Value of Optical Genome Mapping (OGM) for Diagnostics of Rare Diseases: A Family Case Report

Optical genome mapping (OGM) is a novel method enabling the detection of structural genomic variants. The method is based on the laser image acquisition of single, labeled, high-molecular-weight DNA molecules and can detect structural genomic variants such as translocations, inversions, insertions, deletions, duplications, and complex structural rearrangements. We aim to present our experience with OGM at the Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Slovenia. Since its introduction in 2021, we have used OGM for the testing of facioscapulohumeral muscular dystrophy 1, characterization and resolution of variants identified by other technologies such as microarrays, exome and genome next-generation sequencing, karyotyping, as well as testing of rare disease patients in whom no genetic cause could be identified using these methods. We present an example family case of two previously undiagnosed male siblings with an overlapping clinical presentation of thrombocytopenia, obesity, and presacral teratoma. After karyotyping, microarray analysis and next-generation sequencing, by using OGM, a maternally inherited cryptic translocation t(X;18)(q27.1;q12.2) was identified in both brothers. Despite an extended segregation analysis, based on strictly applied ACMG criteria and ClinGen guidelines, the identified translocation remains a variant of unknown significance. Despite the remaining limitations of OGM, which will hopefully be resolved by improvements in databases of known benign SV variation and the establishment of official guidelines on the clinical interpretation of OGM variants, our work highlights the complexity of the diagnostic journey, including this novel method, in rare disease cases.