H1153Y-KCNH2 Mutation Identified in a Sudden Arrhythmic Death Syndrome Case Alters Channel Gating

Long QT syndrome is one of the most common hereditary channelopathies inducing fatal arrhythmias and sudden cardiac death. We identified in a sudden arrhythmic death syndrome case a C-term KCNH2 mutation (c.3457C > T; p.His1153Tyr) classified as variant of unknown significance and functional impact. Heterologous expression in HEK293 cells combined with western-blot, flow-cytometry, immunocytochemical and microscope analyses shows no modification of channel trafficking to the cell membrane. Electrophysiological studies reveal that the mutation causes a loss of HERG channel function through an alteration of channel biophysical properties that reduces the current density leading to LQT2. These results provide the first functional evidence for H1153Y-KCNH2 mutation-induced abnormal channel properties. They concur with previous biophysical and clinical presentations of a survived patient with another variant that is G1036D. Therefore, the present report importantly highlights the potential severity of variants that may have useful implications for treatment, surveillance, and follow-up of LQT2 patients.

Rare health conditions 49: sudden arrhythmic death syndrome (SADS), sudden infant death syndrome (SIDS), and Hansen's disease

The purpose of this series is to highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually fewer than 1 person in every 2000. Many healthcare assistants and nurses will encounter some of these conditions, given the high number of them. This 49th article will explore three of these conditions: sudden arrhythmic death syndrome (SADS); sudden infant death syndrome (SIDS); and Hansen's disease.

Low Birth Weight Increases the Risk of Sudden Cardiac Death in the Young: A Nationwide Study of 2.2 Million People

Background Sudden cardiac death (SCD) constitutes a major health problem worldwide. We investigated whether birth weight (BW), small for gestational age (SGA), and large for gestational age are associated with altered risk of SCD among the young (aged 1–36 years). Methods and Results We included all people born in Denmark from 1973 to 2008 utilizing the Danish Medical Birth Register. All SCDs in Denmark in 2000 to 2009 have previously been identified. We defined 5 BW groups, SGA, and large for gestational age as exposure and SCD as the outcome. We estimated the age‐specific relative risk of SCD with 95% CI. Additionally, we investigated if SGA and large for gestational age are associated with pathological findings at autopsy. The study population for the BW analyses comprised 2 234 501 people with 389 SCD cases, and the SGA and large for gestational age analyses comprised 1 786 281 people with 193 SCD cases. The relative risk for SCD was 6.69 for people with BW between 1500 and 2499 g (95% CI, 2.38–18.80, P <0.001) and 5.89 for people with BW ≥4500 g (95% CI, 1.81–19.12, P =0.003) at age 5 years. BW 2500 to 3400 g was the reference group. Compared with an appropriate gestational age, the relative risk for SGA was 2.85 (95% CI, 1.35–6.00, P =0.006) at age 10 years. For the autopsied cases, the relative risk of sudden arrhythmic death syndrome at age 5 years was 4.19 for SGA (95% CI, 1.08–16.22, P =0.038). Conclusions We found an association between BW and SCD in the young, with an increased risk among SGA infants. In addition, we found an association between SGA and sudden arrhythmic death syndrome.

Sudden Cardiac Death in the Young

Background: Sudden cardiac death (SCD) in the young is devastating. Contemporary incidence remains unclear with few recent nationwide studies and limited data addressing risk factors for causes. We aimed to determine incidence, trends, causes, and risk factors for SCD in the young. Methods and Results: The National Coronial Information System registry was reviewed for SCD in people aged 1 to 35 years from 2000 to 2016 in Australia. Subjects were identified by the International Classification of Diseases , Tenth Revision code relating to circulatory system diseases (I00–I99) from coronial reports. Baseline demographics, circumstances, and cause of SCD were obtained from coronial and police reports, alongside autopsy and toxicology analyses where available. During the study period, 2006 cases were identified (median age, 28±7 years; men, 75%; mean body mass index, 29±8 kg/m 2 ). Annual incidence ranged from 0.91 to 1.48 per 100 000 age-specific person-years, which was the lowest in 2013 to 2015 compared with previous 3-year intervals on Poisson regression model ( P =0.001). SCD incidence was higher in nonmetropolitan versus metropolitan areas (0.99 versus 0.53 per 100 000 person-years; P <0.001). The most common cause of SCD was coronary artery disease (40%), followed by sudden arrhythmic death syndrome (14%). Incidence of coronary artery disease–related SCD decreased from 2001–2003 to 2013–2015 ( P <0.001). Proportion of SCD related to sudden arrhythmic death syndrome increased during the study period ( P =0.02) although overall incidence was stable ( P =0.22). Residential remoteness was associated with coronary artery disease–related SCD (odds ratio, 1.44 [95% CI, 1.24–1.67]; P <0.001). For every 1-unit increase, body mass index was associated with increased likelihood of SCD from cardiomegaly (odds ratio, 1.08 [95% CI, 1.05–1.11]; P <0.001) and dilated cardiomyopathy (odds ratio, 1.04 [95% CI, 1.01–1.06]; P =0.005). Conclusions: Incidence of SCD in the young and specifically coronary artery disease–related SCD has declined in recent years. Proportion of SCD related to sudden arrhythmic death syndrome increased over the study period. Geographic remoteness and obesity are risk factors for specific causes of SCD in the young.

Prevalence of sudden arrhythmic death syndrome-related genetic mutations in an Asian cohort of whole genome sequence

Aims Recently, the spectrum of background mutation in the genes implicated in sudden arrhythmic death syndrome (SADS), has been elucidated in the Caucasian populations. However, this information is largely unknown in the Asian populations. Methods and results We assessed the background rare variants (minor allele frequency &lt; 0.01) of major SADS genes in whole genome sequence data of 1514 healthy Taiwanese subjects from the Taiwan Biobank. We found up to 45% of healthy subjects have a rare variant in at least one of the major SADS genes. Around 3.44% of healthy subjects had multiple mutations in one or multiple genes. The background mutation rates in long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy genes were similar, but those in Brugada syndrome (BrS) (SCN5A) and hypertrophic cardiomyopathy (HCM) genes (MYBPC3, MYH7, and TNNT2) were higher, compared to those reported in the Caucasian populations. Furthermore, the rate of incidental pathogenic variant was highest in MYBPC3 gene. Finally, the number of variant was proportional to the exon length of the gene (R2 = 0.486, P = 0.0056) but not related to its functional or evolutionary importance (degree of evolutionary conservation) (R2 = 0.0008, P = 0.9218), suggesting that the mutation was random. The ratio of variant number over exon nucleotide length was highest in MYBPC3, MYH7, and TNNT2 genes. Conclusion Unique features of background SADS gene mutation in the Asian populations include higher prevalence of incidental variant in HCM, BrS, and long QT 3 (SCN5A) genes. HCM genes have the highest variant number per exon length.

Getting to the heart of the matter: investigating the idiopathic sudden cardiac death of a previous well soldier

A 25-year-old infantry soldier, who was previously fit and well, had a cardiac arrest while undertaking an advanced fitness test. Despite early cardiopulmonary resuscitation by colleagues and the emergency services, he was later pronounced dead. A postmortem performed by an expert pathologist and a toxicology screen were normal and the death was attributed to sudden arrhythmic death syndrome (SADS). Screening of his family in our Inherited Cardiac Conditions clinic identified Brugada syndrome (BrS) in two first-degree relatives. This case generates discussion on sudden cardiac death, family screening in SADS, BrS and the limitations of recruit screening with an ECG.

Postmortem genetic testing in sudden death cases

Postmortem analysis of young sudden cardiac death patients leads to a diagnosis of structural cardiac disease in the majority of cases. However, despite thorough autopsy, including toxicological and histological analysis, in one-third of patients no cause of death is identified and these patients are classified as sudden unexplained death or sudden arrhythmic death syndrome. Postmortem genetic testing in these patients can establish a genetic aetiology of sudden cardiac death, which allows for appropriate screening and management of family members at risk of sudden cardiac death.