Genetics Underlying Human Infertility Conditions: Uncovering Monogenic and Polygenic Origins of Reproductive Failure

Infertility affects roughly one in six people of reproductive age worldwide, yet in many cases, the underlying cause remains undetermined after standard clinical investigation. Mounting evidence indicates that a substantial portion of so-called idiopathic infertility originates from genetic factors, including chromosomal abnormalities (numerical changes and structural rearrangements), single-gene defects in monogenic inheritance, and the cumulative influence of multiple genetic variants in polygenic disorders. Rapid progress in exome and genome sequencing, single-cell transcriptomics, and functional genomics has transformed this field by enabling more precise characterization of genetic contributions to reproductive failure. Nevertheless, many candidate genes lack verified causal evidence, and the molecular mechanisms through which genetic variation impairs gametogenesis remain insufficiently understood. Addressing these gaps is essential to strengthen diagnostic accuracy, refine disease classification, and identify potential therapeutic targets for various male and female infertility disorders.

This Research Topic aims to advance understanding of the genetic and molecular basis of human infertility, focusing on gene discovery, functional validation, and mechanistic insight rather than clinical management or assisted reproductive technologies. The objective is to bring together studies that identify and validate genes, variants, and molecular pathways implicated in impaired fertility across sexes, leveraging experimental models and high-powered genomics to clarify underlying mechanisms. Research addressing Mendelian forms of infertility through causal variant discovery and functional demonstration, as well as investigations into the complex polygenic architecture of reproductive traits, are strongly encouraged. The ultimate goal is to integrate multi-level genetic evidence that can bridge association findings with biological causation, fostering a more comprehensive view of reproductive genetics.

The scope of this Research Topic encompasses the genetic architecture, molecular pathways, and translational potential of infertility genetics. It welcomes both mechanistic and computational studies that align with the section’s emphasis on causality and disease understanding. Specifically, we invite submissions addressing, but not limited to, the following themes:

- Monogenic causes of male infertility — identification and functional validation of genes implicated in azoospermia, oligozoospermia, asthenoteratozoospermia, and spermatogenic arrest using in vitro or in vivo models.

- Monogenic causes of female infertility — genetic mechanisms underlying various disorders such as primary ovarian insufficiency (POI), oocyte maturation arrest, empty-follicle syndrome, endometriosis, and hypogonadotropic hypogonadism.

- Meiotic regulation and gametogenesis — molecular control of meiosis, recombination, synaptonemal complex formation, and germ-cell development, and their disruption in infertility.

- Complex-trait genetics of reproductive function — genome-wide and polygenic analyses of fertility-related traits, such as Polyendocrine Metabolic Ovarian Syndrome (PMOS), POI, endometriosis, etc., with rigorous statistical thresholds and functional follow-up.

- Functional and computational approaches — experimental and bioinformatic frameworks that establish causality for candidate variants using model organisms, transcriptomic/proteomic profiling, or novel computational methodologies.

- Diagnostic and translational genetics — refinement of infertility gene panels, allelic contribution analyses, and new diagnostic or therapeutic molecular targets.

- Syndromic and rare disease associations — infertility as a feature within known or novel Mendelian conditions, highlighting mechanistic and clinical implications.

By defining the genetic determinants of infertility across both common and rare disease contexts, this Research Topic seeks to catalyze discovery, mechanistic insight, and translational progress that contribute directly to SDG 3: Good Health and Well-being.

Only the following articles types are accepted for submission in this collection: Brief Research Report, Case Report, Mini Review, Opinion, Original Research, Perspective, Review, Study Protocol, Systematic Review. Please ensure your manuscript aligns with our article type guidelines, as specified here (https://www.frontiersin.org/journals/genetics/for-authors/article-types), paying particular attention to the case report guidelines. Further information about our case report acceptance criteria can be found here (https://www.frontiersin.org/journals/genetics/sections/genetics-of-common-and-rare-diseases/about).

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: infertility genetics, male infertility, female infertility, spermatogenesis, oogenesis, meiosis, gene discovery, functional genomics, monogenic disorders, polygenic traits, variant interpretation

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.