ALU transposition induces familial hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant-negative fashion. However loss-of-function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3, suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis. Here, we investigate MYBPC3 complete deletion as a disease mechanism in HCM by analyzing two unrelated patients with confirmed diagnosis of HCM that tested negative by Sanger sequencing analysis. METHODS: MYBPC3 complete deletion was investigated by Multiplex ligation-dependent probe amplification (MLPA) and microarray analyses. The mechanism of deletion was investigated by interrogating the SINEBase database. RESULTS: Patient-1 was diagnosed with nonobstructive HCM in his mid-40s while undergoing assessment for palpitations, and patient-2 with obstructive HCM in his late-20s while undergoing systolic heart murmur assessment for an unrelated illness. MLPA testing revealed a heterozygous deletion of all MYBPC3 exons in both patients. Subsequent microarray testing confirmed these deletions which extended beyond the 5' and 3' ends of MYBPC3. Genomic assessment suggested that these deletions resulted from Alu/Alu-homologous recombination. CONCLUSION: Our results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM.

Pregnancy in Catecholaminergic Polymorphic Ventricular Tachycardia.

OBJECTIVES: This investigation was a retrospective study of catecholaminergic polymorphic ventricular tachycardia (CPVT) patients in Canada and the Netherlands to compare pregnancy, postpartum, and nonpregnant event rates. BACKGROUND: CPVT is characterized by life-threatening arrhythmias during exertion or emotional stress. The arrhythmic risk in CPVT patients during pregnancy is unknown. METHODS: Baseline demographics, genetics, treatment, and pregnancy complications were reviewed. Event rate calculations assumed a 40-week pregnancy and 24-week postpartum period. RESULTS: Ninety-six CPVT patients had 228 pregnancies (median 2 pregnancies per patient; range: 1 to 10; total: 175.4 pregnant patient-years). The median age of CPVT diagnosis was 40.7 years (range: 12 to 84 years), with a median follow-up of 2.9 years (range: 0 to 20 years; total 448.1 patient-years). Most patients had pregnancies before CPVT diagnosis (82%). Pregnancy and postpartum cardiac events included syncope (5%) and an aborted cardiac arrest (1%), which occurred in patients who were not taking beta-blockers. Other complications included miscarriages (13%) and intrauterine growth restriction (1 case). There were 6 cardiac events (6%) during the nonpregnant period. The pregnancy and postpartum event rates were 1.71 and 2.85 events per 100 patient-years, respectively, and the combined event rate during the pregnancy and postpartum period was 2.14 events per 100 patient-years. These rates were not different from the nonpregnant event rate (1.46 events per 100 patient-years). CONCLUSIONS: The combined pregnancy and postpartum arrhythmic risk in CPVT patients was not elevated compared with the nonpregnant period. Most patients had pregnancies before diagnosis, and all patients with events were not taking beta-blockers at the time of the event.

Loss-of-Function KCNE2 Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?

BACKGROUND: Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel ß-subunit, is limited. We sought to further characterize its clinical phenotype. METHODS AND RESULTS: Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the KCNE2 variant was not the underlying culprit. The collective frequency of KCNE2 variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6. CONCLUSIONS: On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many KCNE2 variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, KCNE2 variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.

A detailed description and assessment of outcomes of patients with hospital recorded QTc prolongation.

Corrected QT (QTc) interval prolongation has been shown to be an independent predictor of mortality in many clinical settings and is a common finding in hospitalized patients. The causes and outcomes of patients with extreme QTc interval prolongation during a hospital admission are poorly described. The aim of this study was to prospectively identify patients with automated readings of QTc intervals >550 ms at 1 academic tertiary hospital. One hundred seventy-two patients with dramatic QTc interval prolongation (574 ± 53 ms) were identified (mean age 67.6 ± 15.1 years, 48% women). Most patients had underlying heart disease (60%), predominantly ischemic cardiomyopathy (43%). At lease 1 credible and presumed reversible cause associated with QTc interval prolongation was identified in 98% of patients. The most common culprits were QTc interval-prolonging medications, which were deemed most responsible in 48% of patients, with 25% of these patients taking ≥2 offending drugs. Two patients were diagnosed with congenital long-QT syndrome. Patients with electrocardiograms available before and after hospital admission demonstrated significantly lower preadmission and postdischarge QTc intervals compared with the QTc intervals recorded in the hospital. In conclusion, in-hospital mortality was high in the study population (29%), with only 4% of patients experiencing arrhythmic deaths, all of which were attributed to secondary causes.

Reduced Uptake of Family Screening in Genotype-Negative Versus Genotype-Positive Long QT Syndrome.

The acceptance and yield of family screening in genotype-negative long QT syndrome (LQTS) remains incompletely characterized. In this study of family screening for phenotype-definite Long QT Syndrome (LQTS, Schwartz score ≥3.5), probands at a regional Inherited Cardiac Arrhythmia clinic were reviewed. All LQTS patients were offered education by a qualified genetic counselor, along with materials for family screening including electronic and paper correspondence to provide to family members. Thirty-eight qualifying probands were identified and 20 of these had family members who participated in cascade screening. The acceptance of screening was found to be lower among families without a known pathogenic mutation (33 vs. 77 %, p = 0.02). A total of 52 relatives were screened; fewer relatives were screened per index case when the proband was genotype-negative (1.7 vs. 3.1, p = 0.02). The clinical yield of screening appeared to be similar irrespective of gene testing results (38 vs. 33 %, p = 0.69). Additional efforts to promote family screening among gene-negative long QT families may be warranted.

Early repolarization is associated with symptoms in patients with type 1 and type 2 long QT syndrome.

BACKGROUND: Early repolarization (ER) is associated with an increased risk for death from cardiac causes. Recent evidence supports ER's role as a modifier and/or predictor of risk in many cardiac conditions. OBJECTIVE: The purpose of this study was to determine the prevalence of ER among genotype-positive patients with long QT syndrome (LQTS) and evaluate its utility in predicting the risk of symptoms. METHODS: ER was defined as QRS slurring and/or notching associated with ≥1-mV QRS-ST junction (J-point) elevation in at least 2 contiguous leads, excluding the anterior precordial leads. The ECG with the most prominent ER was used for analysis. Major ER was defined as ≥ 2-mm J-point elevation. Symptoms of LQTS included cardiac syncope, documented polymorphic ventricular tachycardia (VT), and resuscitated cardiac arrest. RESULTS: One hundred thirteen patients (mean age 41 ± 19 years; 63 female) were reviewed, among whom 414 (mean 3.7 ± 1.5) ECGs were analyzed. Of these, 30 patients (27%) with a history of symptoms. Fifty patients (44%) had ER, and 19 patients (17%) had major ER. Patients with major ER were not different from patients without major ER with respect to age, sex, long QT type, longest QTc recorded, number of patients with QTc >500 ms, or use of beta-blockade. Univariate and independent predictors of symptom status included the presence of major ER, longest QTc recorded >500 ms, and female sex. CONCLUSION: ER ≥2 mm was the strongest independent predictor of symptom status related to LQTS, along with female sex and QTc >500 ms.

Arrhythmogenic right ventricular cardiomyopathy with recessive inheritance related to a new homozygous desmocollin-2 mutation.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia is an inherited cardiomyopathy that is transmitted in autosomal dominant and autosomal recessive forms and involves mutations in desmosomal and extradesmosomal genes. We present a case of arrhythmogenic right ventricular cardiomyopathy that cosegregates in a Lebanese family with a previously unreported desmocollin-2 mutation (c.712_714delGAT). We believe this newly described genetic variant displays autosomal recessive inheritance without the cutaneous manifestations expected in recessive genotypes, and represents the latest addition to the compendium of desmosomal mutations with pathogenic potential.

End-recovery QTc: a useful metric for assessing genetic variants of unknown significance in long-QT syndrome.

INTRODUCTION: Genetic variants represent benign single-nucleotide polymorphisms, disease causing mutations or variants of unknown significance (VUS). Resting, exercise, and recovery QTc intervals have been utilized to detect long-QT syndrome (LQTS) mutations. We sought to provide clinical data that may assist in classifying the presented VUS as disease causing/benign and to determine whether resting and/or end-recovery QT parameters can evaluate the significance of VUS. METHODS AND RESULTS: Twenty-six patients with a VUS in genes associated with LQTS (15 females, age 38 ± 16 years) and 26 age and gender matched controls (age 37 ± 20 years) were included. There were 10 VUS (5 KCNQ1, 4 KCNH2, 1 KCNE1) in 12 families. All but 1 VUS was associated with sudden cardiac death (SCD), aborted SCD or Torsade de pointes. A Schwartz score of ≥3.5 was observed in at least 1 family member with each VUS. Resting QTc was marginally longer in VUS patients compared with controls (458 ± 48 vs 437 ± 25, P = 0.052). A prolonged resting QTc (>470 ms males, >480 ms females) identified 6 VUS carriers and 1 control. VUS carriers had a substantially longer end-recovery QTc (502 ± 68 vs 427 ± 17, P < 0.01) with an end-recovery QTc > 445 ms in 20/26 VUS patients compared to 2/26 controls (P < 0.01). The area under the receiver operating characteristic curve for resting QTc was 0.68 (95% CI, 0.53-0.83, P = 0.03) compared to the end-recovery QTc of 0.88 (95% CI, 0.76-0.99, P < 0.0001). CONCLUSION: Variants in the current study appear to be disease causing. The end-recovery QTc is a useful metric when interpreting LQT VUS.

KCNJ2 variant of unknown significance reclassified as long QT syndrome causing ventricular fibrillation.

KCNJ2 is the only gene implicated in Andersen-Tawil syndrome. Sudden cardiac arrest is rare in Andersen-Tawil syndrome. However, sudden cardiac arrest is often the index presentation in other forms of long QT syndrome. We present an unreported variant in the KCNJ2 gene, associated with long QT syndrome, that presented with ventricular fibrillation. Exercise testing and adrenaline infusion were useful in assigning pathogenicity to this variant of unknown significance.

The effects of prenatal group genetic counselling on knowledge, anxiety and decisional conflict: issues for nuchal translucency screening.

This study evaluates the effects of prenatal genetic group counselling on women's anxiety, decisional conflict and levels of knowledge. Participants (N=271) were aged 35 years and older. ANOVA results indicated that pre/postcounselling scores for anxiety did not change significantly, while decisional conflict decreased significantly (P<0.001). Pre/postcounselling scores on two different knowledge measures were analysed using 2x3 mixed ANOVAs for time by highest level of education and by having discussed prenatal diagnosis with one's health care provider. No potential interactions were statistically significant; time alone had a strong significant effect for both knowledge measures (P<0.01); P<0.01, respectively), suggesting that the effects of the counselling intervention were robust. Group genetic counselling is an effective method for education and decision support in the prenatal context, and may serve as a model for other clinical populations facing genetic screening decisions.