Dataset Information

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

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 National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone 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.

SUBMITTER: Gorsi B

PROVIDER: S-EPMC9006976 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Gorsi Bushra B Hernandez Edgar E Moore Marvin Barry MB Moriwaki Mika M Chow Clement Y CY Coelho Emily E Taylor Elaine E Lu Claire C Walker Amanda A Touraine Philippe P Nelson Lawrence M LM Cooper Amber R AR Mardis Elaine R ER Rajkovic Aleksander A Yandell Mark M Welt Corrine K CK

The Journal of clinical endocrinology and metabolism 20220201 3

<h4>Context</h4>A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI).<h4>Objective</h4>We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI.<h4>Design</h4>The study was an observational study.<h4>Setting</h4>Subjects were recruited at academic institutions.<h4>Patients</h4>Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), ...[more]

PMID: 34718612

Similar Datasets

Project description:Study questionWhat is the prevalence of somatic chromosomal instability among women with idiopathic primary ovarian insufficiency (POI)?Summary answerA subset of women with idiopathic POI may have functional impairment in DNA repair leading to chromosomal instability in their soma.What is known alreadyThe formation and repair of DNA double-strand breaks during meiotic recombination are fundamental processes of gametogenesis. Oocytes with compromised DNA integrity are susceptible to apoptosis which could trigger premature ovarian aging and accelerated wastage of the human follicle reserve. Genomewide association studies, as well as whole exome sequencing, have implicated multiple genes involved in DNA damage repair. However, the prevalence of defective DNA damage repair in the soma of women with POI is unknown.Study design, size, durationIn total, 46 women with POI and 15 family members were evaluated for excessive mitomycin-C (MMC)-induced chromosome breakage. Healthy fertile females (n = 20) and two lymphoblastoid cell lines served as negative and as positive controls, respectively.Participants/materials, setting, methodsWe performed a pilot functional study utilizing MMC to assess chromosomal instability in the peripheral blood of participants. A high-resolution array comparative genomic hybridization (aCGH) was performed on 16 POI patients to identify copy number variations (CNVs) for a set of 341 targeted genes implicated in DNA repair.Main results and the role of chanceArray CGH revealed three POI patients (3/16, 18.8%) with pathogenic CNVs. Excessive chromosomal breakage suggestive of a constitutional deficiency in DNA repair was detected in one POI patient with the 16p12.3 duplication. In two patients with negative chromosome breakage analysis, aCGH detected a Xq28 deletion comprising the Centrin EF-hand Protein 2 (CETN2) and HAUS Augmin Like Complex Subunit 7 (HAUS7) genes essential for meiotic DNA repair, and a duplication in the 3p22.2 region comprising a part of the ATPase domain of the MutL Homolog 1 (MLH1) gene.Limitations reasons for cautionPeripheral lymphocytes, used as a surrogate tissue to quantify induced chromosome damage, may not be representative of all the affected tissues. Another limitation pertains to the MMC assay which detects homologous repair pathway defects and does not test deficiencies in other DNA repair pathways.Wider implications of the findingsOur results provide evidence for functional impairment of DNA repair in idiopathic POI, which may predispose the patients to other DNA repair-related conditions such as accelerated aging and/or cancer susceptibility.Study funding/competing interest(s)Funding was provided by the National Institute of Child Health and Human Development. There were no competing interests to declare.

Dataset Information

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

Context

Objective

Design

Setting

Patients

Intervention

Main outcome

Results

Conclusions

Publications

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

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