Next generation sequencing and linkage analysis for the molecular diagnosis of a novel overlapping syndrome characterized by hypertrophic cardiomyopathy and typical electrical instability of brugada syndrome

Background: Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited disorder; mutations in at least 20 genes have been associated. Brugada syndrome (BrS) is an autosomal dominant inherited disorder caused by mutations mainly in the SCN5A gene. A new clinical entity that consists of HCM, typical electrical instability of BrS and sudden death (SD), is described. Methods and Results: The family was constituted by 7 members, 4 of who presented clinical features of HCM and electrical instability of BrS. The clinical presentation of proband was ventricular fibrillation. All members were clinically evaluated by physical examination, 12-lead electrocardiography, 2-dimensional echocardiography, stress test, electrocardiogram Holter, flecainide test, and electrophysiological study. An integrated linkage analysis and next generation sequencing (NGS) approach was used to identify the causative mutation. Linkage with the α-tropomyosin (TPM1) gene on chromosome 15q22 was identified. The NGS study identified a missense mutation within the TPM1 gene (c.574G>A; p.E192K), exactly located in a binding domain with polycystin-2 protein. No other pathogenic mutations were identified. Conclusions: This is the first report of an association between HCM and BrS, and the first to use a combined approach of linkage and NGS to identify a causative mutation in SD. The present study expands the clinical spectrum of disorders associated with the TPM1 gene and may be useful to report novel mechanisms of electrical instability in HCM and BrS.