A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships

BackgroundHuman male infertility has a notable genetic component, including well established diagnoses like Klinefelter syndrome, Y-chromosome microdeletions, and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a vast majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next generation sequencing technologies, and the absence of clear statements from leaders in the field as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility next generation sequencing studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the extent of evidence for reported GDRs. Objective and rationaleIn 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of July 1st, 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. Search methodsWe performed a literature search according to the PRISMA guidelines up until the 1st of July 2020 for publications in English, using search terms related to "male infertility" in combination with the word "genetics" in PubMed. Next, the quality and the extent of all evidence supporting selected genes was assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment, and functional evidence based on gene expression, mutant in vitro cell and in vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, as expressed by the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the ACMG-AMP guidelines and were recorded in spreadsheets for each GDR, which is available at imigc.org. OutcomesThe primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes. Wider implicationsOur systematic review summarises and curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far past due. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility.