High prevalence of genetic variants previously associated with Brugada syndrome in new exome data

Risgaard, Bjarke; Jabbari, Reza; Refsgaard, Lena; Holst, Anders G.; Haunsø, Stig; Sadjadieh, Ahmed; Winkel, Bo Gregers; Olesen, Morten S.; Tfelt-Hansen, Jacob

doi:10.1111/cge.12126

Cited by 102 publications

(67 citation statements)

References 27 publications

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“…These data have helped to clarify the potential pathogenic role of the variants in BrS. 72 The main problems in using NGS technologies are the large amount of data provided and the insufficient experience to translate this information into clinical practice. One of the crucial elements for the correct interpretation of pathogenicity is the genotype-phenotype correlation in families.…”

Section: Genetic Testing In Brugada Syndromementioning

confidence: 99%

Brugada syndrome: clinical and genetic findings

Sarquella-Brugada

Campuzano

Arbelo

et al. 2016

Genetics in Medicine

114

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Review ARticleMore than 20 years ago, eight individuals were resuscitated from sudden cardiac death (SCD) caused by documented ventricular fibrillation (VF); all showed a characteristic ST segment elevation in the right precordial leads and a structurally normal heart. 1 In 1996, the term "Brugada syndrome" (BrS) was used to describe what was previously known as "right bundle branch block, persistent ST segment elevation, and sudden death syndrome. " 2 A year later, BrS was reported to be the same disease as sudden unexplained nocturnal death syndrome (SUNDS). In other countries, BrS has different names: Lai Tai (Thailand), Pokkuri (Japan), and Bangungut (Philippines). Currently, the prevalence of BrS is estimated at ~3-5 in 10,000 people, and it is higher in young men of Southeast Asian origin. It is the main cause of death among young healthy men in Southeast Asia. 3 Recent reports suggest that BrS could be responsible for 4% of all SCD and up to 12% of sudden death in patients with structurally normal hearts. The clinical phenotype manifests in adulthood, at a mean age of 41 years, and it is 8-to 10-times more frequent in males. Frequently, sudden death can be the first manifestation of the disease. 4 In 1998, the genetic basis of BrS was established when the sodium channel protein type V subunit α gene (SCN5A), which encodes the α-subunit of the voltage-gated Na v 1.5 cardiac sodium channel responsible for regulating rapid sodium current (I Na ), was associated with the disease. 5 Currently, BrS is recognized as a rare, inherited cardiac channelopathy caused by an alteration of ionic currents that leads to ventricular arrhythmias and SCD. It is clinically characterized by ST segment elevation in leads V1-V3 of the electrocardiogram, but incomplete penetrance and variable expressivity confound the diagnosis. 6 Despite the identification of 18 associated genes, 65-70% of clinically diagnosed cases remain without an identifiable genetic cause. 4 CLINICAL DIAGNOSIS Diagnostic criteriaThe clinical diagnosis of BrS requires the identification of the ST segment elevation in the right precordial leads at baseline or after the use of sodium blockers. Three different electrocardiographic (ECG) patterns can be often observed in families with BrS: type I, which consists of a coved-type ST segment elevation greater than 2 mm followed by a descending negative T wave in at least two right precordial leads (V1 to V3); type II ST elevation, saddleback-shaped patterns with a high initial increase followed by an ST elevation greater than 2 mm; and saddleback-shaped patterns with a high initial increase followed by an ST elevation less than 2 mm (Figure 1). The second Brugada Consensus Report proposed that only type I is diagnostic for BrS 7 and, in 2013, it was proposed that a definitive diagnosis of BrS considers both spontaneous type I pattern and a provoked type I pattern (with a baseline type II or III pattern) in at least one right precordial lead (V1 or V2). 8 The diagnosis of BrS is currently accepted in those patients ...

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Section: Genetic Testing In Brugada Syndromementioning

confidence: 99%

Brugada syndrome: clinical and genetic findings

Sarquella-Brugada

Campuzano

Arbelo

et al. 2016

Genetics in Medicine

114

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“…2013; Risgaard et al. 2013). Variants predicted to be damaging by one or two tools were considered to be variants of uncertain significance (VUS).…”

Section: Methodsmentioning

confidence: 99%

“…2013; Risgaard et al. 2013) This method increases the correlation between genetic findings and clinical practice especially in rare diseases.…”

Section: Methodsmentioning

confidence: 99%

The pathogenicity of genetic variants previously associated with left ventricular non‐compaction

Abbasi

Jabbari

et al. 2015

Molec Gen & Gen Med

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BackgroundLeft ventricular non‐compaction (LVNC) is a rare cardiomyopathy. Many genetic variants have been associated with LVNC. However, the number of the previous LVNC‐associated variants that are common in the background population remains unknown. The aim of this study was to provide an updated list of previously reported LVNC‐associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false‐positive LVNC‐associated variants.Methods and ResultsThe Human Gene Mutation Database and PubMed were systematically searched to identify all previously reported LVNC‐associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine the functional effects of these variants. The prediction results of those identified in the ESP and ExAC and those not identified in the ESP and ExAC were compared. In 12 genes, 60 LVNC‐associated missense/nonsense variants were identified. MYH7 was the predominant gene, encompassing 24 of the 60 LVNC‐associated variants. The ESP only harbored nine and ExAC harbored 18 of the 60 LVNC‐associated variants. In total, eight out of nine ESP‐positive variants overlapped with the 18 variants identified in ExAC database.ConclusionsIn this article, we identified 9 ESP‐positive and 18 ExAC‐positive variants of 60 previously reported LVNC‐associated variants, suggesting that these variants are not necessarily the monogenic cause of LVNC.

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“…Other mutations were also identified [102,106], including p.S143F and p.T450I, which were reported in the prevailing BrS-associated variants of NHLBI GO Exome Sequencing Project population [107]. However, the functions of these mutations on the Ca V β 2 subunit remain unknown.…”

Section: Brugada Syndromesmentioning

confidence: 99%

“…It has been found 3 different missense mutations in CACNA2D1 (p.S709N, p.D550Y, and p.Q917H) in 3 BrS patients from a cohort made up of 205 patients with BrS [102]. Among these mutations, p.S709N and p.Q917H were also identified in Exome Sequencing Project population by Risgaard et al [107]. Nevertheless, more works are needed to explore the possible functions of these mutations on Ca V channels.…”

Section: Brugada Syndromesmentioning

confidence: 99%

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

et al. 2018

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The voltage-gated L-type calcium channel (LTCC) is essential for multiple cellular processes. In the heart, calcium influx through LTCC plays an important role in cardiac electrical excitation. Mutations in LTCC genes, including CACNA1C, CACNA1D, CACNB2 and CACNA2D, will induce the dysfunctions of calcium channels, which result in the abnormal excitations of cardiomyocytes, and finally lead to cardiac arrhythmias. Nevertheless, the newly found mutations in LTCC and their functions are continuously being elucidated. This review summarizes recent findings on the mutations of LTCC, which are associated with long QT syndromes, Timothy syndromes, Brugada syndromes, short QT syndromes, and some other cardiac arrhythmias. Indeed, we describe the gain/loss-of-functions of these mutations in LTCC, which can give an explanation for the phenotypes of cardiac arrhythmias. Moreover, we present several challenges in the field at present, and propose some diagnostic or therapeutic approaches to these mutation-associated cardiac diseases in the future.

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High prevalence of genetic variants previously associated with Brugada syndrome in new exome data

Cited by 102 publications

References 27 publications

Brugada syndrome: clinical and genetic findings

Brugada syndrome: clinical and genetic findings

The pathogenicity of genetic variants previously associated with left ventricular non‐compaction

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

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