Solving the unsolved genetic epilepsies: Current and future perspectives
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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Solving the unsolved genetic epilepsies : Current and future perspectives. / Johannesen, Katrine M.; Tümer, Zeynep; Weckhuysen, Sarah; Barakat, Tahsin Stefan; Bayat, Allan.
I: Epilepsia, Bind 64, Nr. 12, 2023, s. 3143-3154.Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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TY - JOUR
T1 - Solving the unsolved genetic epilepsies
T2 - Current and future perspectives
AU - Johannesen, Katrine M.
AU - Tümer, Zeynep
AU - Weckhuysen, Sarah
AU - Barakat, Tahsin Stefan
AU - Bayat, Allan
N1 - Publisher Copyright: © 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
PY - 2023
Y1 - 2023
N2 - Many patients with epilepsy undergo exome or genome sequencing as part of a diagnostic workup; however, many remain genetically unsolved. 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-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 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.
AB - Many patients with epilepsy undergo exome or genome sequencing as part of a diagnostic workup; however, many remain genetically unsolved. 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-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 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.
KW - DNA methylation
KW - epilepsy
KW - epilepsy genetics
KW - metabolomics
KW - non-coding regions
KW - re-analysis
KW - somatic mosaicism
KW - transcriptomics
U2 - 10.1111/epi.17780
DO - 10.1111/epi.17780
M3 - Review
C2 - 37750451
AN - SCOPUS:85174222098
VL - 64
SP - 3143
EP - 3154
JO - Epilepsia
JF - Epilepsia
SN - 0013-9580
IS - 12
ER -
ID: 373612640