Recurrent and founder mutations in the Netherlands—Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy

Abstract

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.

Sudden Cardiac Arrest and Rare Genetic Variants in the Community

“…We looked up the prevalence of this mutation in the database of the PREVEND study, which consisted of 8267 individuals recruited from the region where PLN-p.Arg14del is thought to have originated and where it is, therefore, expected to be most prevalent in the general population. 17,26 We found that PLN-R14del occurred significantly more often in ARREST than in PREVEND (0.56% versus 0.07%, Fisher's exact; P<0.0003, Table 2). …”

“…[11][12][13][14][15] For instance, the PLN-p.Arg14del mutation, identified in 10% to 15% of Dutch patients with DCM or ARVC, is the most prevalent cardiomyopathy-associated mutation in the Netherlands. 17 Similarly, the MYBPC3-p. Trp792fsX17 mutation is found in 17% of hypertrophic cardiomyopathy index patients in the Netherlands. 27 Of note, besides their recurrence in patients with similar phenotypes, the pathogenicity of some of the mutations has also been demonstrated in functional studies.…”

“…For instance, the PLN-p.Arg14del mutation is clearly pathogenic 26 and not unique to the Netherlands because it belongs to the European-shared founder mutation category 36 and was also found in Germany and in the United States, suggesting a possible common ancestor from the Netherlands between these populations. 17 In hot spots for this mutation in these countries, specific screening for this mutation and other locally identified founder mutations may be considered in SCA patients.…”

“…17 This study was conducted at the Academic Medical Center, a university hospital in Amsterdam, the Netherlands, and approved by the relevant Medical Ethics Committees. Informed consent was obtained from all controls and cases who survived their SCA.…”

Founder Mutation Genotyping and Sudden Cardiac Arrest

“…12,13 Similarly within Finland, 2 founder mutations account for as much as 18% of all hypertrophic cardiomyopathy in that population.…”