of the etiology, molecular mechanism and genetic consulting of POI.

Dataset Information

The Genetics of Non-Syndromic Primary Ovarian Insufficiency: A Systematic Review.

Publications

The Genetics of Non-Syndromic Primary Ovarian Insufficiency: A Systematic Review.

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