Molecular diagnosis in a child with sudden infant death syndrome

doi:10.1016/S0140-6736(01)06450-9

The Lancet

Volume 358, Issue 9290, 20 October 2001, Pages 1342-1343

https://doi.org/10.1016/S0140-6736(01)06450-9 Get rights and content

Summary

Although sudden infant death syndrome (SIDS) has been associated with long QT syndrome—a genetic disorder that causes arrhythmia—a causal link has not been shown. We screened genomic DNA from a child who died of SIDS and identified a de-novo mutation in KVLQT1, the gene most frequently associated with long QT syndrome. This mutation (C350T) had already been identified in an unrelated family that was affected by long QT syndrome. These results confirm the hypothesis that some deaths from SIDS are caused by long QT syndrome and support implementation of neonatal electrocardiographic screening.

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There are more references available in the full text version of this article.

Cited by (156)

Exome analysis focusing on epilepsy-related genes in children and adults with sudden unexplained death
2023, Seizure
Genetic studies in sudden infant death syndrome (SIDS) and sudden unexplained death (SUD) cohorts have indicated that cardiovascular diseases might have contributed to sudden unexpected death in 20–35 % of autopsy-negative cases. Sudden unexpected death can also occur in people with epilepsy, termed as sudden unexpected death in epilepsy (SUDEP). The pathophysiological mechanisms of SUDEP are not well understood, but are likely multifactorial, including seizure-induced hypoventilation and arrhythmias as well as genetic risk factors. The sudden death of some of the SIDS/SUD victims might also be explained by genetic epilepsy, therefore this study aimed to expand the post-mortem genetic analysis of SIDS/SUD cases to epilepsy-related genes.
Existing whole-exome sequencing data from our 155 SIDS and 45 SUD cases were analyzed, with a focus on 365 epilepsy-related genes. Nine of the SUD victims had a known medical history of epilepsy, seizures or other underlying neurological conditions and were therefore classified as SUDEP cases.
In our SIDS and SUD cohorts, we found epilepsy-related pathogenic/likely pathogenic variants in the genes OPA1, RAI1, SCN3A, SCN5A and TSC2.
Post-mortem analysis of epilepsy-related genes identified potentially disease-causing variants that might have contributed to the sudden death events in our SIDS/SUD cases. However, the interpretation of identified variants remains challenging and often changes over time as more data is gathered. Overall, this study contributes insight in potentially pathophysiological epilepsy-related mechanisms in SIDS, SUD and SUDEP victims and underlines the importance of sensible counselling on the risk and preventive measures in genetic epilepsy.
hERG1 channel subunit composition mediates proton inhibition of rapid delayed rectifier potassium current (I<inf>Kr</inf>) in cardiomyocytes derived from hiPSCs
2023, Journal of Biological Chemistry
Citation Excerpt :
Long QT syndrome is the leading cause of arrhythmic death in children and accounts for 5-10% of sudden infant death syndrome (SIDS) and intrauterine fetal death cases (3-8). Furthermore, multiple LQTS-associated KCNH2 variants have been linked with intrauterine fetal death and SIDS, underscoring the importance of hERG1 in the young heart (3,9-13). At least two hERG1 subunits comprise native hERG1 channels, hERG1a and hERG1b (14-18).
The voltage-gated channel, hERG1, conducts the rapid delayed rectifier potassium current (I_Kr) and is critical for human cardiac repolarization. Reduced I_Kr causes long QT syndrome and increases the risk for cardiac arrhythmia and sudden death. At least two subunits form functional hERG1 channels, hERG1a and hERG1b. Changes in hERG1a/1b abundance modulate I_Kr kinetics, magnitude, and drug sensitivity. Studies from native cardiac tissue suggest that hERG1 subunit abundance is dynamically regulated, but the impact of altered subunit abundance on I_Kr and its response to external stressors is not well understood. Here, we used a substrate-driven human-induced pluripotent stem cell–derived cardiomyocyte (hiPSC-CM) maturation model to investigate how changes in relative hERG1a/1b subunit abundance impact the response of native I_Kr to extracellular acidosis, a known component of ischemic heart disease and sudden infant death syndrome. I_Kr recorded from immatured hiPSC-CMs displays a 2-fold greater inhibition by extracellular acidosis (pH 6.3) compared with matured hiPSC-CMs. Quantitative RT-PCR and immunocytochemistry demonstrated that hERG1a subunit mRNA and protein were upregulated and hERG1b subunit mRNA and protein were downregulated in matured hiPSC-CMs compared with immatured hiPSC-CMs. The shift in subunit abundance in matured hiPSC-CMs was accompanied by increased I_Kr. Silencing hERG1b’s impact on native I_Kr kinetics by overexpressing a polypeptide identical to the hERG1a N-terminal Per-Arnt-Sim domain reduced the magnitude of I_Kr proton inhibition in immatured hiPSC-CMs to levels comparable to those observed in matured hiPSC-CMs. These data demonstrate that hERG1 subunit abundance is dynamically regulated and determines I_Kr proton sensitivity in hiPSC-CMs.
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Research LettersMolecular diagnosis in a child with sudden infant death syndrome

Summary

The sudden infant death syndrome: cardio-respiratory mechanisms and interventions

Ann NY Acad Sci

Prolongation of the QT interval and the sudden infant death syndrome

N Engl J Med

Research Letters
Molecular diagnosis in a child with sudden infant death syndrome