October 20, 2022

CURE Epilepsy Discovery: CURE Epilepsy Grantees Explore Genetic Determinants of Sudden Unexpected Death in Pediatrics (SUDP)

Key Points:

  • Sudden infant death syndrome (SIDS), sudden unexpected infant death (SUID), and sudden unexplained death in childhood (SUDC) are tragic conditions referring to the unexplained death of an infant or child. While previously thought of as separate entities, evidence suggests that there is an overlap between these conditions and that they may be considered under the overarching umbrella of sudden unexpected death in pediatrics (SUDP).
  • A previous study awarded by CURE Epilepsy and made possible by funding from the Isaiah Stone Foundation to Dr. Annapurna Poduri and colleagues suggested that genes associated with epilepsy may be involved in SUDP.[1]
  • A new study*, which was an outgrowth of the earlier CURE Epilepsy funded research, included 352 SUDP cases and employed state-of-the-art genetic techniques, in-depth analysis of family history and circumstances of death, and analysis of parental genetic information as well.[2]
  • The study showed evidence for genetic factors that may play a role in SUDP; while some genes were already potentially associated with sudden death in children, several variants in genes previously not associated with SUDP were identified.
  • In addition to providing genetic information about SUDP, the group’s work is proof of concept that a multidisciplinary lens to study SUDP is not only feasible, but necessary to advance the field.


Deep dive

The sudden death of a child is a tragic occurrence. Of all the child and infant deaths in the United States, more than 10% occur without any apparent cause, compounding the grief of families who have lost their children.[3] These sudden, unexpected deaths typically impact seemingly healthy children and are classified as sudden infant death syndrome (SIDS), sudden unexpected infant death (SUID), or sudden unexplained death in childhood (SUDC). Together, these three entities are thought of as sudden unexpected death in pediatrics (SUDP).[4] Through the generous support of the Isaiah Stone Foundation, CURE Epilepsy funded Dr. Annapurna Poduri and colleagues Rick Goldstein, Hannah Kinney, and Ingrid Holm in Robert’s Program** at Boston Children’s Hospital to explore the genetic basis of SUDP; the hypothesis for this work is that there are common, underlying, genetic mechanisms behind the three entities of sudden childhood death, epilepsy and sudden unexpected death in epilepsy (SUDEP).

Earlier work from these researchers had highlighted a link between SIDS and variants in a gene called SCN1A, which is associated with epilepsy and SUDEP.[1, 5, 6] What was notable is that while this gene is traditionally thought to be related to epilepsy, the children who died suddenly and unexpectedly had no history of seizures or epilepsy. This and other studies have suggested that SUDP is an overarching disorder consisting of rare and yet-undiagnosed diseases with potentially overlapping genetic mechanisms.[1, 7, 8]

To build on the previous work supported by CURE Epilepsy, Dr. Poduri and colleagues conducted a larger, more extensive study* to explore genetic risk factors for SUDP.[2] The ultimate goal was to find more accurate ways of diagnosing children at risk of sudden death and eventually prevent such incidences. The current study led by Dr. Poduri and her colleagues Drs. Hyunyong Koh and Alireza Haghighi included 352 SUDP cases.[2] This study looked at “trio-based” cohorts; meaning they studied the child and the child’s parents. This is a stronger approach to studying genetic contributions to a disease process, especially for SUDP, where a genetic link is suspected.[9, 10] Additionally, since the mechanisms underlying SUDP are complex and not yet fully known, the team took a “multidisciplinary undiagnosed diseases approach”[11] that combined genetic analysis, autopsy data, and in-depth study of the child’s phenotype (or observable characteristics). Parents agreed to all analyses performed. 

The genetic analysis included a candidate-gene approach where scientists have some information to suggest that a certain gene may be associated with a certain disease. In this case, 294 genes plausibly related to SUDP, called SUDP genes were studied, many of which were associated with neurologic disorders, cardiac disorders, or systemic/syndromic conditions. [12, 13] Systemic conditions and associated genes affect the entire body, and syndromic conditions include genes for metabolism and those responsible for the functioning of multiple body systems. The team performed a genetic technique called exome sequencing, where the parts of genes that eventually become functional proteins were analyzed for variants that may have caused or contributed to sudden death.[2]

The multidisciplinary team at Robert’s Program on SUDP, directed by Dr. Rick Goldstein, characterized fully the conditions surrounding the death of the child, performed an in-depth analysis of the child’s medical and family history, and conducted exome sequencing. The study showed that SUDP was associated with specific genetic factors, some of which were previously known, but many of which were novel. Detailed analysis showed that the majority of the children were between two and six months old, and 57% were male. Out of the 352 cases, death was associated with sleep in an overwhelming majority (346 children).[2] Genetic analysis revealed variants in genes related to cardiac disease, neurologic diseases, and systemic/syndromic diseases. Most variants were de novo, or new, while some were inherited. Burden analysis, in which the trios were compared to controls, showed that there were more SUDP trio cases with rare, damaging de novo variants as compared to controls. There were also clues as to the presence of febrile seizures, a family history of SIDS or SUDC, and a family history of epilepsy and cardiac disease in several cases. When the genes implicated in SUDP were classified by the age of death of the child, a pattern emerged. Specifically, variants in neurological and syndromic genes appeared in the age ranges associated with SIDS (the child being less than one year old) and SUDC (the child is greater than one year old), and variants in cardiac genes were preferentially seen only in the earlier age range, i.e., associated with SIDS.[2]

Overall, the study found that there was a genetic contribution to SUDP in 11% of the cases and suggests that these genetic variants may increase susceptibility to sudden death. Many genes that were previously not linked with SUDP were able to be reclassified as being associated with SUDP. The power of this study is that the genes for SUDP that were investigated were not the ones previously examined. A few specific genes found to be implicated in SUDP are SCN1A and DEPDC5, which have also been shown to be relevant in SUDEP. Other genes were associated with cardiac issues such as arrhythmia and cardiomyopathy (a condition that makes it harder for the heart to pump blood).[2]

The study also shows the importance of looking at trio data, as in this case, it led to the reclassification of several genetic variants. SUDP is a particularly difficult condition to study because unfortunately, a genetic condition may never have been diagnosed or suspected. Hence, the trio approach was instrumental in the success of the current study. The study also adds to evidence [7, 8] that conditions such as stillbirth, SIDS, and SUDC are not separate entities, but represent a continuum of events associated with unexplained death from fetal life to childhood.[14] It is possible and even likely that there are overlapping genetic variants (SCN1A being one) common to these conditions. Notably, another study from a different group also performed genetic analysis from trios and found de novo mutations associated with sudden unexplained death in childhood.[15]

Future studies will look at more trio data and an even more detailed genetic analysis. While many genetic risk factors were found in the current study, it does not mean that they were necessarily the cause of death; more work will be needed to look at specific neurologic mechanisms. In addition to the scientific findings, the study also sets the scene for a model where a multidisciplinary team engages with parents who have lost their children to unexplained death. In addition to providing scientific answers, a multidisciplinary team also can help provide counseling for family members at a much-needed time.



*Supported by funds from the Robert’s Program on Sudden Unexpected Death in Pediatrics, the Cooper Trewin Memorial SUDC Research Fund, CURE Epilepsy through the Isaiah Stone Foundation Award, Three Butterflies SIDS Foundation, The Florida SIDS Alliance, Borrowed Time 151, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development under grant numbers R21 HD096355 and R01 HD090064.

**Robert’s Program at Boston Children‘s Hospital provides comprehensive clinical care to those that have lost a child suddenly and unexpectedly and performs research to better understand SUDP.


Literature Cited:

  1.      Brownstein CA, Goldstein RD, Thompson CH, Haynes RL, Giles E, Sheidley B, et al. SCN1A variants associated with sudden infant death syndrome Epilepsia. 2018 Apr;59:e56-e62.
  2.      Koh HY, Haghighi A, Keywan C, Alexandrescu S, Plews-Ogan E, Haas EA, et al. Genetic Determinants of Sudden Unexpected Death in Pediatrics Genet Med. 2022 Apr;24:839-850.
  3.      About Underlying Cause of Death, 1999-2020. Available at: https://wonder.cdc.gov/ucd-icd10.html. Accessed October 4.
  4.     Goldstein RD, Nields HM, Kinney HC. A New Approach to the Investigation of Sudden Unexpected Death Pediatrics. 2017 Aug;140.  
  5.     Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms Epilepsia. 2010 Sep;51:1650-1658.
  6.    Goldman AM. Mechanisms of sudden unexplained death in epilepsy Curr Opin Neurol. 2015 Apr;28:166-174.
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  8.    Weese-Mayer DE, Ackerman MJ, Marazita ML, Berry-Kravis EM. Sudden Infant Death Syndrome: review of implicated genetic factors Am J Med Genet A. 2007 Apr 15;143a:771-788.
  9.    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med. 2015 May;17:405-424.
  10.   Rehm HL. A new era in the interpretation of human genomic variation Genet Med. 2017 Oct;19:1092-1095.
  11.   MacNamara EF, D’Souza P, Tifft CJ. The undiagnosed diseases program: Approach to diagnosis Transl Sci Rare Dis. 2020 Apr 13;4:179-188.
  12.   An Online Catalog of Human Genes and Genetic Disorders (OMIM). Available at: https://www.omim.org/. Accessed October 4.
  13.   The Human Gene Mutation Database (HGMD®). Available at: https://www.hgmd.cf.ac.uk/ac/index.php. Accessed October 4.
  14.   Goldstein RD, Kinney HC, Willinger M. Sudden Unexpected Death in Fetal Life Through Early Childhood Pediatrics. 2016 Jun;137.
  15.   Halvorsen M, Gould L, Wang X, Grant G, Moya R, Rabin R, et al. De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca(2+) regulation Proc Natl Acad Sci U S A. 2021 Dec 28;118.