Abstract-Mutations in SCN5A, the gene encoding the cardiac Na ϩ channel, have been identified in 2 distinct diseases associated with sudden death: one form of the long-QT syndrome (LQT 3 ) and the Brugada syndrome. We have screened SCN5A in a large 8-generation kindred characterized by a high incidence of nocturnal sudden death, and QT-interval prolongation and the "Brugada ECG" occurring in the same subjects. An insertion of 3 nucleotides (TGA) at position 5537, predicted to cause an insertion of aspartic acid (1795insD) in the C-terminal domain of the protein, was linked to the phenotype and was identified in all electrocardiographically affected family members. ECGs were obtained from 79 adults with a defined genetic status (carriers, nϭ43; noncarriers, nϭ36). In affected individuals, PR and QRS durations and QT intervals are prolonged (PϽ0.0001 for all parameters). ST segment elevation in the right precordial leads is present as well (PϽ0.0001). Twenty-five family members died suddenly, 16 of them during the night. Expression of wild-type and mutant Na ϩ channels in Xenopus oocytes revealed that the 1795insD mutation gives rise to a 7.3-mV negative shift of the steady-state inactivation curve and an 8.1-mV positive shift of the steady-state activation curve. The functional consequence of both shifts is likely to be a reduced Na ϩ current during the upstroke of the action potential. LQT 3 and Brugada syndrome are allelic disorders but may also share a common genotype. Key Words: long-QT syndrome Ⅲ Brugada syndrome Ⅲ SCN5A Ⅲ arrhythmia Ⅲ Na ϩ channel S CN5A, the gene that encodes the human cardiac Na ϩ channel ␣ subunit, 1 is mutated in one form of the long-QT syndrome (LQT 3 ) and in Brugada syndrome. 2,3 There are characteristic and readily distinguishable ECG patterns in these 2 syndromes. In LQT 3 patients, a long isoelectric ST segment precedes a peaked T wave. 4 Brugada syndrome is diagnosed on the basis of characteristic ECG features in the absence of structural heart disease; these features include right precordial ST-segment elevation, which may be intermittent, and which is exacerbated by Na ϩ channel block and ameliorated by isoproterenol. 5,6 QT intervals have been reported to be normal in patients with Brugada syndrome. 5 Clinically, there appears to be some overlap between the 2 syndromes, as both exhibit a relatively high incidence of nocturnal sudden cardiac death without prior symptoms. 6 -8 The prolonged QT interval in LQT 3 results from persistent inward Na ϩ current during the plateau phase of the action potential, secondary to incomplete inactivation of mutated channels. 9 Changes in the ␣ and ␤ 1 subunit interaction have also been implicated. 10 Although functional abnormalities have been described for Brugada syndrome-related SCN5A mutant channels, 3,11 the mechanism(s) whereby these explain the Brugada phenotype are less clear.In this study we present clinical and genetic data of a single large SCN5A-linked family, phenotypically characterized by nocturnal death and electrocardiograph...

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BackgroundRecently, we showed that the c.40_42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10–15 % of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death.MethodsOur goal was to evaluate the geographical distribution and the origin of this specific mutation in the Netherlands and to get an estimation of the prevalence in a Dutch population cohort. Therefore, we investigated the postal codes of the places of residence of PLN p.Arg14del mutation carriers and places of birth of their ancestors. In addition, a large population-based cohort (PREVEND) was screened for the presence of this mutation.ResultsBy April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. A total of 358 family members were also found to carry this mutation, resulting in a total of 459 mutation carriers. The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents’ places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07 %).ConclusionThe p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. The mutation that arose 575–825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands.