Abstract Introduction Arrhythmogenic Cardiomyopathy (AC) is typically caused by mutations in the desmosomal genes, however non-desmosomal genes have been increasingly implicated. Desmin gene (DES) mutations have been previously reported in AC, but in many cases there are insufficient data to support their pathogenicity. Purpose We assessed our AC cohort for DES gene mutations and describe the clinical phenotype associated with a recurring variant present in 3 unrelated families. Methods Genetic testing was performed using next-generation sequencing for 41 genes in a total of 138 AC probands with a definite diagnosis of AC based on the revised 2010 Task Force diagnostic criteria. All candidate variants were confirmed using Sanger sequencing. Clinical and genetic cascade screening were expanded to the first-degree relatives of the probands. Retained tissue from deceased individuals was used for genetic testing. All living mutation carriers underwent clinical assessment including physical examination, 12-lead ECG, signal-averaged ECG, echocardiography, cardiac magnetic resonance imaging (MRI) and 24h Holter-monitoring. Results Two DES gene variants, p.Ser298Leu (n=1) and p.Leu115Ile (n=3), were identified in 4 out of the 138 probands (3%). The former coexisted with a pathogenic DSP gene mutation and has not been further evaluated. The latter is a novel variant, absent in control databases (gnomAD) and was the only variant present in 3 unrelated families (see figure). One carrier required heart transplant (A-II-1), two died suddenly (A-III-1, B-II-1) and one died of non-cardiac causes (B-I-2). Detailed clinical information was present in 8 mutation carriers (2 male, age 45±19 years). Seven (88%) had a definite diagnosis and one had a borderline diagnosis of AC. All cases (100%) had right ventricular (RV) wall motion abnormalities, 6 (75%) had a dilated RV, 6 (75%) a dilated LV and 6 (75%) had LV dysfunction (mild in 5 and severe in 1). LV late gadolinium enhancement (LGE) was present in all 6 carriers that had a cardiac MRI with a circumferential sub-epicardial distribution (see figure, case A-III-2). Non-sustained ventricular tachycardia (VT) was present in 7 (88%) and sustained VT in 2 cases (25%). The ventricular ectopic burden per 24h ranged from 426 to 10583 with a median value of 820. Figure 1 Conclusion Variants of the DES gene are rare causes of AC. The novel p.Leu115Ile variant seems to be prevalent in a large UK-based cohort and it causes a biventricular form of AC, with a characteristic scar pattern on MRI and severe outcomes. Acknowledgement/Funding Alexandros Protonotarios is supported by a BHF Clinical Research Training Fellowship no. FS/18/82/34024
Clinical interpretation of the large number of rare variants identified by high throughput sequencing (HTS) technologies is challenging. The aim of this study was to explore the clinical implications of a HTS strategy for patients with hypertrophic cardiomyopathy (HCM) using a targeted HTS methodology and workflow developed for patients with a range of inherited cardiovascular diseases. By comparing the sequencing results with published findings and with sequence data from a large-scale exome sequencing screen of UK individuals, we sought to quantify the strength of the evidence supporting causality for detected candidate variants.
Methods and results
223 unrelated patients with HCM (46±15 years at diagnosis, 74% males) were studied. In order to analyse coding, intronic and regulatory regions of 41 cardiovascular genes, we used solution-based sequence capture followed by massive parallel resequencing on Illumina GAIIx. Average read-depth in the 2.1 Mb target region was 120. Rare (frequency<0.5%) non-synonymous, loss-of-function and splice-site variants were defined as candidates. Excluding titin, we identified 152 distinct candidate variants in sarcomeric or associated genes (89 novel) in 143 patients (64%). Four sarcomeric genes (MYH7, MYBPC3, TNNI3, TNNT2) showed an excess of rare single non-synonymous single-nucleotide polymorphisms (nsSNPs) in cases compared to controls. The estimated probability that a nsSNP in these genes is pathogenic varied between 57% and near certainty depending on the location. We detected an additional 94 candidate variants (73 novel) in desmosomal, and ion-channel genes in 96 patients (43%).
Conclusions
This study provides the first large-scale quantitative analysis of the prevalence of sarcomere protein gene variants in patients with HCM using HTS technology. Inclusion of other genes implicated in inherited cardiac disease identifies a large number of non-synonymous rare variants of unknown clinical significance.
AimsThe targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible.
Background and Purpose— Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disorder typified by early onset lacunar strokes, subcortical dementia, psychiatric disturbances, and migraine. Mutations in the Notch3 gene are responsible. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Therefore, we determined the yield of screening for Notch3 mutations in lacunar stroke with or without leukoaraiosis. Methods— Two hundred eighteen consecutive patients were studied. All had brain and carotid imaging. Polymerase chain reaction-single-stranded conformational polymorphism analysis was used to screen exons 3, 4, 5, and 6 of the Notch3 gene for mutations and polymorphisms. Results— A single mutation in exon 4 (C697T) was identified in a young patient, giving an overall carrier frequency of 0.05% (95% CI, 0.0 to 2.0). For patients with onset of lacunar stroke at ≤65 years and leukoaraiosis, the yield was 2.0% (95% CI, 0.4 to 10.9). Conclusions— Notch3 mutations are rare in patients with typical strokes due to cerebral small-vessel disease. In the absence of classic features suggestive of CADASIL, screening for Notch3 mutations has a low yield.
To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1×10−6. To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4×10−83) and the phospholamban (PLN) gene (P = 1.9×10−29). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.
Takotsubo cardiomyopathy is a syndrome characterized by transient left ventricular apical ballooning associated with electrocardiogram (ECG) changes and minimal myocardial enzymatic release, mimicking acute myocardial infarction in patients without significant coronary disease at angiography. We report an unusual case of a patient who presented with Takotsubo cardiomyopathy associated with long-QT syndrome and who developed cardiac arrest secondary to torsades de pointes.The relationship between Takotsubo cardiomyopathy and abnormal repolarization has been well documented. Despite this, there have been few reports of malignant ventricular arrhythmias or sudden death. This report suggests that prolongation of QTc interval in Takotsubo cardiomyopathy may not be as benign as previously suggested but may in fact uncover an abnormality of repolarization that may be genetic in basis and carry a risk of sudden death.
Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p = 3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p = 3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.
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