Abstract
Many patients suffering from epilepsy undergo exome or genome sequencing as part of a diagnostic work-up, however, many remain genetically unsolved. There are various factors that account for negative results in exome/genome sequencing for epilepsy patients; 1) the underlying cause is not genetic, 2) there is a complex polygenic explanation, 3) the illness is monogenic but the causative gene remains to be linked to a human disorder, 4) family segregation with reduced penetrance, 5) somatic mosaicism or the complexity of eg. a structural rearrangement, or 6) limited knowledge or diagnostic tools hinder the proper classification of a variant, resulting in its designation as a variant of unknown significance.
The objective of this review is to outline some of the diagnostic options that lie beyond the exome/genome, and that might become clinically relevant within the foreseeable future. These options include: 1) re-analysis of older exome/genome data as knowledge increases or symptoms change, 2) looking for somatic mosaicism or long-read sequencing to detect low-complexity repeat variants or specific structural variants missed by traditional exome/genome sequencing, 3) exploration of the non-coding genome including disruption of topologically associated domains, long range non-coding RNA or other regulatory elements, and finally 4) transcriptomics, DNA methylation signatures and metabolomics as complementary diagnostic methods that may be used in the assessment of variants of unknown significance. Some of these tools are currently not integrated into standard diagnostic work-up. However, it is reasonable to expect that they will become increasingly available and improve current diagnostic capabilities, thereby enabling precision diagnosis in patients that are currently undiagnosed.
OCT