| Summary: | BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes sudden, premature and unexpected deaths, which remain unexplained despite autopsy. Approximately one-third of SADS relates to inherited conditions such as Brugada syndrome (BrS), long QT syndrome (LQT) and catecholaminergic polymorphic ventricular tachycardia (CPVT). AIMS: We aimed to evaluate clinical utility for novel histopathological and genetic molecular investigation following SADS. METHODS: SADS cases were investigated by: [1] morphometric analysis of picrosirius-red histological myocardial staining; [2] a novel enrichment (Fluidigm Access Array) for BrS, LQT and CPVT risk-genes with next generation sequencing (NGS); [3] NGS of risk-genes in an international cohort; [4] genotyping putative functional exomic variants (Illumina BeadChip); 5) whole exome sequencing in a family. RESULTS: [1] Regression analysis demonstrated that BrS cases have a 42% excess in interstitial fibrosis over age and gender-matched non-cardiac deaths (P=0.026, n=6). No association was seen between BrS and intramyocardial fat distribution (P=0.133). [2] Optimisation of bioinformatics of NGS resulted in a sensitivity of 80.72% and specificity of 99.99% for genetic variation on molecular autopsy of 46 British SADS cases; all disease-causing mutations were identified correctly (6.4%). [3] Diagnostic yield ofNGS molecular autopsy was established as 13.2% (95% CI: 7.8-18.9%) by replication in 151 additional multi-ethnic SADS cases. [4] Exomic genotyping of 82 British SADS cases and 376 ethnically-matched controls revealed 8 significantly SADS-associated genes, though none were known cardiac risk-genes. The reported association of rs1559040 (chromosome 2) with cardiac arrest in coronary disease was replicated. [5] Four possible risk-genes for SADS were implicated from 46 candidates using co-segregation analysis and subsequent prioritisation following whole exome sequencing in a multi-generational pedigree. D ISCUSSION: We report here on fibrotic features of BrS, screening utility of NGS molecular autopsy following SADS and novel potential risk-genes for further study.
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