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在初级卵巢缺陷病例中重新分类NOBOX变异,使用纠正的基因模型和新的定量框架

Reiner A Veitia^1,2,3, Jamie D Cowles¹, Sandrine Caburet¹

¹Department of Life Sciences, Université Paris Cité, CNRS, Institut Jacques Monod, CNRS UMR7592, Paris, France.

Human reproduction (Oxford, England)

|April 17, 2025

概括

这项研究使用更新的基因组和转录组数据纠正了NOBOX基因模型,改善了初级卵巢缺陷 (POI) 病例中变异的评估. 修订后的模型重新分类了变体,确定了双的NOBOX变体作为POI的可能原因.

科学领域:

遗传学和基因组学遗传学和基因组学
生殖生物学生殖生物学
分子生物学分子生物学

背景情况:

NOBOX基因对于早期的卵泡发育至关重要,也是原发性卵巢缺陷 (POI) 的主要原因.
之前的变种评估使用了过时的正典转录模型.
功能性研究是基于可能不正确的蛋白质序列.

研究的目的:

通过更新的表达和基因组数据来完善和纠正人类NOBOX基因模型.
重新评估POI患者之前报告的NOBOX变异的致病性.
在遗传性疾病中建立一个准确的变异分类框架.

主要方法:

来自人类和16种哺乳动物的综合基因组和RNAseq数据.
分析了从胎儿卵巢和成人丸中获取的链特异性RNAseq数据.
使用GnomAD4变体频率和POI调整参数 (ACMG/AMP指南) 开发了一个定量框架.

主要成果:

经过纠正的NOBOX基因模型使两个之前的转录无效,包括正规的转录.
在胎儿卵巢中确定了两个正确的异构体,在成年丸中确定了一个.
重新分类了44种POI变种,仅剩下14种可能是致病的;建议双基NOBOX变种作为POI的可能原因.

结论:

修正后的NOBOX基因模型增强了POI中变异性病原性的评估.
对于过时的变种,建议重新分析患者数据并重新考虑功能研究.
量化框架可以应用于其他POI基因和遗传性疾病.

关键词:

没有盒子 NOBOX.在ACMG/AMP指南中.临床解释临床解释女性不孕症女性不孕症卵巢卵巢是一个卵巢.过早的卵巢衰竭可能是早产卵巢衰竭.过早的卵巢功能不充分.原发性卵巢功能不充分症.变种分类的变种分类.变体的病原性变体的病原性.

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