@article{d86b5aee29834c08974c5e327e43e319,
title = "De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+regulation",
abstract = "Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 {"}trios{"} (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C. Both RYR2 mutations are pathogenic (P = 1.7 × 10-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.",
keywords = "Calcium signaling, Cardiac arrhythmia, Genetics, Seizure disorder, Sudden death in children",
author = "Matthew Halvorsen and Laura Gould and Xiaohan Wang and Gariel Grant and Raquel Moya and Rachel Rabin and Ackerman, {Michael J.} and Tester, {David J.} and Lin, {Peter T.} and Pappas, {John G.} and Maurano, {Matthew T.} and Goldstein, {David B.} and Tsien, {Richard W.} and Orrin Devinsky",
note = "Funding Information: ACKNOWLEDGMENTS. We thank our additional Sudden Unexplained Death in Childhood Registry and Research Collaborative (SUDCRRC) investigators T. Andrew, J. C. Downs, D. Friedman, H. Jarrell, K. Landi, K. Lear, J. Lee, K. Malo-ney, J. J. Maleszewski, K. Pinckard, K. Pinneri, R. Reichard, K. Roman, and A. Wil-liamson; the medical examiner and coroner offices for their support in referrals to the SUDCRRC; and the bereaved parents who courageously participated in this study to help us better understand sudden unexplained death in childhood and impact a brighter future for all children. This study was supported by funding from the SUDC Foundation and Finding A Cure for Epilepsy and Seizures (New York University). R.W.T. was supported by NIH Grants R01 DA040484 and R01 MH71739, and a grant from FACES. M.J.A. is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. O.D. had full access to all the data in the study and had final responsibility for the decision to submit for publication. The study sponsors had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Funding Information: Author contributions: M.H., L.G., X.W., G.G., R.M., M.T.M., D.B.G., R.W.T., and O.D. designed research; M.H., L.G., X.W., G.G., R.M., and R.R. performed research; M.H., L.G., X.W., G.G., R.M., M.T.M., D.B.G., R.W.T., and O.D. analyzed data; R.R., M.J.A., D.J.T., P.T.L., J.G.P., M.T.M., D.B.G., and O.D. contributed new reagents/analytic tools; and M.H., L.G., X.W., G.G., R.W.T., and O.D. wrote the paper. Reviewers: A.L.G., Northwestern University Feinberg School of Medicine; G.S.P., Weill Cornell Medicine. Competing interest statement: M.J.A. is a consultant for Abbott, ARMGO Pharma, Boston Scientific, Daiichi Sankyo, Invitae, LQT Therapeutics, Medtronic, and UpToDate. M.J.A. and the Mayo Clinic have an equity/royalty relationship with AliveCor and Anumana. However, none of these entities are related to study. D.B.G. reports he is cofounder and holds equity in Q State–Pairnomix and Praxis Therapeutics, and equity in Apostle Inc. He receives personal fees from AstraZeneca, outside the submitted work. R.W.T. reports his participation on the Scientific Advisory boards of HHMI, the Institute of Neuroscience (Shanghai), and the Institute of Science and Technology (Vienna). R.W.T. also reports his participation in the Actelion Scientific Advisory Board (Basel) with no compensation during 3-y span. O.D. reports equity interest in Empatica and receives funding from National Institute of Neurological Disorders and Stroke on sudden unexplained death in epilepsy research. M.J.A., P.T.L., and O.D. are members of the Sudden Unexplained Death in Children (SUDC) Foundation{\textquoteright}s scientific advisory board. L.G. is President of the SUDC Foundation. L.G., M.J.A., P.T.L., and O.D. do not participate in grant funding decisions or negotiations by the SUDC Foundation to New York University Langone Health. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). 1M.H., L.G., and X.W. contributed equally to this work. 2G.G. and R.M. contributed equally to this work. 3To whom correspondence may be addressed. Email: richard.tsien@nyulangone.org or Orrin.Devinsky@nyulangone.org. This article contains supporting information online at http://www.pnas.org/lookup/ suppl/doi:10.1073/pnas.2115140118/-/DCSupplemental. Funding Information: We thank our additional Sudden Unexplained Death in Childhood Registry and Research Collaborative (SUDCRRC) investigators T. Andrew, J. C. Downs, D. Friedman, H. Jarrell, K. Landi, K. Lear, J. Lee, K. Maloney, J. J.Maleszewski, K. Pinckard, K. Pinneri, R. Reichard, K. Roman, and A.Williamson; the medical examiner and coroner offices for their support in referrals to the SUDCRRC; and the bereaved parents who courageously participated in this study to help us better understand sudden unexplained death in childhood and impact a brighter future for all children. This study was supported by funding from the SUDC Foundation and Finding A Cure for Epilepsy and Seizures (New York University). R.W.T. was supported by NIH Grants R01 DA040484 and R01 MH71739, and a grant from FACES. M.J.A. is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. O.D. had full access to all the data in the study and had final responsibility for the decision to submit for publication. The study sponsors had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = dec,
day = "28",
doi = "10.1073/pnas.2115140118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "52",
}