About 2-7% of familial cardiomyopathy cases are caused by a mutation in the gene encoding cardiac troponin I (TNNI3). The related clinical phenotype is usually severe with early onset. Here we report on all currently known mutations in the Dutch population and compared these with those described in literature.

BACKGROUND AND OBJECTIVE: The long-QT syndrome (LQTS) is associated with premature sudden cardiac deaths affecting whole families and is caused by mutations in genes encoding for cardiac proteins. When the same mutation is found in different families (recurrent mutations), this may imply either a common ancestor (founder) or multiple de novo mutations. We aimed to review recurrent mutations in patients with LQTS. METHODS: By use of our databases, we investigated the number of mutations that were found recurrently (at least three times) in LQT type 1-3 patients in the Netherlands. We studied familial links in the apparently unrelated probands, and we visualised the geographical distribution of these probands. Our results were compared with published literature of founder effects in LQTS outside the Netherlands. RESULTS: We counted 14 recurrent LQT mutations in the Netherlands. There are 326 identified carriers of one of these mutations. For three of these mutations, familial links were found between apparently unrelated probands. CONCLUSION: Whereas true LQT founder mutations are described elsewhere in the world, we cannot yet demonstrate a real founder effect of these recurrent mutations in the Netherlands. Further studies on the prevalence of these mutations are indicated, and haplotype-sharing of the mutation carriers is pertinent to provide more evidence for founder mutation-based LQTS pathology in our country.

Background. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetrance and a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene (PKP2) are detected in about 50% of ARVC/D patients. The p. Arg79X mutation in PKP2 has been identified in Europe and North America and has been functionally characterised. We evaluated the prevalence of the p. Arg79X mutation in PKP2 in the Dutch population.Methods. Twelve index patients and 41 family members were evaluated in three university hospitals in the Netherlands. The diagnosis of ARVC/D was established according to the recently revised Task Force Criteria. Segregation of the p. Arg79X mutation was studied and haplotypes were reconstructed to determine whether the p. Arg79X mutation was a recurrent or a founder mutation.Results. The p. Arg79X mutation in PKP2 was identified in 12 index patients. Haplotype analysis revealed a shared haplotype among Dutch p. Arg79X mutation carriers, indicating a common founder. Six index patients (50%) had a first-or second-degree relative who had died of sudden cardiac death below 40 years of age. At age 60, only 60% of the mutation carriers had experienced any symptoms. There was no significant difference in symptom-free survival and event-free survival between men and women.Conclusion. We have identified the largest series of patients with the same desmosome gene mutation in ARVC/D reported to date. This p. Arg79X mutation in PKP2 is a founder mutation in the Dutch population. The phenotypes of PKP2 p. Arg79X mutation carriers illustrate the clinical variability and reduced penetrance often seen in ARVC/D. (Neth Heart J 2010; 18: 583-91.)

OBJECTIVE:To determine the pattern of referral of Dutch patients with a long-QT syndrome (LQTS) on the basis of the postal codes of the LQTS probands from whom blood samples were submitted for DNA diagnostics.DESIGN:. Retrospective cohort study.METHOD:From the databases that are coupled to DNA diagnostics, all index patients were included for whom LQTS diagnostics had been requested during the period 1996-2005 at two clinical genetics centres (the University Medical Centre in Amsterdam and Maastricht University Hospital). The results were related to the postal code of the referred patient and corrected for the number of inhabitants of the region concerned.RESULTS:A total of 421 potential LQTS probands were included. Corrected for the numbers of inhabitants in the various postal codes, the number of referrals varied from 3 per million to 110 per million inhabitants. In view of the most recent estimated prevalence of LQTS (1:2000), this means that only 15% ofthe carriers of the LQTS mutation have so far been detected.CONCLUSION:There were large regional differences in the Netherlands in the requests for DNA diagnostics in patients with clinical LQTS. The overwhelming majority of the LQTS patients in the Netherlands have not yet been referred or identified. Expanding the available courses for general practitioners and cardiologists that are given by the staff of the cardiogenetic centres would seem to be indicated.

We identified four novel SCN5A mutations in patients with BrS out of eighteen patients tested (22% novel positive identification). A mutation in an untranslated region of the SCN5A gene is recognized, which correlates with a severe clinical phenotype. Thus, our data stress the importance of genetic testing of noncoding regions in BrS.

Background— Mutations in the plakophilin-2 gene ( PKP2 ) have been found in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC). Hence, genetic screening can potentially be a valuable tool in the diagnostic workup of patients with ARVC. Methods and Results— To establish the prevalence and character of PKP2 mutations and to study potential differences in the associated phenotype, we evaluated 96 index patients, including 56 who fulfilled the published task force criteria. In addition, 114 family members from 34 of these 56 ARVC index patients were phenotyped. In 24 of these 56 ARVC patients (43%), 14 different (11 novel) PKP2 mutations were identified. Four different mutations were found more than once; haplotype analyses revealed identical haplotypes in the different mutation carriers, suggesting founder mutations. No specific genotype-phenotype correlations could be identified, except that negative T waves in V 2 and V 3 occurred more often in PKP2 mutation carriers ( P <0.05). Of the 34 index patients whose family members were phenotyped, 23 familial cases were identified. PKP2 mutations were identified in 16 of these 23 ARVC index patients (70%) with familial ARVC. On the other hand, no PKP2 mutations at all were found in 11 probands without additional affected family members ( P <0.001). Conclusions— PKP2 mutations can be identified in nearly half of the Dutch patients fulfilling the ARVC criteria. In familial ARVC, even the vast majority (70%) is caused by PKP2 mutations. However, nonfamilial ARVC is not related to PKP2 . The high yield of mutational analysis in familial ARVC is unique in inherited cardiomyopathies.

BACKGROUND Atrial Fibrillation (AF), the most common cardiac arrhythmia, is a significant public health problem in the United States, affecting approximately 2.2 million Americans. Recently, several chromosomal loci and genes have been found to be associated with familial AF. However, in most other AF cases, the genetic basis is still poorly understood.OBJECTIVE The purpose of this study was to investigate the molecular basis of familial AF in a Dutch kindred group.METHODS We analyzed a four-generation Dutch family in which AF segregated as an autosomal dominant trait. After the exclusion of linkage to 10q22-24, 6q14-16, 5p13, KCNQ1, KCNE2, KCNJ2 and some ion-channel-associated candidate genes, a genome-wide linkage scan using 398 microsatellite markers was performed.RESULTS Two-point logarithms of odds (LOD) scores >1 at recombination fraction [theta] = 0.00 and a haplotype segregating with the disorder were demonstrated only across regions of chromosome 10. Subsequent fine mapping gave a maximum two-point LOD score of 4.1982 at D10S568 at [theta] = 0.00. Distinct recombination in several individuals narrowed the shared region among all affected individuals to 16.4 cM on the Genethon map (flanking markers: D10S578 and D10S1652), which corresponds to chromosome 10p11-q21. Thirteen candidate genes residing in this region, which could be associated with AF, were screened. No mutation has been found in their coding regions including the intron splice regions.CONCLUSION We identify a novel locus for AF on chromosome 10p11-q21, which provides further evidence of genetic heterogeneity in this arrhythmia.

Aims Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes that encode sarcomeric proteins. In this study we investigated the involvement of the sarcomeric myosin binding protein C in the Dutch HCM population.Methods and results We initially. screened 22 Dutch index patients for mutations in the MYBPC3 gene, which revealed four different mutations in 14 patients. The 2373insG mutation was identified in 10 apparently unrelated patients. A subsequent screening for the 2373insG mutation in a group of another 237 unrelated HCM patients revealed 50 additional carriers of the same genetic defect. Genotyping with polymorphic repeat markers and intragenic SNPs of the 60 Dutch as well as two German and five North American 2373insG carriers indicated they all share the same haplotype.Conclusion The 2373insG mutation accounts for almost one-fourth of all HCM cases in the Netherlands (60/259), which is predominantly present in the northwestern part of the country (22/66) and is a founder mutation probably originating from the Netherlands. (C) 2003 Published by Elsevier Ltd on behalf of The European Society of Cardiology.

Congenital long QT syndrome (LQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). As a result of these arrhythmias, patients suffer from recurrent syncopes, seizures, or sudden death as the most dramatic event. Mutations in five genes, encoding cardiac ion channels, have been identified in LQTS. Two potassium-channel genes, KCNQ1 (LQT1) and KCNH2 (LQT2 or HERG), are frequently involved in LQTS. Potassium-channel defects account for approximately 50-60% of LQTS. As patients benefit from preventive medication, early detection of a genetic defect is desired to identify the family members at risk. Speed and sensitivity of mutation detection was improved by applying the denaturing high performance liquid chromatography (DHPLC) technique for analysis of the entire KCNQ1 and KCNH2 genes and the protein encoding part of the KCNE1 and KCNE2 genes. By using this methodology, seven missense mutations in the KCNQ1 gene and nine mutations (four missense, two nonsense, one insertion, and two deletions) in the KCNH2 gene have been identified in a total number of 32 index patients diagnosed with LQTS syndrome. We conclude that this method is suitable for rapid identification of LQT gene defects due to the combination of automation, high throughput, sensitivity, and short time of analysis.