NOR polymorphisms and embryo quality in IVF: current state of evidence (A 10-year' literature review)

Abstract

Relevance: Nucleolar organizer regions (NORs) are clusters of ribosomal DNA (rDNA) located on the short arms of acrocentric chromosomes (13, 14, 15, 21, 22) and are responsible for ribosomal RNA (rRNA) transcription and nucleolus formation.

Classical cytogenetic variants (ps+, pstk+, and satellite size asymmetry) have traditionally been regarded as normal chromosomal polymorphisms without clinical relevance.
However, recent evidence suggests a possible association of NOR variants, particularly within the D/G chromosome group, with disturbances in gametogenesis and outcomes of assisted reproductive technology (ART) programs.
The study aimed to evaluate the impact of NOR polymorphisms on the outcomes of IVF/ICSI programs and to explore potential molecular mechanisms underlying their effect on reproductive potential.
Materials and Methods: An analytical review was conducted covering publications from the last decade (2015–2025), including clinical-cytogenetic and embryological data from carriers of chromosomal polymorphisms participating in IVF/ICSI programs. The analysis considered oocyte and embryo quality, rates of clinical pregnancy, miscarriage, and neonatal outcomes. Additional studies on rDNA expression, methylation patterns, and nucleolar morphology were also reviewed.
Results: The available data demonstrate significant heterogeneity. Several studies reported no statistically significant differences between NOR variant carriers and controls, while others showed a moderate reduction in embryo quality, implantation rate, and an increased risk of early pregnancy loss. Among patients undergoing ICSI combined with preimplantation genetic testing for aneuploidy (PGT-A), no adverse neonatal outcomes were observed. The proposed mechanisms involve variability in rDNA copy number and methylation, disturbances in ribosome biogenesis, and activation of ribosomal stress pathways.
Conclusion: The influence of NOR polymorphisms on reproductive outcomes remains controversial. Their potential role is likely mediated through epigenetic and structural-functional alterations of the nucleolus that affect cellular proliferation and gamete quality. Further standardized prospective studies are needed, with stratification of specific NOR subtypes and integration of cytogenetic, molecular, and embryological data, to clarify their clinical significance.