Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients

Fodstad, Heidi; Bendahhou, Saı̈d; Rougier, Jean-Sébastien; Laitinen-Forsblom, Päivi J.; Barhanin, Jacques; Abriel, Hugues; Schild, Laurent; Kontula, Kimmo; Swan, Heikki

doi:10.1080/07853890600756065

Cited by 38 publications

(57 citation statements)

References 43 publications

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“…22) Contrasting evidence of the pathogenicity of this mutation can be found in the literature and many authors report clinical variability and low penetrance. [23][24][25] Since we identified the p.(Arg176Trp) in two healthy individuals from two different families, our results seem to support the hypothesis that this variation is likely benign. The proband is on beta-blocker therapy with good clinical results.…”

Section: Discussionsupporting

confidence: 74%

Gene-Targeted Analysis of Clinically Diagnosed Long QT Russian Families

Maltese¹,

Orlova

Красикова

et al. 2017

Int. Heart J.

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SummaryLong QT syndrome (LQTS) has great genetic heterogeneity: more than 500 mutations have been described in several genes. Despite many advances, a genetic diagnosis still cannot be established in 25-30% of patients. The aim of the present study was to perform genetic evaluation in 9 Russian families with LQTS; here we report the results of 4 positive probands and their relatives (a total of 16 individuals). All subjects underwent clinical examination, 12-lead ECG, and Holter monitoring. Genetic analysis of the 14 genes mainly involved in LQTS was performed using a next-generation sequencing approach. We identified two new mutations (KCNQ1 gene) and 6 known mutations (AKAP9, ANK2, KCNE1 and KCNJ2 genes) in 4 out of 9 probands, some of which have already been described in association with LQTS. Segregation studies suggest a possible causative role for KCNQ1 p.(Leu342Pro), AKAP9 p.(Arg1609Lys), KCNE1 p.(Asp85Asn), and KCNJ2 p.(Arg82Gln) variations. Our study confirmed the high genetic heterogeneity of this disease and highlights the difficulties to reveal clear pathogenic genotypes also in large pedigrees. To the best of our knowledge, this is the first genetic study of LQTS patients from Russian families. (Int Heart J 2017; 58: 81-87)

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Section: Discussionsupporting

confidence: 74%

Gene-Targeted Analysis of Clinically Diagnosed Long QT Russian Families

Maltese¹,

Orlova

Красикова

et al. 2017

Int. Heart J.

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“…Antiarrhythmic effects associated with HSP70 cellular expression [31] may just be one of many functions of these proteins and a sign of stress handling capacity of an individual, which can be lost due to defects of members of this family of proteins. Because of the important function of HSP70 protein for the maturation of cardiac potassium channel hERG [28] and hERGs’ involvements in long QT phenotype [33, 34], we examined the effect of 493Thr on the QTc measurements in the patients. However, we did not find statistically significant differences between different genetic groups (p > 0.1, table 3).…”

Section: Discussionmentioning

confidence: 99%

Association of Met439Thr Substitution in Heat Shock Protein 70 Gene with Postoperative Atrial Fibrillation and Serum HSP70 Protein Levels

et al. 2007

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Background: Atrial fibrillation (AF) is a common arrhythmia encountered following cardiac surgery. Previously, we have shown that higher expression of heat shock protein (HSP) 70 was associated with decreased incidence of postoperative AF (PoAF), suggestive of an antiarrhythmic role. Objective: We have hypothesised that Met493Thr substitution of one of the important hsp70 genes may cause loss of these protective antiarrhythmic effects. We therefore set out to examine the influence of hsp70 genotype on the incidence of PoAF. Methods and Results: We prospectively recruited 244 Caucasian patients undergoing elective coronary artery bypass surgery. The median age was 65 years (40–80 years). PoAF was defined as the characteristic arrhythmia lasting for at least 15 min, occurring within first week following surgery and requiring treatment. This occurred in 48 patients (19.7%). Validated Met493Thr substitution in hsp70-Hom was determined using established techniques. Of 244 patients, genotype was determined for 242 cases. The three genotypes (MM, MT, and TT) were present at frequencies of 0.66, 0.31, and 0.03, respectively, and were in Hardy-Weinberg equilibrium. In unifactorial analysis patients carrier or homozygous for 493Thr mutation had significantly higher incidence of PoAF (Pearson χ² = 4.3, p = 0.037). Multivariate analysis confirmed the positive association of hsp70-Hom with PoAF (OR, 2.43; p = 0.016) independent of age, sex, previous myocardial infarction, number of distal anastomoses, and duration of ventilation, respectively. Serum HSP70 was ranging from 0.74 to 31.91 ng/ml (median, 2.89) and was not correlated with PoAF. Presence of 493Thr mutation was also significantly correlated with higher levels of serum HSP70 (p = 0.009). Conclusions: Our data show that a mutation in hsp70-Hom gene is associated with higher incidence of PoAF. These findings are consistent with our previous results and may suggest that patients harbouring this substitution will have less endogenous myocardial protection against AF in stressful situations.

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“…Strategies for efficient mutation identification by judicious selection of genes-which would reduce the resources required in screening-based on the relative frequencies of different genetic etiologies have been proposed , but the occurrence of compound heterozygotes [Berge et al, 2008], digenic inheritance [Larsen et al, 1999b;Priori et al, 1998;Ning et al, 2003;Fodstad et al, 2006;Schwartz et al, 2003], and modifying genes [Westenskow et al, 2004;Crotti et al, 2005;Ye et al, 2003] would seem to necessitate a comprehensive screening strategy comprising all genes. This also seems to be the case even in populations where founder mutations are frequent; e.g., the white South African population [Hedley et al, unpublished data].…”

Section: Methods Of Mutation Screeningmentioning

confidence: 99%

The genetic basis of long QT and short QT syndromes: A mutation update

et al. 2009

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Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS-and SQTS-associated mutations.

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Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients

Abstract: The HERG R176W mutation represents a population-prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS.

Cited by 38 publications

References 43 publications

Gene-Targeted Analysis of Clinically Diagnosed Long QT Russian Families

Gene-Targeted Analysis of Clinically Diagnosed Long QT Russian Families

Association of Met439Thr Substitution in Heat Shock Protein 70 Gene with Postoperative Atrial Fibrillation and Serum HSP70 Protein Levels

The genetic basis of long QT and short QT syndromes: A mutation update

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