Genetic landscape of primary ovarian insufficiency in Bangladeshi women through whole exome sequencing

IF 3.2 3区医学 Q2 MEDICAL LABORATORY TECHNOLOGY

Clinica Chimica Acta Pub Date : 2025-06-10 DOI:10.1016/j.cca.2025.120423

Hasna Hena Pervin , Rabeya Akter Mim , Athoi Ganguly , Rezaul Karim Kazal , Rohit Gutgutia , Tamannyat Binte Eshaque , Farjana Binta Omar , Md.Atikur Rahaman , Md.Nahid Hasan , Amirul Islam , Nasna Nassir , Mohammad Shahnoor Hossain , Hosneara Akter , Mohammed Uddin

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引用次数: 0

Abstract

Background

Primary Ovarian Insufficiency (POI), a significant cause of female infertility, involves premature ovarian dysfunction before the age of 40 and is influenced by genetic predispositions, autoimmune disorders, environmental factors, and metabolic changes. In this study, we employed Whole Exome Sequencing (WES) to explore genetic variations linked to POI in Bangladeshi women.

Materials and methods

This study encompassed 30 Bangladeshi women aged 16 to 40 diagnosed with POI. The diagnosis was based on clinical criteria, including elevated Follicle-Stimulating Hormone levels and a history of at least four months of oligomenorrhea or amenorrhea. WES was performed on POI cases and used population specific internal cohort to filter out and identify genes impacting ovarian function. Subsequently, Sanger Sequencing was used to validate pathogenic or likely pathogenic variants.

Results

We detected seven pathogenic variants in 23% of all POI cases (7/30) across six genes: Thyroglobulin (TG), Thyroid-Stimulating Hormone Receptor (TSHR), tubulin beta 8 class viii (TUBB8), PR/SET domain 9 (PRDM9), required for meiotic nuclear division 1 homolog (RMND1), and homologous recombination factor with OB-fold (HROB). Two novel likely pathogenic variants were identified, including a heterozygous frameshift variant in TG (p.H209Pfs11) and a heterozygous missense variant in TSHR (p.T1904C). Additionally, variants of uncertain significance were found in 63% (19/30) of the cases, with seven being novel. Incidental findings of pathogenic variants were observed in several genes, with Hemoglobin subunit Beta (HBB) being the most common.

Conclusions

This study highlights the utility of whole exome sequencing in identifying genetic risk factors for POI, suggesting that incorporating genetic screening into routine clinical practice could improve diagnostic and therapeutic strategies, particularly in regions lacking genomic data on this condition.

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通过全外显子组测序研究孟加拉国妇女原发性卵巢功能不全的遗传景观

原发性卵巢功能不全（POI）是女性不孕症的重要原因，涉及40岁前卵巢早衰，受遗传易感性、自身免疫性疾病、环境因素和代谢变化的影响。在这项研究中，我们使用全外显子组测序（WES）来探索与孟加拉国妇女POI相关的遗传变异。材料和方法本研究包括30名年龄在16至40岁之间被诊断为POI的孟加拉国妇女。诊断基于临床标准，包括促卵泡激素水平升高和至少四个月的少经或闭经史。对POI病例进行WES，并使用群体特异性内部队列筛选和鉴定影响卵巢功能的基因。随后，Sanger测序被用于验证致病或可能致病的变异。结果在23%（7/30）的POI病例中检测到7种致病变异，涉及6个基因：甲状腺球蛋白（TG）、促甲状腺激素受体（TSHR）、微管蛋白β 8 viii类（TUBB8）、PR/SET结构域9 （PRDM9）、减数分裂核分裂1同源物（RMND1）和同源OB-fold重组因子（HROB）。发现了两种新的可能的致病变异，包括TG的杂合移码变异（p.H209Pfs11）和TSHR的杂合错链变异（p.T1904C）。此外，在63%（19/30）的病例中发现了不确定意义的变异，其中7个是新发现的。在几个基因中观察到偶然发现的致病变异，血红蛋白亚单位β (HBB)是最常见的。本研究强调了全外显子组测序在识别POI遗传危险因素方面的作用，表明将遗传筛查纳入常规临床实践可以改善诊断和治疗策略，特别是在缺乏这种疾病基因组数据的地区。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinica Chimica Acta 医学-医学实验技术

CiteScore

10.10

自引率

2.00%

发文量

1268

审稿时长

23 days

期刊介绍： The Official Journal of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Clinica Chimica Acta is a high-quality journal which publishes original Research Communications in the field of clinical chemistry and laboratory medicine, defined as the diagnostic application of chemistry, biochemistry, immunochemistry, biochemical aspects of hematology, toxicology, and molecular biology to the study of human disease in body fluids and cells. The objective of the journal is to publish novel information leading to a better understanding of biological mechanisms of human diseases, their prevention, diagnosis, and patient management. Reports of an applied clinical character are also welcome. Papers concerned with normal metabolic processes or with constituents of normal cells or body fluids, such as reports of experimental or clinical studies in animals, are only considered when they are clearly and directly relevant to human disease. Evaluation of commercial products have a low priority for publication, unless they are novel or represent a technological breakthrough. Studies dealing with effects of drugs and natural products and studies dealing with the redox status in various diseases are not within the journal''s scope. Development and evaluation of novel analytical methodologies where applicable to diagnostic clinical chemistry and laboratory medicine, including point-of-care testing, and topics on laboratory management and informatics will also be considered. Studies focused on emerging diagnostic technologies and (big) data analysis procedures including digitalization, mobile Health, and artificial Intelligence applied to Laboratory Medicine are also of interest.