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 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.

scholarly journals OR31-06 Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Bushra Gorsi ◽  
Mika Moriwaki ◽  
Marvin B Moore ◽  
Aleksandar Rajkovic ◽  
Lawrence M Nelson ◽  
...  
Keyword(s):  
Functional Model ◽  
Primary Ovarian Insufficiency ◽  
Composite Likelihood ◽  
Large Cohort ◽  
Gene Variants ◽  
Loss Of Function ◽  
Test Statistic ◽  
Ovarian Insufficiency ◽  
Total N

Abstract Primary ovarian insufficiency (POI) is highly heritable. The majority of cases have no known cause. We hypothesized that mutations in previously identified genes or genes from the same pathways are the cause of POI in a recessive or dominant manner. Subjects included 294 women diagnosed with POI (amenorrhea with an elevated FSH level). All had a 46XX karyotype, and normal FMR1 repeat number. Subjects were recruited in Boston (n=95), at the NIH and Washington University (n=98), and in Pittsburgh (n=98). Controls included subjects recruited for health in old age and disorders unrelated to reproduction or cancer, and subjects from the 1000 Genomes Project (total n=587). Variants were called using the Sentieon software package (https://www.sentieon.com). Case and control samples were stratified on ethnicity, relatedness and heterozygosity. Peddy and XPAT were used to calculate quality control metrics to detect outlier samples for removal from analysis to create a homogenous dataset. The number of cases (227) and controls (458) was adjusted for downstream analysis. XPAT imposed additional quality filters and removed variants. A second filter removed variants that did not pass a Gnomad filter of <0.001 allele frequency. VAAST was used to determine a composite likelihood ratio (CLR) as the test statistic to represent the aggregate burden of variants of affected individuals in each transcript relative to a set of 458 control genomes. The significance of each transcript’s VAAST CLR score was evaluated by 1 million permutations. We screened exomes for variants in previously identified genes causing POI in humans and those demonstrating infertility in a male or female mouse model. We also used the American College of Medical Genetics and Genomics standards for interpretation of pathogenicity of a variant, with priority on null variants in genes with probability of loss of function intolerance based on the observed vs. expected rate in gnomAD, in vivo or in vitro functional evidence of a damaging effect, significantly increased prevalence compared to controls, i.e. not found in any controls or in fewer than 10 in the gnomAD database if the subject had a matching race/ethnicity. Thirty-four subjects were removed for poor quality exomes and relatedness. Fifty-three subjects had at least one variant in a previously identified POI gene or one in which there was a previously identified functional model. Two subjects carried recessive variants and 30 carried at least one novel heterozygous candidate variant for follow up. Analysis of genetic causes of POI in this large cohort identified candidate causal gene variants in over half of the subjects. The data demonstrate that the genetic architecture is heterogeneous. Although recessive mutations have been identified in consanguineous families, the data suggest that a dominant or oligogenic pattern of inheritance may be important.

scholarly journals New NOBOX Mutations Identified in a Large Cohort of Women With Primary Ovarian Insufficiency Decrease KIT-L Expression

2015 ◽  
Vol 100 (3) ◽  
pp. 994-1001 ◽  
Author(s):  
Justine Bouilly ◽  
Florence Roucher-Boulez ◽  
Anne Gompel ◽  
Hélène Bry-Gauillard ◽  
Kemal Azibi ◽  
...  
Keyword(s):  
Protein Function ◽  
Target Gene ◽  
Rare Variants ◽  
Primary Ovarian Insufficiency ◽  
Large Cohort ◽  
Luciferase Reporter ◽  
Ovarian Insufficiency ◽  
High Prevalence ◽  
Reporter Assays ◽  
Novel Target

Context: Primary ovarian insufficiency (POI) is a major cause of anovulation and infertility in women. This disease affects 1% of women before 40 years, and several genetic causes have been reported. Objective: The aim of the study was to evaluate the prevalence of NOBOX mutations in a new large cohort of women with POI and to characterize these variants and identify a NOBOX novel target gene. Patients and Methods: A total of 213 unrelated patients with POI were screened for NOBOX mutations, and luciferase reporter assays were performed for the mutations identified. Results: We reported 3 novel and 2 recurrent heterozygous missense NOBOX rare variants found in 12 patients but not in 724 alleles from ethnic-matched individual women with occurrence of menopause at a normal age. Their functional impact had been tested on the classic growth differentiation factor-9 (GDF9) promoter and on KIT-L, a new NOBOX target gene. The p.Gly91Thr, p.Gly111Arg, p.Arg117Trp, p.Lys371Thr, and p.Pro619Leu mutations were deleterious for protein function. Conclusions: In our series, 5.6% of the patients with POI displayed heterozygous NOBOX mutations. We demonstrate that KIT-L could be now a direct NOBOX target. These findings replicate the high prevalence of the association between the NOBOX rare variants and POI.

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 Novel Ultra-Rare Exonic Variants Identified in a Founder Population Implicate Cadherins in Schizophrenia

2020 ◽  
Author(s):  
Todd Lencz ◽  
Jin Yu ◽  
Raiyan Rashid Khan ◽  
Shai Carmi ◽  
Max Lam ◽  
...  
Keyword(s):  
Rare Variant ◽  
Rare Variants ◽  
Gene List ◽  
Ashkenazi Jewish ◽  
Founder Population ◽  
Total N ◽  
Gene Set ◽  
Complex Disorders ◽  
Gene Sets ◽  
Common Genetic Variants

AbstractIMPORTANCESchizophrenia is a serious mental illness with high heritability. While common genetic variants account for a portion of the heritability, identification of rare variants associated with the disorder has proven challenging.OBJECTIVETo identify genes and gene sets associated with schizophrenia in a founder population (Ashkenazi Jewish), and to determine the relative power of this population for rare variant discovery.DESIGN, SETTING, AND PARTICIPANTSData on exonic variants were extracted from whole genome sequences drawn from 786 patients with schizophrenia and 463 healthy control subjects, all drawn from the Ashkenazi Jewish population. Variants observed in two large publicly available datasets (total n≈153,000, excluding neuropsychiatric patients) were filtered out, and novel ultra-rare variants (URVs) were compared in cases and controls.MAIN OUTCOMES AND MEASURESThe number of novel URVs and genes carrying them were compared across cases and controls. Genes in which only cases or only controls carried novel, functional URVs were examined using gene set analyses.RESULTSCases had a higher frequency of novel missense or loss of function (MisLoF) variants compared to controls, as well as a greater number of genes impacted by MisLoF variants. Characterizing 141 “case-only” genes (in which ≥ 3 AJ cases in our dataset had MisLoF URVs with none found in our AJ controls), we replicated prior findings of both enrichment for synaptic gene sets, as well as specific genes such as SETD1A and TRIO. Additionally, we identified cadherins as a novel gene set associated with schizophrenia including a recurrent mutation in PCDHA3. Several genes associated with autism and other neurodevelopmental disorders including CACNA1E, ASXL3, SETBP1, and WDFY3, were also identified in our case-only gene list, as was TSC2, which is linked to tuberous sclerosis. Modeling the effects of purifying selection demonstrated that deleterious rare variants are greatly over-represented in a founder population with a tight bottleneck and rapidly expanding census, resulting in enhanced power for rare variant association studies.CONCLUSIONS AND RELEVANCEIdentification of cell adhesion genes in the cadherin/protocadherin family is consistent with evidence from large-scale GWAS in schizophrenia, helps specify the synaptic abnormalities that may be central to the disorder, and suggests novel potential treatment strategies (e.g., inhibition of protein kinase C). Study of founder populations may serve as a cost-effective way to rapidly increase gene discovery in schizophrenia and other complex disorders.

NR5A1 (SF-1) gene variants in a group of 26 young women with XX primary ovarian insufficiency

2013 ◽  
Vol 99 (2) ◽  
pp. 484-489 ◽  
Author(s):  
Pascal Philibert ◽  
Françoise Paris ◽  
Besma Lakhal ◽  
Françoise Audran ◽  
Laura Gaspari ◽  
...  
Keyword(s):  
Young Women ◽  
Primary Ovarian Insufficiency ◽  
Gene Variants ◽  
Ovarian Insufficiency

scholarly journals Targeted whole exome sequencing and Drosophila modelling to unveil the molecular basis of primary ovarian insufficiency

2021 ◽  
Author(s):  
I Bestetti ◽  
C Barbieri ◽  
A Sironi ◽  
V Specchia ◽  
S A Yatsenko ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Rare Variants ◽  
Case Control ◽  
Ovarian Insufficiency ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Drosophila Model ◽  
Burden Test ◽  
Italian Cohort

Abstract STUDY QUESTION Can a targeted whole exome sequencing (WES) on a cohort of women showing a primary ovarian insufficiency (POI) phenotype at a young age, combined with a study of copy number variations, identify variants in candidate genes confirming their deleterious effect on ovarian function? SUMMARY ANSWER This integrated approach has proved effective in identifying novel candidate genes unveiling mechanisms involved in POI pathogenesis. WHAT IS KNOWN ALREADY POI, a condition occurring in 1% of women under 40 years of age, affects women’s fertility leading to a premature loss of ovarian reserve. The genetic causes of POI are highly heterogeneous and several determinants contributing to its prominent oligogenic inheritance pattern still need to be elucidated. STUDY DESIGN, SIZE, DURATION WES screening for pathogenic variants of 41 Italian women with non-syndromic primary and early secondary amenorrhoea occurring before age 25 was replicated on another 60 POI patients, including 35 French and 25 American women, to reveal statistically significant shared variants. PARTICIPANTS/MATERIALS, SETTING, METHODS The Italian POI patients’ DNA were processed by targeted WES including 542 RefSeq genes expressed or functioning during distinct reproductive or ovarian processes (e.g. DNA repair, meiosis, oocyte maturation, folliculogenesis and menopause). Extremely rare variants were filtered and selected by means of a Fisher Exact test using several publicly available datasets. A case-control Burden test was applied to highlight the most significant genes using two ad-hoc control female cohorts. To support the obtained data, the identified genes were screened on a novel cohort of 60 Caucasian POI patients and the same case-control analysis was carried out. Comparative analysis of the human identified genes was performed on mouse and Drosophila melanogaster by analysing the orthologous genes in their ovarian phenotype, and two of the selected genes were fruit fly modelled to explore their role in fertility. MAIN RESULTS AND THE ROLE OF CHANCE The filtering steps applied to search for extremely rare pathogenic variants in the Italian cohort revealed 64 validated single-nucleotide variants/Indels in 59 genes in 30 out of 41 screened women. Burden test analysis highlighted 13 ovarian genes as being the most enriched and significant. To validate these findings, filtering steps and Burden analysis on the second cohort of Caucasian patients yielded 11 significantly enriched genes. Among them, AFP, DMRT3, MOV10, FYN and MYC were significant in both patient cohorts and hence were considered strong candidates for POI. Mouse and Drosophila comparative analysis evaluated a conserved role through the evolution of several candidates, and functional studies using a Drosophila model, when applicable, supported the conserved role of the MOV10 armitage and DMRT3 dmrt93B orthologues in female fertility. LARGE SCALE DATA The datasets for the Italian cohort generated during the current study are publicly available at ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/): accession numbers SCV001364312 to SCV001364375. LIMITATIONS, REASONS FOR CAUTION This is a targeted WES analysis hunting variants in candidate genes previously identified by different genomic approaches. For most of the investigated sporadic cases, we could not track the parental inheritance, due to unavailability of the parents’ DNA samples; in addition, we might have overlooked additional rare variants in novel candidate POI genes extracted from the exome data. On the contrary, we might have considered some inherited variants whose clinical significance is uncertain and might not be causative for the patients’ phenotype. Additionally, as regards the Drosophila model, it will be extremely important in the future to have more mutants or RNAi strains available for each candidate gene in order to validate their role in POI pathogenesis. WIDER IMPLICATIONS OF THE FINDINGS The genomic, statistical, comparative and functional approaches integrated in our study convincingly support the extremely heterogeneous oligogenic nature of POI, and confirm the maintenance across the evolution of some key genes safeguarding fertility and successful reproduction. Two principal classes of genes were identified: (i) genes primarily involved in meiosis, namely in synaptonemal complex formation, asymmetric division and oocyte maturation and (ii) genes safeguarding cell maintenance (piRNA and DNA repair pathways). STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Italian Ministry of Health grants ‘Ricerca Corrente’ (08C621_2016 and 08C924_2019) provided to IRCCS Istituto Auxologico Italiano, and by ‘Piano Sostegno alla Ricerca’ (PSR2020_FINELLI_LINEA_B) provided by the University of Milan; M.P.B. was supported by Telethon-Italy (grant number GG14181). There are no conflicts of interest.

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.

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