Abstract:Objective:SCN5A encodes alpha subunit of the major sodium channel (Nav1.5) in human cardiac tissue. Malfunction of this cardiac sodium channel is associated with a variety of cardiac arrhythmias and myocardial inherited diseases.Methods:Fifty-three members from three families each diagnosed with long-QT syndrome type 3 (LQTS3), Brugada syndrome (BrS), or sick sinus syndrome (SSS) were included in this observational, cross-sectional study. In this study, we analyzed the sequences of coding region of the SCN5A g… Show more
“…Loss‐of‐function variants in SCN5A are known to be pathogenic [60, 61]. This particular variant has been reported in individuals with Brugada syndrome [62–64]. Genetic testing of the deceased's family members identified the same sequence variant in three of four siblings and the mother of the deceased (Figure 3).…”
Sudden unexplained death in the young poses a diagnostically challenging situation for practicing autopsy pathologists, especially in the absence of anatomic and toxicological findings. Postmortem genetic testing may identify pathogenic variants in the deceased of such cases, including those associated with arrhythmogenic channelopathies and cardiomyopathies. The Wisconsin State Laboratory of Hygiene (WSLH) is a state‐run public health laboratory which performs postmortem genetic testing at no cost to Wisconsin medical examiners and coroners. The current study examines sequencing data from 18 deceased patients (ages 2 months to 49 years, 5 females) submitted to WSLH, from 2016 to 2021. Panel‐based analysis was performed on 10 cases, and whole exome sequencing was performed on the most recent 8 cases. Genetic variants were identified in 14 of 18 decedents (77.8%), including 7 with pathogenic or likely pathogenic variants (38.9%). Whole exome sequencing was more likely to yield a positive result, more variants per decedent, and a larger number of variants of uncertain significance. While panel‐based testing may offer definitive pathogenic variants in some cases, less frequent variants may be excluded. Whole exome testing may identify rare variants missed by panels, but increased yield of variants of uncertain significance may be difficult to interpret. Postmortem genetic testing in young decedents of sudden unexplained death can provide invaluable information to autopsy pathologists to establish accurate cause and manner of death and to decedent's relatives to allow appropriate management. A public health laboratory model may be a financially advisable alternative to commercial laboratories for medical examiner's/coroner's offices.
“…Loss‐of‐function variants in SCN5A are known to be pathogenic [60, 61]. This particular variant has been reported in individuals with Brugada syndrome [62–64]. Genetic testing of the deceased's family members identified the same sequence variant in three of four siblings and the mother of the deceased (Figure 3).…”
Sudden unexplained death in the young poses a diagnostically challenging situation for practicing autopsy pathologists, especially in the absence of anatomic and toxicological findings. Postmortem genetic testing may identify pathogenic variants in the deceased of such cases, including those associated with arrhythmogenic channelopathies and cardiomyopathies. The Wisconsin State Laboratory of Hygiene (WSLH) is a state‐run public health laboratory which performs postmortem genetic testing at no cost to Wisconsin medical examiners and coroners. The current study examines sequencing data from 18 deceased patients (ages 2 months to 49 years, 5 females) submitted to WSLH, from 2016 to 2021. Panel‐based analysis was performed on 10 cases, and whole exome sequencing was performed on the most recent 8 cases. Genetic variants were identified in 14 of 18 decedents (77.8%), including 7 with pathogenic or likely pathogenic variants (38.9%). Whole exome sequencing was more likely to yield a positive result, more variants per decedent, and a larger number of variants of uncertain significance. While panel‐based testing may offer definitive pathogenic variants in some cases, less frequent variants may be excluded. Whole exome testing may identify rare variants missed by panels, but increased yield of variants of uncertain significance may be difficult to interpret. Postmortem genetic testing in young decedents of sudden unexplained death can provide invaluable information to autopsy pathologists to establish accurate cause and manner of death and to decedent's relatives to allow appropriate management. A public health laboratory model may be a financially advisable alternative to commercial laboratories for medical examiner's/coroner's offices.
“…11 , 12 SCN5A c.664C>T, p.Arg222Ter mutation is a nonsense mutation in exon 6 and is observed in individuals tested for LQTS and 1 with BrS. 6 , 7 , 8 Although in vitro recapitulation of the patient’s mixed phenotypes was not provided, we introduced a case enabling further exploration of SCN5A and interpretation of the cardiac sodium channel.…”
Section: Discussionmentioning
confidence: 99%
“…Therefore, multiple clinical features may coexist within a patient, which is referred to as SCN5A overlap syndrome. 4 , 5 In this case, we describe a patient with SCN5A nonsense mutation (c.664C>T, p.Arg222Ter), previously classified as a pathogenic variant observed in both BrS and individuals tested for LQTS, 6 , 7 , 8 displaying a wide spectrum of rhythm disturbances in conjunction with familial history. Key Teaching Points We reported a novel clinical presentation of a known pathogenic mutation of SCN5A (c.664C>T, p.Arg222Ter) with a family history encompassing various transient electrocardiogram (ECG) features of long QT syndrome, Brugada syndrome, sick sinus syndrome, conduction abnormalities, atrial fibrillation, and marginally increased left ventricular cavity size.…”
Section: Introductionmentioning
confidence: 96%
“…Therefore, multiple clinical features may coexist within a patient, which is referred to as SCN5A overlap syndrome. 4,5 In this case, we describe a patient with SCN5A nonsense mutation (c.664C>T, p.Arg222Ter), previously classified as a pathogenic variant observed in both BrS and individuals tested for LQTS, [6][7][8] displaying a wide spectrum of rhythm disturbances in conjunction with familial history.…”
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