Systematic Review of the Genetics of Sudden Unexpected Death in Epilepsy: Potential Overlap With Sudden Cardiac Death and Arrhythmia‐Related Genes

Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the gen...

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Published in:	Journal of the American Heart Association Vol. 9; no. 1; p. e012264
Main Authors:	Chahal, C. Anwar A., Salloum, Mohammad N., Alahdab, Fares, Gottwald, Joseph A., Tester, David J., Anwer, Lucman A., So, Elson L., Murad, Mohammad Hassan, St Louis, Erik K., Ackerman, Michael J., Somers, Virend K.
Format:	Journal Article
Language:	English
Published:	England John Wiley and Sons Inc 07.01.2020 Wiley
Subjects:	Adolescent Adult Arrhythmias, Cardiac - diagnosis Arrhythmias, Cardiac - genetics Arrhythmias, Cardiac - mortality channelopathy Child Child, Preschool Death, Sudden, Cardiac - etiology epilepsy Epilepsy - diagnosis Epilepsy - genetics Epilepsy - mortality Female Genetic Predisposition to Disease Genetic Variation Humans Infant K‐channel long QT syndrome Male Middle Aged Phenotype Potassium Channels - genetics Risk Assessment Risk Factors seizure sodium channels Sodium Channels - genetics Sudden Unexpected Death in Epilepsy - etiology Systematic Review and Meta‐analysis Young Adult epilepsy sudden death seizure long QT syndrome sodium channels channelopathy K‐channel
ISSN:	2047-9980, 2047-9980
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Abstract	Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na and K ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.
AbstractList	Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy‐related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In‐Process & Other Non‐Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia‐related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta‐analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na+ and K+ ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia‐related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage. Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na and K ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage. Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na+ and K+ ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na+ and K+ ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.
Author	Anwer, Lucman A. Tester, David J. Chahal, C. Anwar A. St Louis, Erik K. Alahdab, Fares Somers, Virend K. So, Elson L. Salloum, Mohammad N. Gottwald, Joseph A. Murad, Mohammad Hassan Ackerman, Michael J.
AuthorAffiliation	10 Department of Pediatrics Mayo Clinic Rochester MN 11 Department of Cardiovascular Surgery Mayo Clinic Rochester MN 6 Division of Preventive, Occupational and Aerospace Medicine Mayo Clinic Rochester MN 3 Department of Cardiovascular Medicine Mayo Clinic Rochester MN 1 Mayo Clinic College of Medicine Mayo Clinic Rochester MN 5 Evidence‐Based Practice Research Program Mayo Clinic Rochester MN 4 Internal Medicine Icahn School of Medicine at Mount Sinai Queens Hospital Center New York NY 8 Department of Neurology Mayo Clinic Rochester MN 7 Windland Smith Rice Sudden Death Genomics Laboratory Mayo Clinic Rochester MN 9 Mayo Center for Sleep Medicine Mayo Clinic Rochester MN 2 Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester MN 12 General Surgery UIC/MGH Chicago IL
AuthorAffiliation_xml	– name: 9 Mayo Center for Sleep Medicine Mayo Clinic Rochester MN – name: 4 Internal Medicine Icahn School of Medicine at Mount Sinai Queens Hospital Center New York NY – name: 6 Division of Preventive, Occupational and Aerospace Medicine Mayo Clinic Rochester MN – name: 8 Department of Neurology Mayo Clinic Rochester MN – name: 5 Evidence‐Based Practice Research Program Mayo Clinic Rochester MN – name: 12 General Surgery UIC/MGH Chicago IL – name: 11 Department of Cardiovascular Surgery Mayo Clinic Rochester MN – name: 2 Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester MN – name: 3 Department of Cardiovascular Medicine Mayo Clinic Rochester MN – name: 1 Mayo Clinic College of Medicine Mayo Clinic Rochester MN – name: 10 Department of Pediatrics Mayo Clinic Rochester MN – name: 7 Windland Smith Rice Sudden Death Genomics Laboratory Mayo Clinic Rochester MN
Author_xml	– sequence: 1 givenname: C. Anwar A. surname: Chahal fullname: Chahal, C. Anwar A. organization: Mayo Clinic College of Medicine Mayo Clinic Rochester MN, Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester MN, Department of Cardiovascular Medicine Mayo Clinic Rochester MN – sequence: 2 givenname: Mohammad N. surname: Salloum fullname: Salloum, Mohammad N. organization: Internal Medicine Icahn School of Medicine at Mount Sinai Queens Hospital Center New York NY – sequence: 3 givenname: Fares surname: Alahdab fullname: Alahdab, Fares organization: Evidence‐Based Practice Research Program Mayo Clinic Rochester MN, Division of Preventive, Occupational and Aerospace Medicine Mayo Clinic Rochester MN – sequence: 4 givenname: Joseph A. surname: Gottwald fullname: Gottwald, Joseph A. organization: Mayo Clinic College of Medicine Mayo Clinic Rochester MN – sequence: 5 givenname: David J. surname: Tester fullname: Tester, David J. organization: Mayo Clinic College of Medicine Mayo Clinic Rochester MN, Department of Cardiovascular Medicine Mayo Clinic Rochester MN, Windland Smith Rice Sudden Death Genomics Laboratory Mayo Clinic Rochester MN – sequence: 6 givenname: Lucman A. surname: Anwer fullname: Anwer, Lucman A. organization: Mayo Clinic College of Medicine Mayo Clinic Rochester MN, Department of Cardiovascular Surgery Mayo Clinic Rochester MN, General Surgery UIC/MGH Chicago IL – sequence: 7 givenname: Elson L. surname: So fullname: So, Elson L. organization: Evidence‐Based Practice Research Program Mayo Clinic Rochester MN – sequence: 8 givenname: Mohammad Hassan surname: Murad fullname: Murad, Mohammad Hassan organization: Evidence‐Based Practice Research Program Mayo Clinic Rochester MN, Division of Preventive, Occupational and Aerospace Medicine Mayo Clinic Rochester MN – sequence: 9 givenname: Erik K. surname: St Louis fullname: St Louis, Erik K. organization: Mayo Clinic College of Medicine Mayo Clinic Rochester MN, Department of Neurology Mayo Clinic Rochester MN, Mayo Center for Sleep Medicine Mayo Clinic Rochester MN – sequence: 10 givenname: Michael J. surname: Ackerman fullname: Ackerman, Michael J. organization: Mayo Clinic College of Medicine Mayo Clinic Rochester MN, Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester MN, Department of Cardiovascular Medicine Mayo Clinic Rochester MN, Windland Smith Rice Sudden Death Genomics Laboratory Mayo Clinic Rochester MN, Department of Pediatrics Mayo Clinic Rochester MN – sequence: 11 givenname: Virend K. surname: Somers fullname: Somers, Virend K. organization: Mayo Clinic College of Medicine Mayo Clinic Rochester MN, Department of Cardiovascular Medicine Mayo Clinic Rochester MN
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Keywords	epilepsy sudden death seizure long QT syndrome sodium channels channelopathy K‐channel
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Snippet	Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and... Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy‐related death. SUDEP shares many features with sudden cardiac death and...
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SubjectTerms	Adolescent Adult Arrhythmias, Cardiac - diagnosis Arrhythmias, Cardiac - genetics Arrhythmias, Cardiac - mortality channelopathy Child Child, Preschool Death, Sudden, Cardiac - etiology epilepsy Epilepsy - diagnosis Epilepsy - genetics Epilepsy - mortality Female Genetic Predisposition to Disease Genetic Variation Humans Infant K‐channel long QT syndrome Male Middle Aged Phenotype Potassium Channels - genetics Risk Assessment Risk Factors seizure sodium channels Sodium Channels - genetics Sudden Unexpected Death in Epilepsy - etiology Systematic Review and Meta‐analysis Young Adult
Title	Systematic Review of the Genetics of Sudden Unexpected Death in Epilepsy: Potential Overlap With Sudden Cardiac Death and Arrhythmia‐Related Genes
URI	https://www.ncbi.nlm.nih.gov/pubmed/31865891 https://www.proquest.com/docview/2330064470 https://pubmed.ncbi.nlm.nih.gov/PMC6988156 https://doaj.org/article/a74293868f5c4884b606b4b5bd86a1b9
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