Enhanced resolution of optical genome mapping utilizing telomere-to-telomere reference in genetic disorders

Reference genomes serve as a baseline criterion for comparison of personal genomes to deduce clinical variants. The widely used reference genome, GRCh38, contains stretches of gaps and unresolved bases particularly in complex regions which could obscure variant discovery. In contrast, the gapless telomere-to-telomere CHM13 (T2T-CHM13) reference genome can be used to assess difficult regions of the genome. Optical genome mapping (OGM), an imaging technique for structural variation identification has improved resolution compared to traditional cytogenetic methods. Our study showcases the utility of the T2T-CHM13 reference genome for enhanced structural variant (SV) detection in complex regions. We illustrate this through two clinical cases, where improved alignment with T2T-CHM13 led to significantly higher confidence scores for critical SVs. We demonstrate improved clinical diagnostic outcomes with the updated T2T-CHM13 reference and advocate its adoption.