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Aims: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible.Methods and Results: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands.Conclusion: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Takotsubo cardiomyopathy is a syndrome characterized by transient left ventricular apical ballooning associated with electrocardiogram (ECG) changes and minimal myocardial enzymatic release, mimicking acute myocardial infarction in patients without significant coronary disease at angiography. We report an unusual case of a patient who presented with Takotsubo cardiomyopathy associated with long-QT syndrome and who developed cardiac arrest secondary to torsades de pointes.The relationship between Takotsubo cardiomyopathy and abnormal repolarization has been well documented. Despite this, there have been few reports of malignant ventricular arrhythmias or sudden death. This report suggests that prolongation of QTc interval in Takotsubo cardiomyopathy may not be as benign as previously suggested but may in fact uncover an abnormality of repolarization that may be genetic in basis and carry a risk of sudden death. [ABSTRACT FROM PUBLISHER]