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Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases.

ABSTRACT: Sudden infant death syndrome (SIDS) is the most frequent manner of post-perinatal death among infants. One of the suggested causes of the syndrome is inherited cardiac diseases, mainly channelopathies, that can trigger arrhythmias and sudden death. The purpose of this study was to investigate cases of sudden unexpected death in infancy (SUDI) for potential causative variants in 100 cardiac-associated genes. We investigated 47 SUDI cases of which 38 had previously been screened for variants in RYR2, KCNQ1, KCNH2 and SCN5A. Using the Haloplex Target Enrichment System (Agilent) and next-generation sequencing (NGS), the coding regions of 100 genes associated with inherited channelopathies and cardiomyopathies were captured and sequenced on the Illumina MiSeq platform. Sixteen (34%) of the SUDI cases had variants with likely functional effects, based on conservation, computational prediction and allele frequency, in one or more of the genes screened. The possible effects of the variants were not verified with family or functional studies. Eight (17%) of the SUDI cases had variants in genes affecting ion channel functions. The remaining eight cases had variants in genes associated with cardiomyopathies. In total, one third of the SUDI victims in a forensic setting had variants with likely functional effect that presumably contributed to the cause of death. The results support the assumption that channelopathies are important causes of SUDI. Thus, analysis of genes associated with cardiac diseases in SUDI victims is important in the forensic setting and a valuable supplement to the clinical investigation in all cases of sudden death.

SUBMITTER: Hertz CL

PROVIDER: S-EPMC4867441 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases.

Hertz Christin Loeth CL Christiansen Sofie Lindgren SL Larsen Maiken Kudahl MK Dahl Morten M Ferrero-Miliani Laura L Weeke Peter Ejvin PE Pedersen Oluf O Hansen Torben T Grarup Niels N Ottesen Gyda Lolk GL Frank-Hansen Rune R Banner Jytte J Morling Niels N

European journal of human genetics : EJHG 20150909 6

Sudden infant death syndrome (SIDS) is the most frequent manner of post-perinatal death among infants. One of the suggested causes of the syndrome is inherited cardiac diseases, mainly channelopathies, that can trigger arrhythmias and sudden death. The purpose of this study was to investigate cases of sudden unexpected death in infancy (SUDI) for potential causative variants in 100 cardiac-associated genes. We investigated 47 SUDI cases of which 38 had previously been screened for variants in RY ...[more]

PMID: 26350513

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Project description:Background: Sudden Unexpected Death in Infancy (SUDI) is a leading cause of preventable infant mortality and strongly associated with social adversity. While this has been noted over many decades, most previous studies have used single economic markers in social disadvantage analyses. To date there have been no previous attempts to analyze the cumulative effect of multiple adversities in combination on SUDI risk. Methods: Based on sociological theories of social exclusion, a multidimensional framework capable of producing an overall measure of family-level social vulnerability was developed, accounting for both increasing disadvantage with increasing prevalence among family members and effect of family structures. This framework was applied retrospectively to all cases of SUDI that occurred in Queensland between 2010 and 2014. Additionally, an exploratory factor analysis was performed to investigate whether differing "types" of vulnerability could be identified. Results: Increased family vulnerability was associated with four major known risk factors for sudden infant death: smoking, surface sharing, not-breastfeeding and use of excess bedding. However, families with lower levels of social vulnerability were more likely to display two major risk factors: prone infant sleep position and not room-sharing. There was a significant positive relationship between family vulnerability and the cumulative total of risk factors. Exploratory factor analysis identified three distinct vulnerability types (chaotic lifestyle, socioeconomic and psychosocial); the first two were associated with presence of major SUDI risk factors. Indigenous infants had significantly higher family vulnerability scores than non-Indigenous families. Conclusion: A multidimensional measure that captures adversity across a range of indicators highlights the need for proportionate universalism to reduce the stalled rates of sudden infant death. In addition to information campaigns continuing to promote the importance of the back-sleeping position and close infant-caregiver proximity, socially vulnerable families should be a priority population for individually tailored or community based multi-model approaches.

Project description:ObjectiveOgival palate (i.e., a narrow and high-arched palate) is usually described in obstructive breath disorder but has been found in infants unexpectedly deceased. We studied the association between ogival palate and sudden unexpected death in infancy (SUDI) on the basis of a computed tomography (CT) evaluation.MethodsWe conducted a monocentric case-control study of children under 2 years of age who died of SUDI, for which a head CT scan and an autopsy were performed between 2011 and 2018. Each case was matched by sex and age (± 30 days) to two controls selected among living children in the same center who benefited from a cranio-encephalic CT scan. Four parameters of the hard palate were measured by CT: height, width, length, and sagittal angle; the height/width ratio was calculated. The presence of an ogival palate was also subjectively evaluated by the radiologists, independently from the measurements. Standardized odds ratios (OR) were calculated using conditional logistic regression models, all expressed for +1 standard deviation (SD).ResultsThirty-two deceased children were matched to 64 living control children. Mean ages were 5.0 and 5.3 months, respectively. Twenty-eight cases were considered to have died as a result of SIDS. The mean heights of the hard palate were significantly higher in the deceased children [4.1 (± 0.7) millimeters (mm)] than in the living children [3.2 (± 0.6) mm], with OR (+1SD) = 4.30 (95% confidence interval [CI], 2.04-9.06, P = 0.0001). The mean widths of the hard palate were 21.0 (± 1.9) mm and 23.2 (± 2.1) mm, respectively, with OR = 0.15 (95% CI, 0.06-0.40, P = 0.0001). The mean sagittal angles were significantly more acute in deceased children [134.5° (± 9.3)] than in living children [142.9° (± 8.1)], with OR = 0.28 (95% CI, 0.14-0.56, P = 0.0003). The mean height/width ratios were 19.8 (± 3.7) and 14.1 (± 3.3), respectively, with OR = 6.10 (95% CI, 2.50-14.9, P = 0.0001). The hard palate was subjectively considered as ogival in 59.4% (19/32) of the cases versus 12.5% (8/64) of the controls.ConclusionRadiological features of the ogival palate were strongly associated with SUDI. This observation still needs to be confirmed and the corresponding clinical features must be identified.

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Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases.

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Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases.

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