Table 1_A systematic review and evidence assessment of monogenic gene-disease relationships in human male infertility.docx

BackgroundGenetic factors play a significant role in human male infertility, with about 4% of infertile men currently identified with genetic reasons, yet most (60–70%) still lack a definitive diagnosis and remain unexplained. Similar to other medical fields, the advent of next-generation sequencing (NGS) has resulted in the discovery of a growing array of genetic variations in infertility issues affecting both genders. With the rising count of newly discovered genes, precise diagnoses are now possible for cases of male infertility that were once considered idiopathic. Nonetheless, substantial proof supporting the gene-disease relationships (GDR) remains absent in numerous instances.
Objective and rationaleThe year 2019 and 2021 saw the release and revision of the standardized clinical validity evaluation for monogenic reasons behind male infertility. In this report, we offer an extensive review to methodically assess all existing data (spanning from 1 Jan, 2020, to 24 Sep, 2024) regarding the singular causes of either isolated or syndromic male infertility, hormonal imbalances, or reproductive irregularities in male reproductive organs.
Search methodThe PRISMA protocols were utilized to gather comprehensive data from PubMed and Web of Science regarding the genetics of human female infertility and disorders of sex development (DSD) resulting in infertility, spanning from 1 January 2020 to 24 September 2024. The pathologies examined encompass both isolated infertility and syndromic male infertility, along with disorders of the endocrine and reproductive systems. A standardized scoring system was used to evaluate whether pathogenic variations in a particular gene lead to a recognized phenotype. Each GDR received a conclusive rating, ranging from no evidence to definitive.
OutcomesOut of 19885 identified and screened publications, 229 were chosen for gene and variant analysis. Our research has pinpointed 191 genes and confirmed 191 GDRs, encompassing all documented single-gene reasons for male infertility and DSD. Additionally, our research pinpointed 100 genes with at least a moderate connection to male infertility or atypical genitourinary development traits. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of male infertility.
Systematic review registrationhttp://www.crd.york.ac.uk/PROSPERO, identifier CRD42024593082.

研究背景
遗传因素在人类男性不育中发挥关键作用：目前约4%的不育男性可明确归因于遗传病因，但仍有60%~70%的患者无法获得明确诊断，病因仍未阐明。与其他医学领域类似，下一代测序（next-generation sequencing, NGS）技术的问世，使得与男女不育相关的越来越多的遗传变异被发现。随着新发现基因数量的不断增加，既往被归类为特发性的男性不育病例现已可实现精准诊断。然而，在众多案例中，仍缺乏足够证据支持基因-疾病关联（gene-disease relationships, GDR）的存在。

研究目标与依据
2019年与2021年，针对男性不育单基因病因的标准化临床有效性评估方案先后发布与修订。本综述旨在系统评估2020年1月1日至2024年9月24日期间的所有现有数据，涵盖孤立性或综合征性男性不育、激素失衡或男性生殖器官发育异常的单一致病病因。

研究方法
本研究遵循PRISMA指南，从PubMed与Web of Science数据库中检索2020年1月1日至2024年9月24日期间的相关文献，涵盖人类女性不育遗传学及导致不育的性发育异常（disorders of sex development, DSD）相关研究。本次研究纳入的病理类型包括孤立性不育、综合征性男性不育，以及内分泌与生殖系统疾病。采用标准化评分体系评估特定基因的致病变异是否可导致公认的表型，对每一项基因-疾病关联均给出从“无证据”到“明确证据”的最终评级。

研究结果
在19885篇经筛选识别的文献中，最终纳入229篇用于基因与变异分析。本研究共明确191个基因，确认了191项基因-疾病关联，涵盖所有已报道的男性不育及性发育异常的单基因病因。此外，本研究还确定了100个与男性不育或非典型泌尿生殖系统发育特征至少存在中等程度关联的基因。本研究未纳入相关遗传风险因素或寡基因/多基因病因导致的男性不育病例。

系统评价注册信息
系统评价注册平台：http://www.crd.york.ac.uk/PROSPERO，注册编号：CRD42024593082。