Optical genome mapping improves structural variant detection and characterization in syndromic and neurogenetic disorders

Abstract Optical Genome Mapping (OGM) offers superior resolution compared to standard diagnostic methods such as karyotyping and FISH, enabling the detection of nearly all types of chromosomal aberrations with non-centromeric breakpoints. This study evaluated OGM’s potential to enhance the genetic findings in unsolved cases of neurogenetic and syndromic disease requiring further investigation after standard genetic testing. In 10 patients with various neurogenetic diagnoses, OGM confirmed all structural findings previously detected by karyotyping, chromosomal microarray (CMA), and/or NGS. Moreover, OGM provided additional structural insights in five cases, such as identifying a novel candidate gene in a patient with a balanced translocation, redefining of breakpoint regions in familial translocations, characterization of complex rearrangements, and revising of initial diagnostic interpretations. Most importantly, we present OGM results for three individuals with ring chromosomes 18, 20, and 22, highlighting the need to adjust filter settings and to incorporate the rare variant pipeline for accurate detection. Based on our experiences, we propose a strategic approach for identifying ring chromosomes using OGM. On the other hand, OGM did not identify causative variants in three unsolved cases with strong clinical suspicion of hereditary neuropathy. In summary, while OGM did not yield new insights for hereditary neuropathy, it provided additional or refined information in 6 out of 10 cases with other syndromic diseases. These findings underscore the value of OGM in increasing the diagnostic yield and precision of genetic testing.