Rare Genetic Variants Associated With Sudden Cardiac Death in Adults

Khera, Amit; Mason‐Suares, Heather; Brockman, Deanna; Wang, Minxian; VanDenburgh, Martin; Senol-Cosar, Ozlem; Patterson, Candace; Newton‐Cheh, Christopher; Zekavat, Seyedeh M.; Pester, Julie; Chasman, Daniel I.; Kabrhel, Christopher; Jensen, Majken K.; Manson, Jo Ann E.; Gaziano, J. Michael; Taylor, Kent D.; Sotoodehnia, Nona; Post, Wendy S.; Rich, Stephen S.; Rotter, Jerome I.; Lander, Eric S.; Rehm, Heidi L.; Ng, Kenney; Philippakis, Anthony; Lebo, Matthew S.; Chen, Albert; Kathiresan, Sekar

doi:10.1016/j.jacc.2019.08.1060

Cited by 30 publications

(22 citation statements)

References 52 publications

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“…In recent years, 49 genes could be identified that are associated with important causes of SCD-CMP, CHD and primary arrhythmia syndromes [48]. New developments especially the increased use of nextgeneration sequencing (NGS) have detected hundreds of mutations within these genes.…”

Section: Genetic Causes Of Scdmentioning

confidence: 99%

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Sudden cardiac death—update

et al. 2020

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Sudden cardiac death (SCD) is one of the most common causes of death worldwide with a higher frequency especially in the young. Therefore, SCD is represented frequently in forensic autopsy practice, whereupon pathological findings in the heart can explain acute death. These pathological changes may not only include myocardial infarction, coronary thrombosis, or all forms of myocarditis/endocarditis but also rare diseases such as hereditary structural or arrythmogenic anomalies, lesions of the cardiac conduction system, or primary cardiac tumours.

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Section: Genetic Causes Of Scdmentioning

confidence: 99%

“…In recent years, 49 genes could be identified that are associated with important causes of SCD-CMP, CHD and primary arrhythmia syndromes [ 48 ].…”

Section: Genetic Causes Of Scdmentioning

confidence: 99%

Sudden cardiac death—update

et al. 2020

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“…8) Исследования случай-контроль; исследования на базе проспективных когорт. 9) По критериям включения/исключения, ВСС на фоне: только каналопатии и КМП; с дополнением в виде ишемической болезни сердца и аортопатий (в т. ч. расслоение аорты) [3], на фоне семейной гиперхолестеринемии [38].…”

Section: ] -Kcnq1 Kcnh2 Scn5a Akap9 Ank2 Cacna1c Calm1 Calm2 unclassified

“…В Соединенных Штатах >220 тыс. человек погибают от ВСС каждый год [3]. Известно, что внезапные смерти составляют 20% общей смертности и 50% сердечнососудистой смертности в западных странах [1].…”

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Next generation sequencing in sudden cardiac death (pilot study)

et al. 2020

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Aim. To search for causal mutations in candidate genes responsible for the development of sudden cardiac death (SCD) in men who died under the age of 45.Material and methods. The SCD group (n=37) was formed using the criteria the World Health Organization and the European Society of Cardiology. Autopsy material was collected from men who died suddenly outside medical institutions and underwent forensic medical examination according to the standard protocol. Autopsy revealed no morphological changes that could explain sudden death. The mean age was 32,4±6,4 years. Genomic DNA was isolated from myocardial tissue using phenol-chloroform extraction. Clinical exome sequencing was performed. At first, we analyzed the results of sequencing of 24 genes, mutations in which lead to cardiovascular diseases associated with an increased risk of SCD: KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KNCJNE2, KCNE2, SCN4B, SNTA1, MYH2, APOB, KCNA5, TGFB3, NEB, PDX1, FLNC, PLEC, KCND3.Results. Of 37 samples, we revealed 13 probable pathogenic missense mutations in 9 samples (24,3%). Of 13 probable pathogenic variants, 5 were new.Conclusion. This pilot study provides following conclusions: it is necessary to continue molecular autopsy research in Russia; to increase the effectiveness of detecting causal mutations, it is necessary to reduce the age of patients with SCD included in the study; studying the families of deceased; cooperation of experienced specialists — forensic pathologist, laboratory geneticist, cardiologist.

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“…Therefore, genetic causes and underlying molecular mechanisms for CAD and AMI remain to be elucidated. Recent studies suggested that low-frequency and rare genetic variants may confer susceptibility to cardiovascular diseases [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Identification of TFEB gene genetic variants in acute myocardial infarction

Zhang¹,

Zhang²,

He³

et al. 2020

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Background: Abnormal lipid metabolism and inflammation play critical roles in the initiation and progression of atherosclerosis and its associated complications, including coronary artery disease (CAD) and acute myocardial infarction (AMI). Autophagic-lysosomal system is involved in many physiological processes, such as lipid metabolism and inflammation. TFEB, a master regulator of the system, coordinates the expression of lysosomal hydrolases, lysosomal membrane proteins, and autophagic proteins. Altered level of TFEB gene expression and subsequent changes of autophagic-lysosomal system may be involved in the onset of CAD and AMI.Methods: In this study, the promoter of the TFEB gene was genetically and functionally analyzed in AMI patients (n=352) and ethnic-matched healthy controls (n=337).Results: A total of fifteen genetic variants, including eight single nucleotide polymorphisms (SNPs), were identified in the participants. Two novel genetic variants and four SNPs were only identified in six AMI patients, and significantly altered the transcriptional activity of the TFEB gene in cultured cells. Further electrophoretic mobility shift assay revealed that two genetic variants (g.41737144A>G and g.41736544C>T) and two SNPs [g.41737274T>C (rs533895008) and g.41736987C>T (rs760293138)] evidently affected the binding of transcription factors.Conclusions: Our findings suggested that the genetic variants in TFEB gene promoter may change TFEB levels, contributing to AMI as a low-frequency risk factor.

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Rare Genetic Variants Associated With Sudden Cardiac Death in Adults

Cited by 30 publications

References 52 publications

Sudden cardiac death—update

Sudden cardiac death—update

Next generation sequencing in sudden cardiac death (pilot study)

Identification of TFEB gene genetic variants in acute myocardial infarction

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