Back to the future: Revisiting whole genome sequencing through a cytogenetic lens helps gain insights for complex phenotypes
Authors: Mantzouratou, A., Wieland, J., Buchan, S., SenGupta, S.
Conference: European Human Genetics Conference Hybrid Conference - Gothenburg, Sweden
Publication Date: 13/06/2026
Abstract:Whole-genome sequencing (WGS) has transformed clinical genetics, yet interpretation remains largely variant-centric, prioritising gene-level pathogenicity over broader genomic context. In complex and heterogeneous conditions, this approach may fail to capture higher-order structural and architectural features of the genome unless it is accompanied by a very large chromosomal abnormality or imbalance. We explored whether revisiting WGS data from a cytogenetic perspective and examining genome-wide architecture, could provide complementary insight beyond conventional variant filtering. Using a clinically diverse cohort undergoing genomic investigations we evaluated whole-genome data at multiple scales. Rather than focusing on individual pathogenic variants alone, this approach considers how different regions of the genome behave relative to one another, and how structural context may influence interpretation. Illustrative case-based observations demonstrate that this approach can highlight features that are not immediately apparent through standard gene-centred pipelines.
We propose that integrating classical cytogenetic principles with modern sequencing technologies offers a complementary analytical framework for interpreting WGS data in multifactorial and heterogeneous conditions. Such a perspective does not replace established variant interpretation strategies but may enhance understanding of genome behaviour across individuals and clinical contexts.
Source: Manual