Pervin Hasna Hena, Mim Rabeya Akter, Ganguly Athoi, Kazal Rezaul Karim, Gutgutia Rohit, Eshaque Tamannyat Binte, Omar Farjana Binta, Rahaman Md Atikur, Hasan Md Nahid, Islam Amirul, Nassir Nasna, Hossain Mohammad Shahnoor, Akter Hosneara, Uddin Mohammed
Department of Obstetrics & Gynaecology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, Dhaka, Bangladesh.
Clin Chim Acta. 2025 Aug 15;576:120423. doi: 10.1016/j.cca.2025.120423. Epub 2025 Jun 10.
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.
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.
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.
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.
原发性卵巢功能不全（POI）是女性不孕的一个重要原因，涉及40岁之前的卵巢功能过早衰退，受遗传易感性、自身免疫性疾病、环境因素和代谢变化影响。在本研究中，我们采用全外显子组测序（WES）来探索孟加拉国女性中与POI相关的基因变异。
本研究纳入了30名年龄在16至40岁之间被诊断为POI的孟加拉国女性。诊断基于临床标准，包括促卵泡生成素水平升高以及至少四个月的月经过少或闭经病史。对POI病例进行了WES，并使用特定人群的内部队列来筛选和鉴定影响卵巢功能的基因。随后，使用桑格测序法验证致病或可能致病的变异。
我们在所有POI病例的23%（7/30）中检测到七个致病变异，分布在六个基因中：甲状腺球蛋白（TG）、促甲状腺激素受体（TSHR）、微管蛋白β8类八（TUBB8）、PR/SET结构域9（PRDM9）、减数分裂核分裂1同源物（RMND1）和含OB折叠的同源重组因子（HROB）。鉴定出两个新的可能致病变异，包括TG中的一个杂合移码变异（p.H209Pfs11）和TSHR中的一个杂合错义变异（p.T1904C）。此外，在63%（19/30）的病例中发现了意义未明的变异，其中七个是新的。在几个基因中观察到致病变异的偶发发现，血红蛋白亚基β（HBB）最为常见。
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，表明将基因筛查纳入常规临床实践可以改善诊断和治疗策略，特别是在缺乏关于这种情况的基因组数据的地区。
