Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Medicine, Haukeland University Hospital, Bergen, Norway.
Hum Reprod. 2024 Jan 5;39(1):177-189. doi: 10.1093/humrep/dead233.
Is it possible to find the cause of primary ovarian insufficiency (POI) in more women by extensive screening?
Adding next generation sequencing techniques including a POI-associated gene panel, extended whole exome sequencing data, as well as specific autoantibody assays to the recommended diagnostic investigations increased the determination of a potential etiological diagnosis of POI from 11% to 41%.
POI affects ∼1% of women. Clinical presentations and pathogenic mechanisms are heterogeneous and include genetic, autoimmune, and environmental factors, but the underlying etiology remains unknown in the majority of cases.
STUDY DESIGN, SIZE, DURATION: Prospective cross-sectional study of 100 women with newly diagnosed POI of unknown cause consecutively referred to Haukeland University Hospital, Bergen, Norway, January 2019 to December 2021.
PARTICIPANTS/MATERIALS, SETTING, METHODS: In addition to standard recommended diagnostic investigations including screening for chromosomal anomalies and premutations in the fragile X mental retardation 1 gene (FMR1) we used whole exome sequencing, including targeted analysis of 103 ovarian-related genes, and assays of autoantibodies against steroid cell antigens.
We identified chromosomal aberrations in 8%, FMR1 premutations in 3%, genetic variants related to POI in 16%, and autoimmune POI in 3%. Furthermore in 11% we identified POI associated genetic Variants of unknown signifcance (VUS). A homozygous pathogenic variant in the ZSWIM7 gene (NM_001042697.2) was found in two women, corroborating this as a novel cause of monogenic POI. No associations between phenotypes and genotypes were found.
LIMITATIONS, REASONS FOR CAUTION: Use of candidate genetic and autoimmune markers limit the possibility to discover new markers. To further investigate the genetic variants, family studies would have been useful. We found a relatively high proportion of genetic variants in women from Africa and lack of genetic diversity in the genomic databases can impact diagnostic accuracy.
Since no specific clinical or biochemical markers predicted the underlying cause of POI discussion of which tests should be part of diagnostic screening in clinical practice remains open. New technology has altered the availability and effectiveness of genetic testing, and cost-effectiveness analyses are required to aid sustainable diagnostics.
STUDY FUNDING/COMPETING INTEREST(S): The study was supported by grants and fellowships from Stiftelsen Kristian Gerhard Jebsen, the Novonordisk Foundation, the Norwegian Research Council, University of Bergen, and the Regional Health Authorities of Western Norway. The authors declare no conflict of interest.
NCT04082169.
通过广泛的筛查，是否可以在更多女性中找到原发性卵巢功能不全（POI）的病因？
在推荐的诊断性检查中增加下一代测序技术，包括与 POI 相关的基因panel、扩展的全外显子测序数据以及特定的自身抗体检测，将 POI 潜在病因的确定率从 11%提高到 41%。
POI 影响约 1%的女性。临床表现和发病机制具有异质性，包括遗传、自身免疫和环境因素，但大多数情况下，其潜在病因仍未知。
研究设计、规模、持续时间：2019 年 1 月至 2021 年 12 月，对挪威卑尔根 Haukeland 大学医院连续收治的 100 名新诊断为不明原因 POI 的女性进行了前瞻性横断面研究。
参与者/材料、地点、方法：除了标准的推荐诊断性检查，包括染色体异常筛查和脆性 X 智力低下 1 基因（FMR1）前突变筛查外，我们还使用了全外显子测序，包括对 103 个卵巢相关基因的靶向分析和类固醇细胞抗原自身抗体检测。
我们发现 8%的患者存在染色体异常，3%的患者存在 FMR1 前突变，16%的患者存在与 POI 相关的遗传变异，3%的患者存在自身免疫性 POI。此外，我们还发现了 11%的 POI 相关遗传变异不明（VUS）。在两名女性中发现了 ZSWIM7 基因（NM_001042697.2）的纯合致病性变异，证实这是一种新的单基因 POI 病因。未发现表型与基因型之间存在关联。
局限性、谨慎的原因：候选遗传和自身免疫标志物的使用限制了发现新标志物的可能性。为了进一步研究遗传变异，家族研究将是有用的。我们发现来自非洲的女性中存在相对较高比例的遗传变异，而基因组数据库中缺乏遗传多样性可能会影响诊断的准确性。
由于没有特定的临床或生化标志物可以预测 POI 的潜在病因，因此在临床实践中，讨论哪些检查应该作为诊断性筛查的一部分仍然存在争议。新技术改变了基因检测的可用性和有效性，需要进行成本效益分析，以帮助实现可持续的诊断。
研究资助/利益冲突：该研究得到了 Kristian Gerhard Jebsen 基金会、诺和诺德基金会、挪威研究理事会、卑尔根大学和挪威西部区域卫生当局的资助和奖学金的支持。作者声明没有利益冲突。
NCT04082169。
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