Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands.
Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
Hum Reprod. 2019 May 1;34(5):932-941. doi: 10.1093/humrep/dez022.
Which genes are confidently linked to human monogenic male infertility?
Our systematic literature search and clinical validity assessment reveals that a total of 78 genes are currently confidently linked to 92 human male infertility phenotypes.
The discovery of novel male infertility genes is rapidly accelerating with the availability of next-generating sequencing methods, but the quality of evidence for gene-disease relationships varies greatly. In order to improve genetic research, diagnostics and counseling, there is a need for an evidence-based overview of the currently known genes.
STUDY DESIGN, SIZE, DURATION: We performed a systematic literature search and evidence assessment for all publications in Pubmed until December 2018 covering genetic causes of male infertility and/or defective male genitourinary development.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Two independent reviewers conducted the literature search and included papers on the monogenic causes of human male infertility and excluded papers on genetic association or risk factors, karyotype anomalies and/or copy number variations affecting multiple genes. Next, the quality and the extent of all evidence supporting selected genes was weighed by a standardized scoring method and used to determine the clinical validity of each gene-disease relationship as expressed by the following six categories: no evidence, limited, moderate, strong, definitive or unable to classify.
From a total of 23 526 records, we included 1337 publications about monogenic causes of male infertility leading to a list of 521 gene-disease relationships. The clinical validity of these gene-disease relationships varied widely and ranged from definitive (n = 38) to strong (n = 22), moderate (n = 32), limited (n = 93) or no evidence (n = 160). A total of 176 gene-disease relationships could not be classified because our scoring method was not suitable.
Not applicable.
LIMITATIONS, REASONS FOR CAUTION: Our literature search was limited to Pubmed.
The comprehensive overview will aid researchers and clinicians in the field to establish gene lists for diagnostic screening using validated gene-disease criteria and help to identify gaps in our knowledge of male infertility. For future studies, the authors discuss the relevant and important international guidelines regarding research related to gene discovery and provide specific recommendations for the field of male infertility.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a VICI grant from The Netherlands Organization for Scientific Research (918-15-667 to J.A.V.), the Royal Society, and Wolfson Foundation (WM160091 to J.A.V.) as well as an investigator award in science from the Wellcome Trust (209451 to J.A.V.).
None.
哪些基因与人类单基因男性不育症有明确关联？
通过系统的文献检索和临床有效性评估，我们发现目前共有 78 个基因与 92 个人类男性不育表型有明确关联。
随着下一代测序方法的出现，新的男性不育基因的发现正在迅速加速，但基因-疾病关系的证据质量差异很大。为了提高遗传研究、诊断和咨询的水平，我们需要对目前已知的基因进行基于证据的概述。
研究设计、规模、持续时间：我们进行了系统的文献检索和证据评估，检索了截至 2018 年 12 月发表的所有关于男性不育的遗传原因和/或男性泌尿生殖发育缺陷的文献。
参与者/材料、设置、方法：两名独立的评审员进行了文献检索，并纳入了关于人类男性不育单基因病因的论文，排除了关于遗传关联或风险因素、染色体异常和/或影响多个基因的拷贝数变异的论文。接下来，使用标准化评分方法衡量支持选定基因的所有证据的质量和程度，并用于确定每个基因-疾病关系的临床有效性，分为以下六个类别：无证据、有限、中度、强、明确或无法分类。
从总共 23526 条记录中，我们纳入了 1337 篇关于男性不育单基因病因的文献，列出了 521 个基因-疾病关系。这些基因-疾病关系的临床有效性差异很大，从明确（n=38）到强（n=22）、中度（n=32）、有限（n=93）或无证据（n=160）。由于我们的评分方法不适用，共有 176 个基因-疾病关系无法分类。
不适用。
局限性、谨慎的原因：我们的文献检索仅限于 Pubmed。
该综合概述将帮助该领域的研究人员和临床医生建立使用经过验证的基因-疾病标准进行诊断筛查的基因列表，并有助于确定我们对男性不育知识的差距。对于未来的研究，作者讨论了与基因发现相关的相关和重要的国际指南，并为男性不育领域提供了具体建议。
研究资金/竞争利益：这项工作得到了荷兰科学研究组织（荷兰组织为科学研究）的 VICI 拨款（918-15-667 给 J.A.V.）、皇家学会和沃尔夫森基金会（WM160091 给 J.A.V.）以及威康信托基金会的科学研究员奖（209451 给 J.A.V.）的支持。
PROSPERO 注册号：无。
