Small Supernumerary Marker Chromosomes in Humans: From Classical Cytogenetics to High-Resolution Cytogenomics

Small supernumerary marker chromosomes (sSMCs) are additional chromosomal elements smaller than or equal to chromosome 20, with a prevalence of ~0.044% in the population. Their clinical impact ranges from asymptomatic carriage to severe congenital, neurodevelopmental, and other disorders. Accurate diagnosis and interpretation remain challenging due to their small physical size, frequent tissue-specific mosaicism, and variable expression of similar gene content across different genetic backgrounds, which is well known for numerous clinically significant gene variants. This review synthesizes current knowledge on sSMC biology, diagnostics, and clinical management, highlighting the paradigm shift from classical cytogenetics to high-resolution genomic and cytogenomic approaches, including long-read genome sequencing combined with telomere-to-telomere chromosome assemblies. We present an updated sSMC classification based on sSMC DNA content and structural organization, discuss molecular mechanisms of sSMC biogenesis, and critically evaluate the diagnostic utility of microarray comparative genomic hybridization, whole-genome sequencing, and chromosome microdissection-based approaches. We also discuss breakpoint positions in sSMC formation, sSMC localization in nuclear spatial compartments, and tissue distribution patterns as factors with possible influence on the sSMC manifestation. Some of these properties might be used as criteria for assessing the pathogenic potential of sSMCs, while others require further investigation. Furthermore, we refine pathogenicity assessment frameworks by incorporating sSMC content and morphology. By integrating cutting-edge molecular cytogenetics with standardized interpretive guidelines, this narrative review provides a useful framework for precise sSMC characterization, which is essential for genetic counseling and targeted clinical management.