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

Optical genome mapping on ultra-long DNA molecules, with adjusted filter settings and use of the rare variant pipeline to detect ring chromosomes

Ten patients with neurogenetic or syndromic diagnoses left unresolved after karyotyping, chromosomal microarray and/or NGS were analysed by optical genome mapping. OGM confirmed all previously detected structural findings and provided additional structural insight in five cases: a novel candidate gene in a patient with a balanced translocation, redefinition of breakpoint regions in familial translocations, characterization of complex rearrangements, and revision of initial diagnostic interpretations. The authors detail three cases of ring chromosomes (18, 20 and 22) and show that their detection requires adjusting filter settings and incorporating the rare variant pipeline, from which they propose a strategic approach for identifying ring chromosomes by OGM. OGM identified no causative variant in three unsolved cases with strong clinical suspicion of hereditary neuropathy. Overall, additional or refined information was obtained in 6 of 10 cases.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The real contribution of OGM here is not finding what other techniques miss but characterizing what they already saw: breakpoint position, disrupted gene, architecture of a complex rearrangement — which changes genetic counselling far more than the diagnostic rate. The operational point is that ring chromosomes go unnoticed with default settings: a routine pitfall, and the proposed strategy is worth testing by any team deploying OGM. With only 10 patients, the 6-of-10 figure does not generalize, and the failure in three hereditary neuropathy cases is a reminder that OGM does not replace sequencing.

Analysis by Dr Thibaut Benquey