Pathogenicity assessment of genetic variants in reproductive disorders

This review aims to summarize the available methods and current challenges in assessing the pathogenicity of genetic variants associated with reproductive disorders, with a particular focus on variants affecting oocyte maturation and early embryonic development. It also discusses how functional studied, computational approaches, and clinical evidence can be integrated with the ACMG/AMP framework to support more accurate variant interpretation and clinical decision-making.

In this review, we included the ACMG/AMP guidelines, studies on genes related to oocyte maturation and early embryonic development, and research on ACMG/AMP-based pathogenicity assessment tools. We searched PubMed, Embase, and Web of Science for literature published up from January 2000 to June 2026. We excluded pre-2000 publications (except foundational articles) and non-English papers. Results were reported descriptively.

The application of the ACMG/AMP general framework to variants associated with oocyte maturation defects and early embryonic arrest faces challenges. In infertility-related variant interpretation, there are clinical practice barriers, difficulties in obtaining functional evidence, limitations of general population databases, and high false-positive rates of in silico prediction tools that collectively result in pathogenic variants being classified as variants of uncertain significance (VUS). Corresponding adaptation strategies include prioritizing reproduction-specific databases (IMIGC, FeRGI), introducing gene-/domain-specific weighting, employing automated ACMG-based classification tools (Franklin, VarSome, InterVar) with manual review, and adopting organoid technology for high-level functional evidence.

Accurate interpretation of genetic variants associated with reproductive disorder requires integrating clinical evidence, functional study together with ACMG/AMP general framework. Gene-specific standards, supported by reproductive databases and calibrated evidence rules, may improve molecular diagnosis and personalized assisted reproductive technology (ART) strategy. A ClinGen Variant Curation Expert Panel (VCEP) focusing on oocyte and embryonic developmental deficiencies may also be required.