Centromere Stability and Chromosome Segregation: Implications for Trisomies, Cancer & Other Genetic Disorders

Chromosome segregation is an important process for maintaining genetic stability during mitosis and meiosis. This paper examines the role of centromere structure, epigenetic regulation, and kinetochore function for supporting chromosome segregation. Defects in centromeric DNA organization, CENP-A mislocalization, impaired kinetochore-spindle attachment, defective spindle checkpoint regulation, centromere size asymmetry, altered methylation patterns, and disrupted heterochromatin organization can contribute to chromosome missegregation, nondisjunction, and aneuploidy. This review focuses on Trisomy 13, Trisomy 18, and Trisomy 21, highlighting how similar segregation errors can lead to distinct clinical outcomes and are beyond developmental disorders. The paper also explores related mechanisms in cancer biology, where centromere and kinetochore abnormalities contribute to chromosomal instability, tumor progression, and potential biomarker development.

A systematic literature review approach was used, drawing on studies from PubMed, Google Scholar, Nature Reviews, Cold Spring Harbor Perspectives in Biology, and related scientific sources. The review synthesizes evidence from research on centromeric DNA organization, alpha-satellite higher-order repeats, CENP-A localization, DNA methylation, histone modification, R-loop accumulation, kinetochore assembly, and spindle attachment errors. Emerging tools such as long-read sequencing, epigenomic profiling, transcriptomic analysis, human artificial chromosome systems, and genome-editing technologies were among the methods reviewed for studying centromere structure, function, and chromosome segregation.

Even though these approaches remain largely experimental, and no current clinical intervention can reliably prevent trisomy or correct the underlying chromosomal abnormality, continued research into centromere engineering (eg HACs) and kinetochore function may provide valuable insight into the molecular causes of nondisjunction and identify future avenues to correct chromosomal imbalances in trisomy or cancer, or broader prevention, diagnosis, risk management, genetic counseling, and individualized clinical management of trisomy and other genetic disorders.