The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young

Megan J. Puckelwartz; Lorenzo L. Pesce; Edgar J. Hernandez; Gregory Webster; Lisa M. Dellefave-Castillo; Mark W. Russell; Sarah S. Geisler; Samuel D. Kearns; Felix Karthik; Susan P. Etheridge; Tanner O. Monroe; Tess D. Pottinger; Prince J. Kannankeril; M. Benjamin Shoemaker; Darlene Fountain; Dan M. Roden; Meghan Faulkner; Heather M. MacLeod; Kristin M. Burns; Mark Yandell; Martin Tristani-Firouzi; Alfred L. George; Elizabeth M. McNally

doi:10.1186/s13073-024-01284-w

The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young

Megan J. Puckelwartz^*, Lorenzo L. Pesce, Edgar J. Hernandez, Gregory Webster, Lisa M. Dellefave-Castillo, Mark W. Russell, Sarah S. Geisler, Samuel D. Kearns, Felix Karthik, Susan P. Etheridge, Tanner O. Monroe, Tess D. Pottinger, Prince J. Kannankeril, M. Benjamin Shoemaker, Darlene Fountain, Dan M. Roden, Meghan Faulkner, Heather M. MacLeod, Kristin M. Burns, Mark YandellMartin Tristani-Firouzi, Alfred L. George, Elizabeth M. McNally

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Background: Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing. Methods: The SDY Case Registry is a National Institutes of Health/Centers for Disease Control and Prevention surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases < 20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015 to 2019. The cohort included 211 children (median age 0.33 year; range 0–20 years), determined to have died suddenly and unexpectedly and from whom DNA biospecimens for DNA extractions and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex- and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy, and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, pathogenic and likely pathogenic genetic variation was identified using a Bayesian-based artificial intelligence (AI) tool. Results: The SDY cohort was 43% European, 29% African, 3% Asian, 16% Hispanic, and 9% with mixed ancestries and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy, or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, potentially damaging variants in epilepsy, cardiomyopathy, and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death. Conclusions: While damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.

Original language	English (US)
Article number	13
Journal	Genome Medicine
Volume	16
Issue number	1
DOIs	https://doi.org/10.1186/s13073-024-01284-w
State	Published - Dec 2024

Funding

This work used Stampede2 at The Texas Advanced Computing Center (TACC) through allocation XRAC - BIO220012 (PI MJP) from the Extreme Science and Engineering Discovery Environment (XSEDE), which was supported by National Science Foundation grant number #1548562 []. We thank Victor EijKhout for his assistance with porting and optimization, which was made possible through the XSEDE Extended Collaborative Support Service (ECSS) program []. We also thank Justin Wozniak for his support in installing and optimizing our swift-t workflow []. MY serves as consultant to Fabric Genomics Inc. and has received consulting fees and stock grants from Fabric Genomics Inc. EMM is a consultant for Amgen, Avidity, AstraZeneca, Cytokinetics, PepGen, Pfizer, Tenaya Therapeutics, Stealth BioTherapeutics, and Invitae and is the founder of Ikaika Therapeutics. The remaining authors declare that they do not have any competing interests. This work was supported by grants from the National Institutes of Health (U01HL131914, U01HL131698, HL128075, and U01HL131911), the American Heart Association Strategically Focused Research Network on Arrhythmia and Sudden Cardiac Death and Career Development Award (MJP). This study was made possible by the Sudden Death in the Young Case Registry, a collaboration between the National Heart, Lung, and Blood Institute and National Institute of Neurologic Disorders and Stroke of the National Institutes of Health and the Centers for Disease Control and Prevention, and its Data Coordinating Center at the Michigan Public Health Institute and biorepository at the University of Michigan. The views expressed in this manuscript are those of the authors and do not reflect official positions of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the United States Department of Health and Human Services. This work used Stampede2 at The Texas Advanced Computing Center (TACC) through allocation XRAC - BIO220012 (PI MJP) from the Extreme Science and Engineering Discovery Environment (XSEDE), which was supported by National Science Foundation grant number #1548562 [44]. We thank Victor EijKhout for his assistance with porting and optimization, which was made possible through the XSEDE Extended Collaborative Support Service (ECSS) program [45]. We also thank Justin Wozniak for his support in installing and optimizing our swift-t workflow [46]. The information that is the basis of this presentation and/or publication was provided by the National Center for the Review and Prevention of Child Deaths (NCRPCD), which is funded in part by the US Centers for Disease Control and Prevention Division of Reproductive Health (CDC) and the Health Resources and Services Administration. The data is part of the Sudden Death in the Young (SDY) Case Registry, which is funded by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH) and the CDC. The contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRPCD, CDC, NIH, or the participating states. The information that is the basis of this presentation and/or publication was provided by the National Center for the Review and Prevention of Child Deaths (NCRPCD), which is funded in part by the US Centers for Disease Control and Prevention Division of Reproductive Health (CDC) and the Health Resources and Services Administration. The data is part of the Sudden Death in the Young (SDY) Case Registry, which is funded by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH) and the CDC. The contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRPCD, CDC, NIH, or the participating states.

Keywords

Arrhythmia
Cardiomyopathy
Epilepsy
Gene burden
Genome sequencing
Sudden death in the young

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Genetics(clinical)

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Cite this

Puckelwartz, M. J., Pesce, L. L., Hernandez, E. J., Webster, G., Dellefave-Castillo, L. M., Russell, M. W., Geisler, S. S., Kearns, S. D., Karthik, F., Etheridge, S. P., Monroe, T. O., Pottinger, T. D., Kannankeril, P. J., Shoemaker, M. B., Fountain, D., Roden, D. M., Faulkner, M., MacLeod, H. M., Burns, K. M., ... McNally, E. M. (2024). The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young. Genome Medicine, 16(1), Article 13. https://doi.org/10.1186/s13073-024-01284-w

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title = "The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young",

abstract = "Background: Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing. Methods: The SDY Case Registry is a National Institutes of Health/Centers for Disease Control and Prevention surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases < 20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015 to 2019. The cohort included 211 children (median age 0.33 year; range 0–20 years), determined to have died suddenly and unexpectedly and from whom DNA biospecimens for DNA extractions and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex- and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy, and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, pathogenic and likely pathogenic genetic variation was identified using a Bayesian-based artificial intelligence (AI) tool. Results: The SDY cohort was 43% European, 29% African, 3% Asian, 16% Hispanic, and 9% with mixed ancestries and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy, or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, potentially damaging variants in epilepsy, cardiomyopathy, and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death. Conclusions: While damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.",

keywords = "Arrhythmia, Cardiomyopathy, Epilepsy, Gene burden, Genome sequencing, Sudden death in the young",

author = "Puckelwartz, {Megan J.} and Pesce, {Lorenzo L.} and Hernandez, {Edgar J.} and Gregory Webster and Dellefave-Castillo, {Lisa M.} and Russell, {Mark W.} and Geisler, {Sarah S.} and Kearns, {Samuel D.} and Felix Karthik and Etheridge, {Susan P.} and Monroe, {Tanner O.} and Pottinger, {Tess D.} and Kannankeril, {Prince J.} and Shoemaker, {M. Benjamin} and Darlene Fountain and Roden, {Dan M.} and Meghan Faulkner and MacLeod, {Heather M.} and Burns, {Kristin M.} and Mark Yandell and Martin Tristani-Firouzi and George, {Alfred L.} and McNally, {Elizabeth M.}",

note = "Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

month = dec,

doi = "10.1186/s13073-024-01284-w",

language = "English (US)",

volume = "16",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central",

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Puckelwartz, MJ , Pesce, LL, Hernandez, EJ, Webster, G , Dellefave-Castillo, LM, Russell, MW, Geisler, SS, Kearns, SD, Karthik, F, Etheridge, SP, Monroe, TO, Pottinger, TD, Kannankeril, PJ, Shoemaker, MB, Fountain, D, Roden, DM, Faulkner, M, MacLeod, HM, Burns, KM, Yandell, M, Tristani-Firouzi, M, George, AL & McNally, EM 2024, 'The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young', Genome Medicine, vol. 16, no. 1, 13. https://doi.org/10.1186/s13073-024-01284-w

TY - JOUR

T1 - The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young

AU - Puckelwartz, Megan J.

AU - Pesce, Lorenzo L.

AU - Hernandez, Edgar J.

AU - Webster, Gregory

AU - Dellefave-Castillo, Lisa M.

AU - Russell, Mark W.

AU - Geisler, Sarah S.

AU - Kearns, Samuel D.

AU - Karthik, Felix

AU - Etheridge, Susan P.

AU - Monroe, Tanner O.

AU - Pottinger, Tess D.

AU - Kannankeril, Prince J.

AU - Shoemaker, M. Benjamin

AU - Fountain, Darlene

AU - Roden, Dan M.

AU - Faulkner, Meghan

AU - MacLeod, Heather M.

AU - Burns, Kristin M.

AU - Yandell, Mark

AU - Tristani-Firouzi, Martin

AU - George, Alfred L.

AU - McNally, Elizabeth M.

PY - 2024/12

Y1 - 2024/12

N2 - Background: Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing. Methods: The SDY Case Registry is a National Institutes of Health/Centers for Disease Control and Prevention surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases < 20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015 to 2019. The cohort included 211 children (median age 0.33 year; range 0–20 years), determined to have died suddenly and unexpectedly and from whom DNA biospecimens for DNA extractions and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex- and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy, and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, pathogenic and likely pathogenic genetic variation was identified using a Bayesian-based artificial intelligence (AI) tool. Results: The SDY cohort was 43% European, 29% African, 3% Asian, 16% Hispanic, and 9% with mixed ancestries and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy, or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, potentially damaging variants in epilepsy, cardiomyopathy, and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death. Conclusions: While damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.

AB - Background: Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing. Methods: The SDY Case Registry is a National Institutes of Health/Centers for Disease Control and Prevention surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases < 20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015 to 2019. The cohort included 211 children (median age 0.33 year; range 0–20 years), determined to have died suddenly and unexpectedly and from whom DNA biospecimens for DNA extractions and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex- and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy, and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, pathogenic and likely pathogenic genetic variation was identified using a Bayesian-based artificial intelligence (AI) tool. Results: The SDY cohort was 43% European, 29% African, 3% Asian, 16% Hispanic, and 9% with mixed ancestries and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy, or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, potentially damaging variants in epilepsy, cardiomyopathy, and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death. Conclusions: While damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.

KW - Arrhythmia

KW - Cardiomyopathy

KW - Epilepsy

KW - Gene burden

KW - Genome sequencing

KW - Sudden death in the young

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DO - 10.1186/s13073-024-01284-w

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SN - 1756-994X

VL - 16

JO - Genome Medicine

JF - Genome Medicine

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The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young

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