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Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1(+/-) mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.

Unlabelled: Women with Brugada Syndrome., Introduction: Spontaneous type-1 ECG has been recognized as a risk factor for sudden cardiac death (SCD) in Brugada syndrome (BrS), but studied populations predominantly consisted of men. We sought to investigate whether a spontaneous type-1 ECG pattern was also associated in women with severely symptomatic BrS. Other known risk factors were also examined for gender specificity., Methods: Patients with severely symptomatic BrS, defined as resuscitated SCD and/or appropriate implantable cardioverter-defibrillator (ICD) shock, were included from 11 European centers. Clinical data, investigation of family history, 12-lead ECG, and results of electrophysiological study (EPS) were collected. The average follow-up was 4 +/- 3 years., Results: Fifty-eight patients fulfilled the inclusion criteria (mean age 47 +/- 11 years, 8 women). Thirty-six men (72%) but only two women (25%) had a spontaneous type-1 ECG at baseline (P = 0.02). Maximal ST elevation before or after drug challenge was 3.7 +/- 1.3 mm in men versus 2.4 +/- 0.7 mm in women (P = 0.007). The proportion of patients with a family history of SCD or an SCN5A mutation was not significantly different between both groups. Of those patients with high-risk BrS who underwent EPS, 76%(12/25) of men and 50%(2/4) of women had a positive study., Conclusion: In contrast to men, most women with BrS and resuscitated SCD or appropriate ICD shock do not have a spontaneous type-1 ECG pattern. In addition, the degree of ST elevation is less pronounced in women than men. While women represent a lower-risk group overall, risk factors established from a predominantly male population may not be helpful in identifying high-risk females.

Background: The prevalence of genetic risk factors has not been systematically evaluated in the setting of complete atriventricular (AV) block complicated by long QT syndrome (LQTS)., Objective: This study was performed to determine to what extent acquired LQTS in the context of AV block has a genetic substrate., Methods: Among 420 recipients of pacemakers implanted over a 3-year period, we identified retrospectively 29 patients with complete AV block and a QT interval >600 ms in duration. A second study group included 22 randomly selected patients who had AV block and a QT interval <600 ms. Normal controls were 100 consecutive individuals without medical history. Genetic studies screening for HERG, KCNQ1 KCNE1, KCNE2, and SCN5A mutations were performed., Results: We identified four mutations on genes encoding potassium channels in five patients with AV block and acquired LQTS. These mutations were not found among patients with AV block and a QT interval <600 ms in duration or in healthy volunteers. Functional expression of three HERG mutations (R328C, R696C, and R1047L) had a dominant negative effect on wild-type I(Kr). One KCNE2 mutation (R77W) identified in a patient treated with flecainide did not alter I(Kr)., Conclusions: This study showed that complete AV block complicated by LQTS was associated with HERG mutations in 17% of cases. Further studies are needed to identify factors, genetic or environmental, which may be implicated in bradycardia-related abnormalities of ventricular repolarization.

The pathophysiology of primary Raynaud's phenomenon (Raynaud's disease) remains uncertain but the transmission of this primary microcirculatory dysregulation seems strongly influenced by genetic factors. For a long time, physicians have found that the hereditary factor plays an important role in the genesis of Raynaud's disease. Familial analysis and twin studies have confirmed the role of an hereditary factor. It seems heterogeneous but pedigree analysis indicates the possibility of an autosomal dominant transmission influenced by sex, in some families, allowing an approach called "reverse genetic" based on linkage analysis. Such an approach has focused on few loci but sequencing of candidate genes for genetic mutations remains negative. Given the supposed heterogeneity of the genetic transmission of Raynaud's disease, diversification of strategies in molecular genetics is suitable with reference to techniques applied to multifactorial heredity.

Objectives: We have tested whether a genotype-phenotype relationship exists in Brugada syndrome (BS) by trying to distinguish BS patients with (carriers) and those without (non-carriers) a mutation in the gene encoding the cardiac sodium channel (SCN5A) using clinical parameters., Background: Brugada syndrome is an inherited cardiac disease characterized by a varying degree of ST-segment elevation in the right precordial leads and (non)specific conduction disorders. In a minority of patients, SCN5A mutations can be found. Genetic heterogeneity has been demonstrated, but other causally related genes await identification. If a genotype-phenotype relationship exists, this might facilitate screening., Methods: In a multi-center study, we have collected data on demographics, clinical history, family history, electrocardiogram (ECG) parameters, His to ventricle interval (HV), and ECG parameters after pharmacologic challenge with I(Na) blocking drugs for BS patients with (n = 23), or those without (n = 54), an identified SCN5A mutation., Results: No differences were found in demographics, clinical history, or family history. Carriers had a significantly longer PQ interval on the baseline ECG and a significantly longer HV time. A PQ interval of > or =210 ms and an HV interval > or =60 ms seem to be predictive for the presence of an SCN5A mutation. After I(Na) blocking drugs, carriers had significantly longer PQ and QRS intervals and more increase in QRS duration., Conclusions: We observed significantly longer conduction intervals on baseline ECG in patients with established SCN5A mutations (PQ and HV interval and, upon class I drugs, more QRS increase). These results concur with the observed loss of function of mutated BS-related sodium channels. Brugada syndrome patients with, and those without, an SCN5A mutation can be differentiated by phenotypical differences.

Sixty patients with recurrent inducible sustained ventricular tachycardia were prospectively treated with nadolol (40 or 80 mg/day). Old myocardial infarction was present in 43 patients and dilated cardiomyopathy in 12. In group I (n = 36), nadolol was given alone, whereas in group II (n = 24), previously ineffective treatment with amiodarone was continued in combination with nadolol. Left ventricular ejection fraction was higher in patients in group I (0.40 +/- 0.12) than in group II (0.30 +/- 0.10, p less than 0.01) patients. Electrophysiologic study was repeated after short-term treatment with nadolol, which was continued regardless of the results of this test, according to the scheme of the parallel approach. Recurrence of spontaneous tachycardia or sudden death occurred in 21 patients after 10 +/- 9.2 months; sustained tachycardia was inducible in 19 on nadolol therapy. The remaining 39 patients (of whom 21 had inducible tachycardia while taking the drug) have had no recurrence of tachycardia after 27.8 +/- 9.3 months of follow-up study. Sensitivity, specificity and predictive value of a positive and negative test were 90.5%, 46%, 47.5% and 90%, respectively. The results differ between group I and group II patients, the latter having a high percent of false positive responses. This difference is even more obvious with respect to left ventricular ejection fraction: the predictive value of a positive test was 86% when ejection fraction was greater than 0.40 and 39% when it was less than 0.40.(ABSTRACT TRUNCATED AT 250 WORDS)