Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young

Methner, D. Nicole R.; Scherer, Steven E.; Welch, Katherine O.; Walkiewicz, Magdalena; Eng, Christine M.; Belmont, John W.; Powell, Mark C.; Korchina, Viktoriya; Doddapaneni, Harshavardhan; Muzny, Donna M.; Gibbs, Richard A.; Wolf, Dwayne A.; Sánchez, Luis A.; Kahn, Roger

doi:10.1101/gr.195800.115

Cited by 28 publications

(23 citation statements)

References 47 publications

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“…From a cohort of 10 infants with SIDS, we identified 2 cases with heterozygous SCN1A variants. The variants we report, similar to those we have cited, are predicted to be pathogenic using in silico assessments. These predictions are further strengthened by association with previously reported cases with epilepsy, location of the variants in critical, disease‐associated domains of the protein, and functional evidence that the variants present in both cases exhibit partial loss of function.…”

Section: Discussionsupporting

confidence: 83%

“…SCN1A ‐related mechanisms have been postulated to underlie a risk of SUDEP in patients with Dravet syndrome, with evidence from rodent models providing supporting evidence . In recent reports, SCN1A was not included in the panel of genes interrogated . A report of SCN1A Leu61Pro in association with SUDC underscores the potential for SIDS and SUDC to share SCN1A‐related mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…24 In recent reports, SCN1A was not included in the panel of genes interrogated. 9,20 A report of SCN1A Leu61Pro in association with SUDC 25 underscores the potential for SIDS and SUDC to share SCN1A-related mechanisms. Additional SCN1A variants associated with SUDEP 8 support the extension of the spectrum of SCN1A into the realm of SUDEP.…”

Section: Discussionmentioning

confidence: 99%

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SCN1A variants associated with sudden infant death syndrome

et al. 2018

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We identified SCN1A variants in 2 infants who died of sudden infant death syndrome (SIDS) with hippocampal abnormalities from an exome sequencing study of 10 cases of SIDS but no history of seizures. One harbored SCN1A G682V, and the other had 2 SCN1A variants in cis: L1296M and E1308D, a variant previously associated with epilepsy. Functional evaluation in a heterologous expression system demonstrated partial loss of function for both G682V and the compound variant L1296M/E1308D. Our cases represent a novel association between SCN1A and SIDS, extending the SCN1A spectrum from epilepsy to SIDS. Our findings provide insights into SIDS and support genetic evaluation focused on epilepsy genes in SIDS.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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SCN1A variants associated with sudden infant death syndrome

et al. 2018

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“…While reports have estimated that up to 15% of SIDS were related to specific genetic variants [e.g., Ref. (154)], a recent study that sequenced the full exons of 64 genes associated with sudden death in the largest known cohort (351) of infant and young sudden death decedents reported that less than 4% of unexpected deaths were associated with a pathogenic genetic variant (155). These results suggest that many pathogenic variants involved in SIDS are unknown or, most likely, that pathogenic variants play a minute role is SIDS.…”

Section: Introductionmentioning

confidence: 99%

A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

Elhaik

2016

Front. Neurol.

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Sudden infant death syndrome (SIDS) is the leading cause of death among USA infants under 1 year of age accounting for ~2,700 deaths per year. Although formally SIDS dates back at least 2,000 years and was even mentioned in the Hebrew Bible (Kings 3:19), its etiology remains unexplained prompting the CDC to initiate a sudden unexpected infant death case registry in 2010. Due to their total dependence, the ability of the infant to allostatically regulate stressors and stress responses shaped by genetic and environmental factors is severely constrained. We propose that SIDS is the result of cumulative painful, stressful, or traumatic exposures that begin in utero and tax neonatal regulatory systems incompatible with allostasis. We also identify several putative biochemical mechanisms involved in SIDS. We argue that the important characteristics of SIDS, namely male predominance (60:40), the significantly different SIDS rate among USA Hispanics (80% lower) compared to whites, 50% of cases occurring between 7.6 and 17.6 weeks after birth with only 10% after 24.7 weeks, and seasonal variation with most cases occurring during winter, are all associated with common environmental stressors, such as neonatal circumcision and seasonal illnesses. We predict that neonatal circumcision is associated with hypersensitivity to pain and decreased heart rate variability, which increase the risk for SIDS. We also predict that neonatal male circumcision will account for the SIDS gender bias and that groups that practice high male circumcision rates, such as USA whites, will have higher SIDS rates compared to groups with lower circumcision rates. SIDS rates will also be higher in USA states where Medicaid covers circumcision and lower among people that do not practice neonatal circumcision and/or cannot afford to pay for circumcision. We last predict that winter-born premature infants who are circumcised will be at higher risk of SIDS compared to infants who experienced fewer nociceptive exposures. All these predictions are testable experimentally using animal models or cohort studies in humans. Our hypothesis provides new insights into novel risk factors for SIDS that can reduce its risk by modifying current infant care practices to reduce nociceptive exposures.

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“…We have published a more detailed analysis of state laws and the implications of differences elsewhere (Moore et al 2016). In this paper, we describe the experiences and reflections of the Molecular Autopsy Consortium of Houston (MATCH), a collaboration between the Harris County Institute of Forensic Sciences (an integrated operation including Medical Examiner services and Crime Laboratory services) and Baylor College of Medicine, which conducted genetic analysis on a large cohort of 351 deceased infants, children, and young adults (age range 0-37) in an effort to determine the cause and manner of death (Methner et al 2016).…”

mentioning

confidence: 99%