<p>Non-coding DNA, long considered “junk”, is now recognized as a central regulator of genome architecture. Highly repetitive satellite DNA sequences shape heterochromatin and are essential for chromosome stability, segregation, and gene regulation. Pericentromeric heterochromatic variants, or chromosomal heteromorphisms (CHs), have emerged as modulators of human fertility, potentially affecting gametogenesis and early embryonic development. Despite their ubiquity, the functional and clinical significance of CHs remains largely enigmatic. Molecular reference genomes fail to fully capture these repetitive domains, and cytogenetic assessment has shown critical inconsistencies due to the lack of standardized evaluation criteria. To address this gap, we proposed a comparison-based scoring system to reliably identify and characterize CHs. By applying this framework to 300 individuals with idiopathic reproductive disorders and 155 fertile controls, we observed a significantly higher CH frequency in the infertile cohort (2.4-fold increase; p &lt; 0.001). Chromosome 9 variants were the most prevalent (5.3%; p = 0.036), with 1qh+ and 16qh+ as the most common type-specific variants. Cases of recurrent pregnancy loss exhibited the highest CH burden. These results support a significant association between CHs and adverse reproductive outcomes, suggesting that heterochromatic variants may act as predisposing factors for infertility. Importantly, the proposed scoring system addresses critical cytogenetic inconsistencies and provides a comprehensive, reproducible framework that will enhance cross-study comparability and enable future investigations into the structural, functional, evolutionary, and clinical relevance of satellite DNA-enriched heterochromatic regions.</p>