Retrospective study on the utility of optical genome mapping as a follow-up method in genetic diagnostics

Current standard-of-care (SOC) methods for genetic testing are capable of resolving deletions and sequence variants, but they mostly fail to provide information on the breakpoints of duplications and balanced structural variants (SV). However, this information may be necessary for their clinical assessment, especially if the carrier's phenotype is difficult to assess and/or carrier analysis of relatives is not viable. A promising approach to solving such challenging cases arises with access to optical genome mapping (OGM) but has not been systematically explored as of yet.

In this retrospective study, we evaluated diagnostic cases from a 1-year period (2023) in which an SV discovery by SOC methods (microarray, karyotyping and whole-exome sequencing) was followed up by OGM, with the objective to unlock clinically relevant information about the SV.

Seven cases were shown by SOC methods to bear potential pathogenic SVs and were consequently followed up by OGM. Of these, six were solved by the additional use of OGM alone. One case required sequencing after OGM analysis to further specify the SV's breakpoints. In all seven cases, OGM was crucial for determining the clinical relevance of the detected SV.

This study describes the use of OGM as a valuable method for characterising duplications and balanced SVs. Often, this additional information does not add to the quality of a clinical report. However, for a subset of patients, these data are critical, especially in the prenatal setting or when no familial analyses are possible.