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. 2022 Apr;24(4):839-850.
doi: 10.1016/j.gim.2021.12.004. Epub 2022 Jan 10.

Genetic Determinants of Sudden Unexpected Death in Pediatrics

Hyun Yong Koh  1 , Alireza Haghighi  2 , Christine Keywan  3 , Sanda Alexandrescu  4 , Erin Plews-Ogan  5 , Elisabeth A Haas  6 , Catherine A Brownstein  7 , Sara O Vargas  4 , Robin L Haynes  8 , Gerard T Berry  7 , Ingrid A Holm  9 , Annapurna H Poduri  10 , Richard D Goldstein  11
Affiliations

Genetic Determinants of Sudden Unexpected Death in Pediatrics

Hyun Yong Koh et al. Genet Med. 2022 Apr.

Abstract

Purpose: This study aimed to evaluate genetic contributions to sudden unexpected death in pediatrics (SUDP).

Methods: We phenotyped and performed exome sequencing for 352 SUDP cases. We analyzed variants in 294 "SUDP genes" with mechanisms plausibly related to sudden death. In a subset of 73 cases with parental data (trios), we performed exome-wide analyses and conducted cohort-wide burden analyses.

Results: In total, we identified likely contributory variants in 37 of 352 probands (11%). Analysis of SUDP genes identified pathogenic/likely pathogenic variants in 12 of 352 cases (SCN1A, DEPDC5 [2], GABRG2, SCN5A [2], TTN [2], MYBPC3, PLN, TNNI3, and PDHA1) and variants of unknown significance-favor-pathogenic in 17 of 352 cases. Exome-wide analyses of the 73 cases with family data additionally identified 4 de novo pathogenic/likely pathogenic variants (SCN1A [2], ANKRD1, and BRPF1) and 4 de novo variants of unknown significance-favor-pathogenic. Comparing cases with controls, we demonstrated an excess burden of rare damaging SUDP gene variants (odds ratio, 2.94; 95% confidence interval, 2.37-4.21) and of exome-wide de novo variants in the subset of 73 with trio data (odds ratio, 3.13; 95% confidence interval, 1.91-5.16).

Conclusion: We provide strong evidence for a role of genetic factors in SUDP, involving both candidate genes and novel genes for SUDP and expanding phenotypes of disease genes not previously associated with sudden death.

Keywords: Intrinsic vulnerability; Sudden infant death syndrome; Sudden unexpected death in pediatrics; Sudden unexpected infant death; Sudden unexplained death in childhood.

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Conflict of interest statement

Conflict of Interest The authors have no financial or other interests related to the submitted work that (1) could affect or have the perception of affecting the author’s objectivity or (2) could influence or have the perception of influencing the authors or the content of the article.

Figures

Figure 1.
Figure 1.. Burden analysis reveals excess of rare damaging variants in SUDP.
A. Comparing all rare damaging variants in our cohort (n = 352) vs. controls (n = 1,433), we demonstrate an excess of rare damaging variants in the entire SUDP gene list (OR 2.94; 95% CI 2.20-3.91), as well as within each disease-related group: neurological, cardiac, and systemic/syndromic disease. B. Considering all genes exome-wide, we observed an excess of rare damaging de novo variants in SUDP cohort trios (n = 73) vs. control trios (n = 2,317) (OR 3.13; 95% CI, 1.91-5.16; Pearson’s Chi-squared two-tailed p = 2.56x10−6).
Figure 2.
Figure 2.. Rare damaging de novo and maternally inherited X-linked variants among 73 trios.
Analysis of 73 SUDP trios identified rare damaging de novo and maternally inherited X-linked variants in 16 genes with known associations with neurological (blue), cardiac (red), and systemic/syndromic (orange) disease (left) and in 46 additional genes without known disease relevance (right). Genes found in the SUDP gene list analysis are indicated by asterisks.
Figure 3.
Figure 3.. Genes implicated in SUDP according to age of death.
Our SUDP cohort included 320 SIDS and 32 SUDC probands (total 352), among which we identified a pathogenic/likely pathogenic (P/LP) variant or variant of uncertain significance-favor pathogenic (VUS-FP) in 37 (11%). Each case with a likely contributory genetic variant is represented by a box with the associated gene name (bold for P/LP, non-bold for VUS-FP) displayed on a timeline indicating age of death. Each gene’s disease category is indicated by color: neurological (blue), cardiac (red), and systemic/syndromic (orange).
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References

    1. Underlying Cause of Death 1999-2019, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. 2021. http://wonder.cdc.gov/ucd-icd10.html. Accessed Jun 29, 2021.
    1. Goldstein RD, Nields HM, Kinney HC. A New Approach to the Investigation of Sudden Unexpected Death. Pediatrics. 2017;140(2). - PubMed
    1. Centers for Disease Control and Prevention, 2020. https://www.cdc.gov/sids/data.htm#:~:text=In%202018%2C%20the%20SUID%20ra....
    1. Goldstein RD, Trachtenberg FL, Sens MA, Harty BJ, Kinney HC. Overall Postneonatal Mortality and Rates of SIDS. Pediatrics. 2016;137(1). - PubMed
    1. Moon RY, Task Force On Sudden Infant Death S. SIDS and Other Sleep-Related Infant Deaths: Evidence Base for 2016 Updated Recommendations for a Safe Infant Sleeping Environment. Pediatrics. 2016;138(5). - PubMed

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