Genetic Determinants of Sudden Unexpected Death in Pediatrics.
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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.
SUBMITTER: Koh HY
PROVIDER: S-EPMC9164313 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
Publications
Genetic Determinants of Sudden Unexpected Death in Pediatrics.
Koh Hyun Yong HY Haghighi Alireza A Keywan Christine C Alexandrescu Sanda S Plews-Ogan Erin E Haas Elisabeth A EA Brownstein Catherine A CA Vargas Sara O SO Haynes Robin L RL Berry Gerard T GT Holm Ingrid A IA Poduri Annapurna H AH Goldstein Richard D RD
Genetics in medicine : official journal of the American College of Medical Genetics 20220110 4
<h4>Purpose</h4>This study aimed to evaluate genetic contributions to sudden unexpected death in pediatrics (SUDP).<h4>Methods</h4>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.<h4>Results</h4>In total, we identified likely contributory variants in 37 of 352 pro ...[more]
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Project description:BackgroundSudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes.MethodsTo address this hypothesis, we evaluated whole-exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP-associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsIn our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long-standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data.ConclusionWe report variants in several VGSC genes in cases with SUDP, involving both arrhythmia- and epilepsy-associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel-related variants to SUDP.
| S-EPMC7434613 | biostudies-literature
Project description:People with epilepsy are at heightened risk of sudden death compared to the general population. The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). Postmortem investigation of people with SUDEP, including histological and toxicological analysis, does not reveal a cause of death, and the mechanisms of SUDEP remain largely unresolved. In this review we present the possible mechanisms underlying SUDEP, including respiratory dysfunction, cardiac arrhythmia and postictal generalized electroencephlogram suppression. Emerging studies in humans and animal models suggest there may be an underlying genetic basis to SUDEP in some cases. We will highlight a mounting body of evidence for the involvement of genetic risk factors in SUDEP, with a particular focus on the role of cardiac arrhythmia genes in SUDEP.
| S-EPMC5517398 | biostudies-other
Project description:Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy-related cause of death and is characterized by an absence of any identifiable cause of death at post-mortem, suggesting an underlying arrhythmogenic predisposition. This study sought to identify SUDEP cases in a review of post-mortem records and to undertake genetic studies in key familial long QT syndrome (LQTS) genes. All autopsies performed from 1993-2009 at a forensic centre in Sydney, Australia were reviewed and SUDEP cases identified. DNA was extracted from post-mortem blood and the three most common LQTS genes, ie, KCNQ1, KCNH2 (HERG) and SCN5A, were amplified and analyzed. Sixty-eight SUDEP cases were identified (mean age of 40 ± 16 years). Genetic analysis revealed 6 (13%) non-synonymous (amino acid changing) variants in KCNH2 (n = 2) and SCN5A (n = 4), all previously reported in LQTS patients. Specifically, KCNH2 Arg176Trp and SCN5A Pro1090Leu were identified once in SUDEP cases and absent in control alleles. Both DNA variants have been previously identified in the pathogenesis of LQTS. The cause of SUDEP is currently unknown. Our results indicate that investigation of key ion channel genes should be pursued in the investigation of the relationship between epilepsy and sudden death.
| S-EPMC8094243 | biostudies-literature
Project description:The extensive and rapid development of the human brain during the first years of life complicates the postmortem diagnosis of brain edema in infancy. The aim of this study was to describe brain water content, the brain weight/body weight ratio, and the brain weight/head circumference ratio throughout the first years of life. Furthermore, we examined the relationship between these parameters and rs2075575 in the AQP4 gene. Our hypothesis was that dysregulated water homeostasis might be a risk factor for sudden infant death syndrome (SIDS), which may be reflected by increased water content in the brain. The study included 90 subjects with sudden unexpected death < 4 years of age: 22 cases of sudden infant death syndrome, 11 cases of sudden unexplained death in childhood, 47 cases of death due to disease, and 10 cases of accident/violent death. Brain water content, brain weight/body weight ratio, and brain weight/head circumference ratio were investigated according to corrected age, diagnosis group, attempt to resuscitate, and presence of brain edema. We found that brain water content and brain weight/body weight ratio were significantly reduced with increasing age, while brain weight/head circumference were increased. Brain weight/head circumference was correlated with brain water content. Cases with brain edema had a significantly higher brain weight/head circumference than the non-edematous cases. No differences were found between the diagnosis groups for any of the investigated parameters. In summary, the findings contribute to the current body of knowledge regarding brain growth during the first months of life.
| S-EPMC10752850 | biostudies-literature
Project description:AimThis study aimed to systematically analyse the pregnancy, birth and demographic-related factors associated with age of death in sudden unexpected infant death (SUID).MethodsData were analysed from the Centers for Disease Control and Prevention's Cohort Linked Birth/Infant Death data set (2011-2013; 11 737 930 live births). SUID was defined as deaths from sudden infant death syndrome, ill-defined causes, or accidental suffocation and strangulation in bed. There were 9668 SUID cases (7-364 days; gestation >28 weeks; 0.82/1000 live births). The odds of death at different ages were compared to determine which variables significantly affect the SUID age of death.ResultsForty-three features indicated a significant change in age of death with two main patterns: (a) younger chronologic age at death was associated with maternal smoking and factors associated with lower socio-economic status, and (b) older age was associated with low birthweight, prematurity and admission to the neonatal intensive care unit. However, when age was corrected for gestation, these factors were associated with younger age.ConclusionFactors that varied with age of death are well-documented risk factors for SUID. The majority of these risk factors were associated with younger age at death after allowing for gestational age at birth.
| S-EPMC7574313 | biostudies-literature
Project description:Sudden unexpected death in human epileptic patients (SUDEP) is defined as death related to recurrent unprovoked seizures, death occurring unexpectedly, and suddenly in a patient with reasonable state of health, without an obvious medical cause of death, trauma, asphyxia, or intractable status epilepticus, and in post mortem examination no obvious reason for death can be found. "Probable SUDEP" (pSUDEP) is defined as SUDEP not confirmed pathologically. The adapted abbreviation for dogs is used in the following: "pSUDED" (probable sudden unexpected death in dogs with epilepsy). The aim of the present monocentric retrospective study using an online questionnaire was to evaluate the occurrence of pSUDED. Data of canine patients presented with seizures between 01/1998 and 05/2018 were retrospectively analyzed and classified according to their etiology (n = 1,503). Owners were contacted by telephone to participate in answering a validated questionnaire. A total of 509 owners were reached, and 373 owners completed the questionnaire. In addition to signalement (e.g., breed), special attention was paid to the frequency and presentation of seizures and seizures in the context of death. Fifty-one percent (191/373) of the dogs were dead at the endpoint of the study. A large proportion of the dogs was euthanized (149/191) because of seizure severity or health problems unrelated to seizures. Idiopathic epilepsy (IE) was diagnosed in 19/34 dogs which died unexpectedly. Of these seven animals had to be excluded for further investigation of pSUDED because of status epilepticus or aspiration pneumonia as a result of the seizures. In 12 dogs with IE the last seizure event occurred between 6 h and ~3 months before death. pSUDED was suspected in these dogs and an occurrence rate of 4.5-10% was calculated. pSUDED appears in a similar occurrence rate as human SUDEP and should be considered as a possible complication in epileptic dogs. The results of this study suggest that dogs with IE but especially those with brachycephalic syndrome and cluster seizures have an increased risk to die of pSUDED. Owners of dogs with seizures should be educated about the risk of sudden death in dogs with epilepsy.
| S-EPMC8112544 | biostudies-literature
Project description:Sudden unexpected death in epilepsy is a major cause of premature death in people with epilepsy. We aimed to assess whether structural changes potentially attributable to sudden death pathogenesis were present on magnetic resonance imaging in people who subsequently died of sudden unexpected death in epilepsy. In a retrospective, voxel-based analysis of T1 volume scans, we compared grey matter volumes in 12 cases of sudden unexpected death in epilepsy (two definite, 10 probable; eight males), acquired 2 years [median, interquartile range (IQR) 2.8] before death [median (IQR) age at scanning 33.5 (22) years], with 34 people at high risk [age 30.5 (12); 19 males], 19 at low risk [age 30 (7.5); 12 males] of sudden death, and 15 healthy controls [age 37 (16); seven males]. At-risk subjects were defined based on risk factors of sudden unexpected death in epilepsy identified in a recent combined risk factor analysis. We identified increased grey matter volume in the right anterior hippocampus/amygdala and parahippocampus in sudden death cases and people at high risk, when compared to those at low risk and controls. Compared to controls, posterior thalamic grey matter volume, an area mediating oxygen regulation, was reduced in cases of sudden unexpected death in epilepsy and subjects at high risk. The extent of reduction correlated with disease duration in all subjects with epilepsy. Increased amygdalo-hippocampal grey matter volume with right-sided changes is consistent with histo-pathological findings reported in sudden infant death syndrome. We speculate that the right-sided predominance reflects asymmetric central influences on autonomic outflow, contributing to cardiac arrhythmia. Pulvinar damage may impair hypoxia regulation. The imaging findings in sudden unexpected death in epilepsy and people at high risk may be useful as a biomarker for risk-stratification in future studies.
| S-EPMC4671481 | biostudies-literature
Project description:ImportanceRates of maternal obesity are increasing in the US. Although obesity is a well-documented risk factor for numerous poor pregnancy outcomes, it is not currently a recognized risk factor for sudden unexpected infant death (SUID).ObjectiveTo determine whether maternal obesity is a risk factor for SUID and the proportion of SUID cases attributable to maternal obesity.Design, setting, and participantsThis was a US nationwide cohort study using Centers for Disease Control and Prevention National Center for Health Statistics linked birth-infant death records for birth cohorts in 2015 through 2019. All US live births for the study years occurring at 28 weeks' gestation or later from complete reporting areas were eligible; SUID cases were deaths occurring at 7 to 364 days after birth with International Statistical Classification of Diseases, Tenth Revision cause of death code R95 (sudden infant death syndrome), R99 (ill-defined and unknown causes), or W75 (accidental suffocation and strangulation in bed). Data were analyzed from October 1 through November 15, 2023.ExposureMaternal prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared).Main outcome and measureSUID.ResultsOf 18 857 694 live births eligible for analysis (median [IQR] age: maternal, 29 [9] years; paternal, 31 [9] years; gestational, 39 [2] weeks), 16 545 died of SUID (SUID rate, 0.88/1000 live births). After confounder adjustment, compared with mothers with normal BMI (BMI 18.5-24.9), infants born to mothers with obesity had a higher SUID risk that increased with increasing obesity severity. Infants of mothers with class I obesity (BMI 30.0-34.9) were at increased SUID risk (adjusted odds ratio [aOR], 1.10; 95% CI, 1.05-1.16); with class II obesity (BMI 35.0-39.9), a higher risk (aOR, 1.20; 95% CI, 1.13-1.27); and class III obesity (BMI ≥40.0), an even higher risk (aOR, 1.39; 95% CI, 1.31-1.47). A generalized additive model showed that increased BMI was monotonically associated with increased SUID risk, with an acceleration of risk for BMIs greater than approximately 25 to 30. Approximately 5.4% of SUID cases were attributable to maternal obesity.Conclusions and relevanceThe findings suggest that infants born to mothers with obesity are at increased risk of SUID, with a dose-dependent association between increasing maternal BMI and SUID risk. Maternal obesity should be added to the list of known risk factors for SUID. With maternal obesity rates increasing, research should identify potential causal mechanisms for this association.
| S-EPMC11287443 | biostudies-literature
Project description:ObjectiveTo develop and validate a tool for individualized prediction of sudden unexpected death in epilepsy (SUDEP) risk, we reanalyzed data from 1 cohort and 3 case-control studies undertaken from 1980 through 2005.MethodsWe entered 1,273 epilepsy cases (287 SUDEP, 986 controls) and 22 clinical predictor variables into a Bayesian logistic regression model.ResultsCross-validated individualized model predictions were superior to baseline models developed from only average population risk or from generalized tonic-clonic seizure frequency (pairwise difference in leave-one-subject-out expected log posterior density = 35.9, SEM ± 12.5, and 22.9, SEM ± 11.0, respectively). The mean cross-validated (95% bootstrap confidence interval) area under the receiver operating curve was 0.71 (0.68-0.74) for our model vs 0.38 (0.33-0.42) and 0.63 (0.59-0.67) for the baseline average and generalized tonic-clonic seizure frequency models, respectively. Model performance was weaker when applied to nonrepresented populations. Prognostic factors included generalized tonic-clonic and focal-onset seizure frequency, alcohol excess, younger age at epilepsy onset, and family history of epilepsy. Antiseizure medication adherence was associated with lower risk.ConclusionsEven when generalized to unseen data, model predictions are more accurate than population-based estimates of SUDEP. Our tool can enable risk-based stratification for biomarker discovery and interventional trials. With further validation in unrepresented populations, it may be suitable for routine individualized clinical decision-making. Clinicians should consider assessment of multiple risk factors, and not focus only on the frequency of convulsions.
| S-EPMC8205449 | biostudies-literature
Project description:ObjectiveTo determine the association between serum lipid measurements and the occurrence of out-of-hospital sudden unexpected death (OHSUD).Patients and methodsWe compared 139 OHSUD cases (43 female patients [30.9%]) and 968 controls (539 female patients [55.7%]) from Wake County, North Carolina, from March 1, 2013, through February 28, 2015. Individuals were included if they were aged 18 to 64 years and had lipid measurements in the 5 years before their death (cases) or the most recent health care encounter (controls). Covariates were abstracted from medical records for all subjects, and those with triglyceride (TG) levels greater than 400 mg/dL (to convert to mmol/L, multiply by 0.0259) were excluded for low-density lipoprotein (LDL)-related analyses.ResultsBy linear regression using age- and sex-adjusted models, cases of OHSUD had lower adjusted mean total cholesterol (170.3±52.2 mg/dL vs 188.9±39.7 mg/dL; P<.001), LDL cholesterol (90.9±39.6 mg/dL vs 109.6±35.2 mg/dL; P<.001), and non-high-density lipoprotein (HDL) (121.6±49.8 mg/dL vs 134.3±39.6 mg/dL; P<.001) levels and a higher adjusted TG/HDL-C ratio (4.7±7 vs 3±2.7; P<.001) than did controls. By logistic regression using age- and sex-adjusted models, the odds of OHSUD were elevated per unit increase in TG/HDL-C ratio (1.08; 95% CI, 1.03-1.12).ConclusionOut-of-hospital sudden unexpected death cases had more favorable levels of total cholesterol, LDL cholesterol, and non-HDL, possibly indicating a lack of association between traditional lipid cardiovascular risk factors and sudden unexpected death. A comparatively elevated TG/HDL-C ratio in cases may corroborate an evolving hypothesis of how vasoactive and prothrombotic remnant-like lipoprotein particles contribute to sudden unexpected death.
| S-EPMC6132208 | biostudies-literature