scholarly journals A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1709
Author(s):  
Simona Mellone ◽  
Marco Zavattaro ◽  
Denise Vurchio ◽  
Sara Ronzani ◽  
Marina Caputo ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Specific Protein ◽  
Primary Ovarian Insufficiency ◽  
Snp Analysis ◽  
Hypergonadotropic Hypogonadism ◽  
Degree Relative ◽  
Ovarian Insufficiency ◽  
Gene Encoding ◽  
Primary Amenorrhoea ◽  
Pathogenic Variants

Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years of age. Most cases are apparently sporadic, but about 10–15% have an affected first-degree relative, indicating a genetic etiology. Pathogenic variations in genes involved in development, meiosis and hormonal signaling have been detected in the hereditary form of the disorder. However, most cases of POI remain unsolved even after exhaustive investigation. A 19-year-old Senegalese female affected by non-syndromic POI presented with primary amenorrhoea and answered well to the hormonal induction of puberty. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) was identified on chromosome 7q21.13-q22.1 where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in STAG3. Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as the cause of POI in only eight families and recently as the cause of infertility in a male. The here-identified mutation leads to the truncation of the last 55 amino acids, confirming the important role in meiosis of the STAG3 C-terminal domain.

scholarly journals A Long contiguous stretches of homozygosity disclosed a novel biallelic pathogenic variant in STAG3 causing Primary Ovarian Insufficiency

2021 ◽  
Author(s):  
Simona Mellone ◽  
Marco Zavattaro ◽  
Denise Vurchio ◽  
Sara Ronzani ◽  
Marina Caputo ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Specific Protein ◽  
Primary Ovarian Insufficiency ◽  
Snp Analysis ◽  
Loss Of Function ◽  
Degree Relative ◽  
Genetic Etiology ◽  
Ovarian Insufficiency ◽  
Pathogenic Variants ◽  
Germ Cell Differentiation

Abstract Background: Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years. Most cases of isolated POI still appear sporadically, but ∼10–15% have an affected first-degree relative, indicating a significant genetic etiology. Several genes implicated in development, meiosis, hormonal signaling and metabolism are involved in the genetic form of the disorder in both syndromic and isolated POI. However, most cases of POI remain unsolved even after exhaustive investigation. Results: Here is reported a 19-year-old Senegalese female affected by non-syndromic POI showing primary amenorrhoea, who well answered to the hormonal induction of puberty reaching a complete sexual maturation in two years. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) region on chromosome 7q21.13-q22.1 was identified where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in STAG3 . Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as cause POI in only seven families and recently as cause of infertility in a male. The here identified mutation leads to the truncation of the last 55 aminoacids, confirming the important role in meiosis of the STAG3 C-terminal domain. Conclusions: In conclusion we identified a loss of function variant in STAG3 in a Senegalese woman with POI reinforcing the role the cohesin complex in the genetic etiology of this disorder. This gene should be included in the screening of POI to offer a better genetic counseling and long term follow-up considering the risk of ovarian tumor in woman carrying pathogenic variants in genes involved in germ cell differentiation.

scholarly journals Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency

2016 ◽  
Vol 101 (12) ◽  
pp. 4541-4550 ◽  
Author(s):  
Justine Bouilly ◽  
Isabelle Beau ◽  
Sara Barraud ◽  
Valérie Bernard ◽  
Kemal Azibi ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Gene Mutations ◽  
Primary Ovarian Insufficiency ◽  
Potential Candidate ◽  
Missense Mutations ◽  
Ovarian Insufficiency ◽  
Monogenic Disorder ◽  
Gene Encoding ◽  
Multiple Loci

Context: Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility. POI affects 1% of women before age 40 years, and several genetic causes have been reported. To date, POI has been considered a monogenic disorder. Objective: The aim of this study was to identify novel gene variations and to investigate if individuals with POI harbor mutation in multiple loci. Patients and Methods: One hundred well-phenotyped POI patients were systematically screened for variants in 19 known POI loci (and potential candidate genes) using next-generation sequencing. Results: At least one rare protein-altering gene variant was identified in 19 patients, including missense mutations in new candidate genes, namely SMC1β and REC8 (involved in the cohesin complex) and LHX8, a gene encoding a transcription factor. Novel or recurrent deleterious mutations were also detected in the known POI candidate genes NOBOX, FOXL2, SOHLH1, FIGLA, GDF9, BMP15, and GALT. Seven patients harbor mutations in two loci, and this digenicity seems to influence the age of symptom onset. Conclusions: Genetic anomalies in women with POI are more frequent than previously believed. Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic effect of several mutations may underlie the POI phenotype.

scholarly journals Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency

2021 ◽  
Author(s):  
Leyla Akin ◽  
Karine Rizzoti ◽  
Louise C. Gregory ◽  
Beatriz Corredor ◽  
Polona Le Quesne Stabej ◽  
...  
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Pathogenic Variants

scholarly journals Causal and Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency

2021 ◽  
Author(s):  
Bushra Gorsi ◽  
Edgar Hernandez ◽  
Marvin Barry Moore ◽  
Mika Moriwaki ◽  
Clement Y Chow ◽  
...  
Keyword(s):  
Bayes Factor ◽  
Rare Variants ◽  
Primary Ovarian Insufficiency ◽  
Gene Variants ◽  
Scoring Method ◽  
Ovarian Insufficiency ◽  
Dna Damage And Repair ◽  
Total N ◽  
Pathogenic Variants ◽  
Gene Sets

Abstract Context A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). Objective We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. Design The study was an observational study. Setting Subjects were recruited at academic institutions. Patients Subjects from Boston (n=98), the NIH and Washington University (n=98), Pittsburgh (n=20), Italy (n=43) and France (n=32) were diagnosed with POI (amenorrhea with an elevated FSH level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n=233). Intervention We performed whole exome sequencing (WES) and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. Main Outcome Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. Results Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1 and BOD1L1). Conclusions Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.

scholarly journals Women with spontaneous 46,XX primary ovarian insufficiency (hypergonadotropic hypogonadism) have lower perceived social support than control women

2009 ◽  
Vol 92 (2) ◽  
pp. 688-693 ◽  
Author(s):  
Susan A. Orshan ◽  
June L. Ventura ◽  
Sharon N. Covington ◽  
Vien H. Vanderhoof ◽  
James F. Troendle ◽  
...  
Keyword(s):  
Social Support ◽  
Perceived Social Support ◽  
Primary Ovarian Insufficiency ◽  
Hypergonadotropic Hypogonadism ◽  
Ovarian Insufficiency

A Novel Phenotype Combining Primary Ovarian Insufficiency Growth Retardation and Pilomatricomas With MCM8 Mutation

2020 ◽  
Vol 105 (6) ◽  
pp. 1973-1982 ◽  
Author(s):  
Abdelkader Heddar ◽  
Dominique Beckers ◽  
Baptiste Fouquet ◽  
Dominique Roland ◽  
Micheline Misrahi
Keyword(s):  
Growth Retardation ◽  
Genetic Defect ◽  
Postnatal Growth ◽  
Primary Ovarian Insufficiency ◽  
Primary Amenorrhea ◽  
Dna Breaks ◽  
Ovarian Insufficiency ◽  
Messenger Ribonucleic Acid ◽  
Adverse Health Outcomes ◽  
Chromosomal Breaks

Abstract Context Primary Ovarian insufficiency (POI) affects 1% of women aged <40 years and leads most often to definitive infertility with adverse health outcomes. Very recently, genes involved in deoxyribonucleic acid (DNA) repair have been shown to cause POI. Objective To identify the cause of a familial POI in a consanguineous Turkish family. Design Exome sequencing was performed in the proposita and her mother. Chromosomal breaks were studied in lymphoblastoid cell lines treated with mitomycin (MMC). Setting and patients The proposita presented intrauterine and postnatal growth retardation, multiple pilomatricomas in childhood, and primary amenorrhea. She was treated with growth hormone (GH) from age 14 to 18 years. Results We identified a novel nonsense variant in exon 9 of the minichromosome maintenance complex component 8 gene (MCM8) NM_001281522.1: c0.925C > T/p.R309* yielding either a truncated protein or nonsense-mediated messenger ribonucleic acid decay. The variant was homozygous in the daughter and heterozygous in the mother. MMC induced DNA breaks and aberrant metaphases in the patient’s lymphoblastoid cells. The mother’s cells had intermediate but significantly higher chromosomal breaks compared with a control. Conclusion We describe a novel phenotype of syndromic POI related to a novel truncating MCM8 variant. We show for the first time that spontaneous tumors (pilomatricomas) are associated with an MCM8 genetic defect, making the screening of this gene necessary before starting GH therapy in patients with POI with short stature, especially in a familial or consanguineous context. Appropriate familial monitoring in the long term is necessary, and fertility preservation should be considered in heterozygous siblings to avoid rapid follicular atresia.

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