A systematic review and standardized clinical validity assessment of male infertility genes

Abstract

Study question: Which genes are confidently linked to human monogenic male infertility?

Summary answer: 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.

What is known already: 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.

Main results and the role of chance: 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.

Large scale data: Not applicable.

Limitations, reasons for caution: Our literature search was limited to Pubmed.

Wider implications of the findings: 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.).

Prospero registration number: None.

Keywords: clinical validity; gene panel; genetics; gene–disease relation; male infertility; next-generation sequencing; spermatogenic failure; systematic review.

Figure 1

PRISMA flow chart showing our search and screening strategy to identify publications and genes eligible for clinical validity assessment in male infertility. GD, gene–disease relationships; AR, autosomal recessive; AD, autosomal dominant; XL, X-linked; YL, Y-linked.

Figure 2

Genetic studies in male infertility between 1958 and 2018. (A) Graphical overview of genetic studies in male infertility. (B) Graphical representation of type of genetic research in male infertility. (C) The use of Sanger sequencing and next-generation sequencing for the discovery of genes in male infertility. (D) Increase of genes linked to human male infertility. AZF, azoospermia factor; CNV, copy number variants.

Figure 3

Biological overview of the genetics of male infertility. The color of each gene indicates the amount of evidence: Brown: Definitive; Red: Strong; Orange: Moderate. GnRHR: GnRH receptor, LHCGR: LHCG receptor. A list of gene names and definitions is available in Supplementary Table SIX.