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There are various factors that account for negative results in exome\/genome sequencing for patients with epilepsy: (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, for example, a structural rearrangement; or (6) limited knowledge or diagnostic tools that 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\u2010analysis of older exome\/genome data as knowledge increases or symptoms change; (2) looking for somatic mosaicism or long\u2010read sequencing to detect low\u2010complexity repeat variants or specific structural variants missed by traditional exome\/genome sequencing; (3) exploration of the non\u2010coding genome including disruption of topologically associated domains, long range non\u2010coding 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 workup. However, it is reasonable to expect that they will become increasingly available and improve current diagnostic capabilities, thereby enabling precision diagnosis in patients who are currently undiagnosed.<\/jats:p>","DOI":"10.1111\/epi.17780","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T10:45:45Z","timestamp":1695725145000},"page":"3143-3154","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Solving the unsolved genetic epilepsies: Current and future perspectives"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7356-3109","authenticated-orcid":false,"given":"Katrine M.","family":"Johannesen","sequence":"first","affiliation":[{"name":"Department of Genetics Copenhagen University Hospital  Copenhagen Denmark"},{"name":"Department of Epilepsy Genetics and Personalized Medicine The Danish Epilepsy Center  Dianalund 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