Whole-exome sequencing to identify causative variants in juvenile sudden cardiac death.

BACKGROUND: Juvenile sudden cardiac death (SCD) remains unexplained in approximately 40% of cases, leading to a significant emotional burden for the victims' families and society. Comprehensive investigations are essential to uncover its elusive causes and enable cascade family screening. This study aimed to enhance the identification of likely causative variants in juvenile SCD cases (age ≤ 50 years), particularly when autopsy findings are inconclusive. RESULTS: Autopsy revealed diagnostic structural abnormalities in 46%, non-diagnostic findings in 23%, and structurally normal hearts in 31% of cases. Whole-exome sequencing (WES), refined through a customized virtual gene panel was used to identify variants. These variants were then evaluated using a multidisciplinary approach and a structured variant prioritization scheme. Our extended approach identified likely causative variants in 69% of cases, outperforming the diagnostic yields of both the cardio panel and standard susceptibility gene analysis (50% and 16%, respectively). The extended cardio panel achieved an 80% diagnostic yield in cases with structurally normal hearts, demonstrating its efficacy in challenging scenarios. Notably, half of the positive cases harboured a single variant, while the remainder had two or more variants. CONCLUSION: This study highlights the efficacy of a multidisciplinary approach employing WES and a tailored virtual gene panel to elucidate the aetiology of juvenile SCD. The findings support the expansion of genetic testing using tailored gene panels and prioritization schemes as part of routine autopsy evaluations to improve the identification of causative variants and potentially facilitate early diagnosis in first-degree relatives.

Magnetic Resonance Imaging Characterization and Clinical Outcomes of Dilated and Arrhythmogenic Left Ventricular Cardiomyopathies.

BACKGROUND: Nondilated left ventricular cardiomyopathy (NDLVC) has been recently differentiated from dilated cardiomyopathy (DCM). A comprehensive characterization of these 2 entities using cardiac magnetic resonance (CMR) and genetic testing has never been performed. OBJECTIVES: This study sought to provide a thorough characterization and assess clinical outcomes in a large multicenter cohort of patients with DCM and NDLVC. METHODS: A total of 462 patients with DCM (227) or NDLVC (235) with CMR data from 4 different referral centers were retrospectively analyzed. The study endpoint was a composite of sudden cardiac death or major ventricular arrhythmias. RESULTS: In comparison to DCM, NDLVC had a higher prevalence of pathogenic or likely pathogenic variants of arrhythmogenic genes (40% vs 23%; P < 0.001), higher left ventricular (LV) systolic function (LV ejection fraction: 51% ± 12% vs 36% ± 15%; P < 0.001) and higher prevalence of free-wall late gadolinium enhancement (LGE) (27% vs 14%; P < 0.001). Conversely, DCM showed higher prevalence of pathogenic or likely pathogenic variants of nonarrhythmogenic genes (23% vs 12%; P = 0.002) and septal LGE (45% vs 32%; P = 0.004). Over a median follow-up of 81 months (Q1-Q3: 40-132 months), the study outcome occurred in 98 (21%) patients. LGE with septal location (HR: 1.929; 95% CI: 1.033-3.601; P = 0.039) was independently associated with the risk of sudden cardiac death or major ventricular arrhythmias together with LV dilatation, older age, advanced NYHA functional class, frequent ventricular ectopic activity, and nonsustained ventricular tachycardia. CONCLUSIONS: In a multicenter cohort of patients with DCM and NDLVC, septal LGE together with LV dilatation, age, advanced disease, and frequent and repetitive ventricular arrhythmias were powerful predictors of major arrhythmic events.

A novel TGFßR2 splice variant in patient with aortic aneurysm and family history for aortic dissection: a case report.

We report the clinical presentation and genetic screening of a 31-year-old man with dilatation of the aortic root and ascending aorta and a positive family history for aortic dissection and sudden death. A novel heterozygous variant in a splice acceptor site (c.1600-1G>T) of TGFßR2 gene was identified by using a targeted multi-gene panel analysis. Bioinformatics tools predicted that the c.1600-1G>T variant is pathogenic by altering acceptor splice site at - 1 position affecting pre-mRNA splicing. These data confirm that the diverging splicing in the TGF-ß pathway genes may be an important process in aneurismal disease and emphasize the utility of genetic sequencing in the identification of high-risk patients for a more patient's management able to improve outcomes and minimize costs for the care of patients with heritable thoracic aortic aneurysm and dissection.

[Box: see text].

Low HDL cholesterol and the eNOS Glu298Asp polymorphism are associated with inducible myocardial ischemia in patients with suspected stable coronary artery disease.

BACKGROUND: The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD). AIM: To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD. METHODS: A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient. RESULTS: In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD. CONCLUSION: In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD.

Prognostic value of right ventricular refractory period heterogeneity in Type-1 Brugada electrocardiographic pattern.

AIMS: To investigate the prognostic significance of heterogeneity in the refractoriness of right ventricular (RV) outflow tract (RVOT) and RV apex at the electrophysiological study (EPS) in Brugada syndrome (BrS). METHODS AND RESULTS: A cohort of BrS patients (primary prevention) from five Italian centres was retrospectively analysed. Patients with spontaneous or drug-induced Type-1 electrocardiogram (ECG) + symptoms were offered an EPS for prognostic stratification. The primary endpoint was a composite of sudden cardiac death (SCD), resuscitated cardiac arrest, or appropriate intervention by the implantable cardioverter-defibrillator (ICD). Three hundred and seventy-two patients with BrS were evaluated (44 ± 15 years, 69% males, 23% with ICD): 4 SCDs and 17 ICD interventions occurred at follow-up (median 48, interquartile range: 36-60 months). Family history of SCD, syncope, and a spontaneous Type-1 ECG pattern were univariate predictors of the primary endpoint in the whole population. In patients undergoing EPS (n = 198, 53%, 44 ± 12 years, 71% males, 39% with ICD), 3 SCD and 15 ICD interventions occurred at follow-up. In this subset, the primary endpoint was not only predicted by ventricular tachycardia/fibrillation inducibility but also by a difference in the refractory period between RVOT and RV apex (ΔRPRVOT-apex) >60 ms. ΔRPRVOT-apex > 60 ms remained an independent predictor of SCD/ICD shock at bivariate analysis, even when adjusted for the other univariate predictors, showing the highest predictive power at C-statistic analysis (0.75, 95% confidence interval 0.63-0.86). CONCLUSIONS: Heterogeneity of RV refractory periods is a strong, independent predictor of life-threatening arrhythmias in BrS patients, beyond VT/VF inducibility at EPS and common clinical predictors.

Molecular Autopsy of Sudden Cardiac Death in the Genomics Era.

Molecular autopsy is the process of investigating sudden death through genetic analysis. It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. The final goal of molecular autopsy in SUD cases is to aid medico-legal inquiries and to guide cascade genetic screening of the victim's relatives. Early attempts of molecular autopsy relied on Sanger sequencing, which, despite being accurate and easy to use, has a low throughput and can only be employed to analyse a small panel of genes. Conversely, the recent adoption of next-generation sequencing (NGS) technologies has allowed exome/genome wide examination, providing an increase in detection of pathogenic variants and the discovery of newer genotype-phenotype associations. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the clinical interpretation of the large number of variants of unknown significance detected in each individual.

Comparison of different prediction models for the indication of implanted cardioverter defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a high risk of sudden cardiac death. Three different prediction models for the indication of implanted cardioverter defibrillator (ICD) are now available: the 5 year ARVC risk score, the International Task Force Consensus (ITFC) criteria, and the Heart Rhythm Society (HRS) criteria. We compared these three prediction models in a validation cohort of patients with definite ARVC. METHODS AND RESULTS: In a cohort of 140 patients with definite ARVC, the 5 year ARVC risk score and the ITFC and HRS criteria were compared for the prediction of a major combined endpoint of sudden cardiac death, appropriate ICD intervention, resuscitated cardiac arrest, and sustained ventricular tachycardia. During the follow-up, 65 major events occurred. The 5 year ARVC risk score with a threshold >10%, derived from the maximally selected rank statistic, predicted 62 (95%) events [odds ratio (OR) 9.1, 95% confidence interval (CI) 2.6-32, P = 0.0006], the ITFC criteria 53 (81%, OR 4.8, 95% CI 2.2-10.3, P = 0.0001), and the HRS criteria 29 (45%, OR 4.2, 95% CI 1.9-9.3, P = 0.0003). At the analysis of decision curve for ICD implantation, a 5 year ARVC risk score >10% showed a greater net benefit than the ITFC and HRS criteria over a wide range of threshold probability of events. Finally, at multivariate analysis, the 5 year ARVC risk score >10% was the only independent predictor of major events. CONCLUSIONS: The 5 year score with a threshold of >10% was more effective for predicting events than the ITFC and HRS criteria.

Prognostic Value of Magnetic Resonance Phenotype in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Cardiac magnetic resonance (CMR) is widely used to assess tissue and functional abnormalities in arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a ARVC risk score was proposed to predict the 5-year risk of malignant ventricular arrhythmias in patients with ARVC. However, CMR features such as fibrosis, fat infiltration, and left ventricular (LV) involvement were not considered. OBJECTIVES: The authors sought to evaluate the prognostic role of CMR phenotype in patients with definite ARVC and to evaluate the effectiveness of the novel 5-year ARVC risk score to predict cardiac events in different CMR presentations. METHODS: A total of 140 patients with definite ARVC were enrolled (mean age 42 ± 17 years, 97 males) in this multicenter prospective registry. As per study design, CMR was performed in all the patients at enrollment. The novel 5-year ARVC risk score was retrospectively calculated using the patient's characteristics at the time of enrollment. During a median follow-up of 5 years (2 to 8 years), the combined endpoint of sudden cardiac death, appropriate implantable cardioverter-defibrillator intervention, and aborted cardiac arrest was considered. RESULTS: CMR was completely negative in 14 patients (10%), isolated right ventricular (RV) involvement was found in 58 (41%), biventricular in 52 (37%), and LV dominant in 16 (12%). During the follow-up, 48 patients (34%) had major events, but none occurred in patients with negative CMR. At Kaplan-Meier analysis, patients with LV involvement (LV dominant and biventricular) had a worse prognosis than those with lone RV (p < 0.0001). At multivariate analysis, the LV involvement, a LV-dominant phenotype, and the 5-year ARVC risk score were independent predictors of major events. The estimated 5-year risk was able to predict the observed risk in patients with lone RV but underestimated the risk in those with LV involvement. CONCLUSIONS: Different CMR presentations of ARVC are associated with different prognoses. The 5-year ARVC risk score is valid for the estimation of risk in patients with lone-RV presentation but underestimated the risk when LV is involved.

Development and validation of a risk stratification score for new-onset atrial fibrillation in STEMI patients undergoing primary percutaneous coronary intervention.

AIM: New-onset atrial fibrillation (NOAF) is a complication not infrequent in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) and has been associated with worse in-hospital and long-term prognosis. We aimed to develop and validate a risk score based on common clinical risk factors and routine blood biomarkers to assess the early incidence of NOAF post-pPCI, before discharge. METHODS: The risk score for NOAF occurrence during hospitalisation (about 5 days) was developed in a cohort of 1135 consecutive STEMI patients undergoing pPCI while was externally validated in a temporal cohort of 771 STEMI patients. Biomarkers and clinical variables significantly contributing to predicting NOAF were assessed by multivariate Cox-regression analysis. RESULTS: Independent predictors of NOAF were age ≥80 years (6.97 [3.40-14.30], hazard ratio [95% CI], P < .001), leukocyte count > 9.68 × 103 /µL (2.65 [1.57-4.48], P < .001), brain natriuretic peptide (BNP) > 80 ng/L (2.37 [1.13-4.95], P = .02) and obesity (2.07 [1.09-3.92], P = .03). By summing the hazard ratios of these predictors we derived the ALBO (acronym derived from: Age, Leucocyte, BNP and Obesity) risk score which yielded high C-statistics in both the derivation (0.734 [0.675-0.793], P < .001) and validation cohort (0.76 [0.688-0.831], P < .001). In both cohorts, using Kaplan-Meier risk analysis, the ALBO score identified a tertile of patients at highest risk (ALBO >4 points), with percentages of NOAF incidence of 30.8% and 27.4% in the derivation and validation cohort, respectively. CONCLUSION: The ALBO risk score, comprising biomarkers and clinical variables that can be assessed in hospital setting, could help to identify high-risk patients for NOAF after pPCI so that a prompter action can be taken.

The prognostic impact of objective nutritional indices in elderly patients with ST-elevation myocardial infarction undergoing primary coronary intervention.

BACKGROUND: The prognostic impact of nutritional status in ST-elevation myocardial infarction (STEMI) patients is poorly understood. METHODS: We used the controlling nutritional status (CONUT) score and the prognostic nutritional index (PNI) score on outcomes of 945 patients with acute STEMI undergoing primary percutaneous coronary intervention with stent. RESULTS: During a median follow-up of 2years (1-3.3years, interquartile range), 56 patients (5.9%) died for all-cause of death. In the dead group, the CONUT and PNI scores were more severe than in the alive group. Elderly patients (≥71years) had nutritional indices more serious than patients <71years. In the whole population of the study, both CONUT and PNI correlated with clinical markers of poor prognosis such as brain natriuretic peptide (BNP), creatinine and liver enzymes. Kaplan-Meier curves revealed that the patients with severe CONUT but not patients with severe PNI index had the highest event rate for all-cause death, with a log-rank of p<0.001. The Cox proportional hazard analyses showed that, contrary to PNI score, the CONUT score was associated with increased risk of all-cause death for both unadjusted model and age- and sex-adjusted model, while in a full-adjusted model the best predictors were age and BNP. CONCLUSIONS: In STEMI patients, the nutritional status evaluated by the CONUT score, in addition to other comorbidities, can affect the prognosis in elderly patients. These results suggest a personalized nutritional treatment as well as an accurate assessment of the appropriateness of lipid-lowering treatment after coronary revascularization.

Development of a new multiplex quantitative real-time PCR assay for the detection of the mtDNA(4977) deletion in coronary artery disease patients: a link with telomere shortening.

Mitochondrial DNA (mtDNA) and telomere shortening have been proposed as important contributors to vascular disease and atherogenesis. The role of mitochondrial and telomere alterations has been examined frequently, but usually separately. Recently, an integrated model in which DNA damage and metabolic pathways intersect in age-associated cardiovascular disease has been proposed. In this study we developed a fast and reliable real-time PCR-based procedure to investigate relative quantification of the 4,977 bp mitochondrial DNA deletion (also indicated as "mtDNA(4977) deletion"), employing TaqMan probes with a multiplex approach. As a validation of the assay, a nested PCR coamplification was performed. Telomere shortening was evaluated by a real-time monochrome multiplex PCR technique employing a SybrGreen-based analysis. The study of mtDNA(4977) deletion and telomere shortening was carried out in atrial biopsies from 11 patients undergoing coronary artery (n = 5) and valve surgery (n = 6). The relative quantifications showed that the amount of mtDNA(4977) deletion was greater in tissue of patients with coronary artery disease (CAD) (P = 0.01) and that telomere length (expressed as telomere length relative to a single copy reference gene) was significantly shorter in tissue of CAD patients, compared to patients without CAD (P = 0.03). Moreover, most conventional risk factors were significantly more frequent in CAD patients, smoking and dyslipidemia having the strongest association with the degree of mtDNA(4977) deletion and a significant correlation with telomere attrition (P = 0.02 and P = 0.006, respectively). In conclusion, the present study suggests that mtDNA(4977) deletion and telomere shortening may represent additional and synergic major risk factors for the pathogenesis of CAD and its complications.

Sequencing of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes in familial cases of bicuspid aortic valve.

BACKGROUND: The purpose of our study was to investigate the potential contribution of germline mutations in NOTCH1, GATA5 and TGFBR1 and TGFBR2 genes in a cohort of Italian patients with familial Bicuspid Aortic Valve (BAV). METHODS: All the coding exons including adjacent intronic as well as 5' and 3' untranslated (UTR) sequences of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes were screened by direct gene sequencing in 11 index patients (8 males; age = 42 ± 19 years) with familial BAV defined as two or more affected members. RESULTS: Two novel mutations, a missense and a nonsense mutation (Exon 5, p.P284L; Exon 26, p.Y1619X), were found in the NOTCH1 gene in two unrelated families. The mutations segregated with the disease in these families, and they were not found on 200 unrelated chromosomes from ethnically matched controls. No pathogenetic mutation was identified in GATA5, TGFBR1 and TGFBR2 genes. CONCLUSIONS: Two novel NOTCH1 mutations were identified in two Italian families with BAV, highlighting the role of a NOTCH1 signaling pathway in BAV and its aortic complications. These findings are of relevance for genetic counseling and clinical care of families presenting with BAV. Future studies are needed in order to unravel the still largely unknown genetics of BAV.

Molecular markers of cardiovascular damage in hypertension.

There is increasing evidence that an elevation of oxidative stress and associated oxidative damages are mediators of vascular injury in various cardiovascular pathologies, including hypertension. Accumulation of oxidative damage is thought to play an important role in aging and age-associated diseases such as hypertension and oxidative stress may function as a common trigger for activation of the senescence programme. In this regard, the role of telomeres in the onset, development and prognosis of hypertension has generated considerable interest. These structures may deteriorate in the onset and development of arterial hypertension in which their length may be a predictor of outcome. As telomere length by its nature is a marker of cell senescence, this parameter is of particular interest when studying the lifespan and fate of endothelial cells, cardiomyocytes and smooth muscle cells, especially so because telomere length seems to be regulated by various factors notably certain cardiovascular risk factors, such as smoking, sex and obesity that are associated with high levels of oxidative stress. This review focuses on the vascular effects of reactive oxygen species and the role of oxidative stress in hypertension- associated vascular damage. In addition it reviewes the considerable amount of data published recently on the role of telomeres to gain insights into the links between telomere length and hypertension, and assesses the usefulness of telomere length as a new marker of cardiovascular risk.

Individual and summed effects of high-risk genetic polymorphisms on recurrent cardiovascular events following ischemic heart disease.

AIMS: High-risk single nucleotide polymorphisms (SNPs) have been recently identified as risk factors for ischemic heart disease in large epidemiological and genome-wide association studies. However, their influence on prognosis remains uncertain. The aim of the study was to investigate the impact of previously identified SNPs and their joint effects in a genetic score (GS) on Major Adverse Cardiac Events (MACEs). METHODS AND RESULTS: High-throughput genotyping for 48 high-risk SNPs was performed in 498 patients (432 males; 57.4 ± 8.3 years) who were followed-up for 6.9 ± 3.4 years. First MACE-coronary-related death, nonfatal myocardial infarction, or myocardial revascularization- was the endpoint taken into consideration. A GS was obtained by summing the number of significant high-risk alleles associated to MACEs. One-hundred and nineteen patients (24%) had a MACE. The hazard ratio (HR) for SNPs with a significant difference in cumulative survival were: APOC3 -482C > T (HR = 1.7, 95% CI 1.01-3.0), MTHFR (HR = 1.5, 95% CI 1.02-2.2), NADHPH oxidase- p22-PHOX C242T (HR = 1.9, 95% CI 1.2-2.8), PON-2 (HR = 0.2, 95% CI 0.1-0.8), and SELP (HR = 0.6, 95% CI 0.4-0.8). The resulting GS predicted a 25% risk for MACEs per risk allele (HR = 1.25, 95% CI 1.1-1.4, p = 0.001). The highest HR for MACEs was found in patients in the top tertile (HR = 3.0, 95% CI 1.4-6.7, p = 0.0005) of the GS compared with those in the bottom tertile. CONCLUSION: Our findings show that high-risk SNPs may be used to create a useful GS that predicts MACEs in a secondary prevention setting, which in turn allows a better risk stratification.

Deep venous thromboembolism after a trauma in a football player double heterozygous for factor V Leiden and prothrombin G20210A mutation: The role of genetic testing in sport.

Traumatic vascular injuries to the lower limb are frequent in athletes, particularly in sports characterized by high-speed collisions. However, the diagnosis is not always straightforward, for the lack of clearly visible abnormalities without provocative testing or appropriate imaging. The failure of an early diagnosis can lead to devastating consequences. In these subjects, it may be useful to investigate the personal susceptibility to thrombotic events such as the presence of a hereditary hypercoagulable state. We experienced a case of a soccer player with progressive swelling and severe pain of the calf after a trauma during a football match 3 days previously, who came to our hospital for suspected deep vein thrombosis, confirmed by echo-Doppler ultrasound. A thrombophilia screening detected a double heterozygosity for factor V Leiden and prothrombin G20210A mutation in the presence of a strong family history for thromboembolism. Immediate treatment with elastic stocking compression and enoxaparin was started. The patient was discharged on warfarin therapy maintained for six months, with the warning to avoid trauma activities during anticoagulation. Thrombotic genetic testing in athletes who experience episodes of deep vein thrombosis might offer important opportunities for patient management, such as prolonged anticoagulant therapy or avoidance of risk factors such as trauma-related sports.

Maternal and paternal environmental risk factors, metabolizing GSTM1 and GSTT1 polymorphisms, and congenital heart disease.

Congenital heart defects (CHDs) are the most prevalent of all birth malformations arising from the complex interplay of environmental exposures and genes. Modifiable environmental risk factors are still largely unknown, especially for paternal exposure. The aim of the present study was to examine the association between the environmental exposures of both parents and CHD risk and to explore the modification effect of metabolizing gene polymorphisms in children who lack the genetic capacity to produce the glutathione S-transferase (GST) GSTM1 and GSTT1 enzymes. A total of 330 parents of a child with CHD and 330 parents of a child without any congenital malformations were compared in terms of lifestyle habits and toxicant exposure. GST gene polymorphisms were investigated in 180 patients with CHD (104 males, age 4.9 ± 5.8 years). Paternal smoking (≥15 cigarettes/day) was significantly associated with CHD risk (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.3 to 3.5, p = 0.002). Both maternal (OR 2.6, 95% CI 1.6 to 4.2, p <0.0001) and paternal (OR 2.5, 95% CI 1.6 to 3.8, p <0.0001) occupational/environmental exposures increased the risk of CHD. Also, a significant additive risk (OR 4.5, 95% CI 2.5 to 8.3, p <0.0001) was found when both parents were exposed to toxicants. Both maternal (OR 3.6, 95% CI 1.1 to 11.2, p = 0.03) and paternal (OR 3.3, 95% CI 1.0 to 10.8, p = 0.03) exposure to toxicants increased the CHD risk in children who carried the combined null GST genotypes. The effect for the combined null GST genotypes was also stronger (OR 6.5, 95% CI 1.5 to 28.0) when both parents were exposed. In conclusion, paternal smoking and exposure to toxicants for both parents affect the risk of children with CHD. Polymorphisms in GST genes can modify a person's risk of toxicant exposure-induced disease.

[A novel lamin A/C mutation in a family with dilated cardiomyopathy and a strong history of sudden cardiac death]. / Identificazione di una nuova mutazione nel gene della lamina A/C in una famiglia con cardiomiopatia dilatativa e storia di morte improvvisa.

Diseases related to lamin A/C mutations (laminopathies) are extremely heterogeneous. The common cardiac phenotype is idiopathic dilated cardiomyopathy with atrioventricular block and/or arrhythmias. Moreover, patients with lamin A/C gene mutations are at increased risk for sudden cardiac death. Here we present a family with a strong positive history of sudden cardiac death in presence of idiopathic dilated cardiomyopathy and cardiac conduction abnormalities, related to a novel lamin A/C mutation in exon 3.

A novel LMNA mutation (R189W) in familial dilated cardiomyopathy: evidence for a 'hot spot' region at exon 3: a case report.

We describe a case of a patient with idiopathic dilated cardiomyopathy and cardiac conduction abnormalities who presented a strong family history of sudden cardiac death. Genetic screening of lamin A/C gene revealed in proband the presence of a novel missense mutation (R189W), near the most prevalent lamin A/C mutation (R190W), suggesting a "hot spot" region at exon 3.