A systematic review and evidence assessment of monogenic gene–disease relationships in human female infertility and differences in sex development

Abstract

BACKGROUND As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified genes allows an accurate diagnosis for previously idiopathic cases of female infertility and more appropriate patient care. However, robust evidence of the gene–disease relationships (GDR) allowing the proper translation to clinical application is still missing in many cases. OBJECTIVE AND RATIONALE An evidence-based curation of currently identified genes involved in female infertility and differences in sex development (DSD) would significantly improve both diagnostic performance and genetic research. We therefore performed a systematic review to summarize current knowledge and assess the available GDR. SEARCH METHODS PRISMA guidelines were applied to curate all available information from PubMed and Web of Science on genetics of human female infertility and DSD leading to infertility, from 1 January 1988 to 1 November 2021. The reviewed pathologies include non-syndromic as well as syndromic female infertility, and endocrine and reproductive system disorders. The evidence that an identified phenotype is caused by pathogenic variants in a specific gene was assessed according to a standardized scoring system. A final score (no evidence, limited, moderate, strong, or definitive) was assigned to every GDR. OUTCOMES A total of 45 271 publications were identified and screened for inclusion of which 1078 were selected for gene and variant extraction. We have identified 395 genes and validated 466 GDRs covering all reported monogenic causes of female infertility and DSD. Furthermore, we present a genetic diagnostic flowchart including 105 genes with at least moderate evidence for female infertility and suggest recommendations for future research. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of female infertility. WIDER IMPLICATIONS We have comprehensively reviewed the existing research on the genetics of female infertility and DSD, which will enable the development of diagnostic panels using validated genes. Whole genome analysis is shifting from predominantly research to clinical application, increasing its diagnostic potential. These new diagnostic possibilities will not only decrease the number of idiopathic cases but will also render genetic counselling more effective for infertile patients and their families.

The Global Decline in Human Fertility: The Post-Transition Trap Hypothesis

“…In addition, strong data exist indicating that both maternal and paternal smoking can have a significant impact on semen quality in male offspring [ 130 , 131 ]. In combination, these data suggest that exposure to environmental toxicants can have a transgenerational impact on fecundity via genetic/epigenetic pathways [ 132 , 133 ], and may contribute to the establishment of sustained levels of low fertility in polluted, post-transition societies.…”

Fertility Preservation as an Option for Women with Genetic Disorders: Insights from a SWOT Analysis on Elective Oocyte Freezing and Preimplantation Genetic Testing

“…Monogenic causes of female infertility have increased dramatically over the last few decades. Hundreds of genes have been identified, and the clinical validation of just as many gene-disease relationships has been evaluated [51]. In addition, for several known genetic mutations, a possible detrimental effect on ovarian reserve has been poorly investigated, as in the case of over twenty non-BRCA mutations in the BRCA pathway [52].…”

The genetic background of female reproductive disorders: a systematic review

“…Limited only genes have been used in clinical practice to evaluate for female infertility, including FMRI for fragile X mental retardation I gene and CYP21A2 for 21-hydroxylase enzyme [5,6]. Recently, an increasing number of studies have suggested GDR, highlighting gene variants that could be utilized in reproductive medicine [7,8 ▪▪ ,9 ▪ ]. However, there is currently no agreed consensus on the suggested genetic testing for the work-up in subfertility.…”