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

2021 ◽  
Author(s):  
Bushra Gorsi ◽  
Edgar Javier Hernandez ◽  
Barry Moore ◽  
Mika Moriwaki ◽  
Clement Chow ◽  
...  
Keyword(s):  
Bayes Factor ◽  
Primary Ovarian Insufficiency ◽  
Whole Genome Sequencing Data ◽  
Gene Variants ◽  
Sequencing Data ◽  
Scoring Method ◽  
Ovarian Insufficiency ◽  
Dna Damage And Repair ◽  
Pathogenic Variants ◽  
Deleterious Alleles

A genetic etiology accounts for unexplained primary ovarian insufficiency (POI; amenorrhea with an elevated FSH level). Subjects with POI (n=291) and controls recruited for health in old age or 1000 Genomes (n=233) underwent whole exome or whole genome sequencing. Data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. 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). Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.

Demographic characteristics and therapeutical management in patients with primary ovarian insufficiency

2014 ◽  
Author(s):  
Mariana Tome ◽  
Pinillos Guillermo Martinez De ◽  
Mariola Mendez ◽  
Quiros Juan Manuel Garcia De ◽  
Jose Ignacio Fernandez Pena ◽  
...  
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Demographic Characteristics ◽  
Ovarian Insufficiency

scholarly journals Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Mendy M Welsink-Karssies ◽  
Sacha Ferdinandusse ◽  
Gert J Geurtsen ◽  
Carla E M Hollak ◽  
Hidde H Huidekoper ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Newborn Screening ◽  
Clinical Outcomes ◽  
Movement Disorders ◽  
Brain Mri ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Classical Galactosemia ◽  
Intellectual Outcome

Abstract Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI’s demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.

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