Molecular genetics of sudden cardiac death

Congenital long QT syndrome is an inherited cardiac disorder characterized by a prolonged QT interval and polymorphic ventricular arrhythmias that could result in recurrent syncope, seizures or sudden death as the most dramatic event. Until now QT interval mutations have been described in 12 genes, where the majority of mutations reside in three genes KCNQ1, KCNH2, and SCN5A. Diagnosis and prognosis are directly related with the gene and mutation involved. We have developed a diagnostic approach for long QT syndrome and Brugada syndrome based on published mutations and Sequenom MassArray system. Three diagnostic tests have been developed, oriented to each of the three most prevalent genes in the long QT syndrome. A total of 433 mutations are analyzed in 38 multiplex reactions, allowing their detection in about 48 h. Tests were validated on 502 samples from individuals with different clinical conditions and family history. The average call rates obtained for each of the tests were 93, 83, and 73% in KCNQ1, KCNH2, and SCNA, respectively. Sequenom MassARRAY mutation detection is a reliable, highly flexible, and cost-efficient alternative to conventional methods for genetic testing in long QT syndrome and Brugada syndrome, facilitating flexible upgrades of the version of the test presented here with the inclusion of new mutations.

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“…Molecular autopsy might be used in such cases to find the cause of the death, adding the genetic analysis to the autopsy protocol [30].…”

Section: Sequenom Massarraymentioning

confidence: 99%

A new approach to long QT syndrome mutation detection by Sequenom MassARRAY^® system

et al. 2010

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“…It is recognized that changes in cardiac ion channel genes can cause sudden death without any morphological abnormalities in the heart (Márban, 2002). This can make it difficult to identify the cause of death in legal medicine reviews (Rodríguez-Calvo et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Post mortem genetic analyses (molecular autopsy) can potentially substantiate the pathogenic basis for the SCD, and may prevent further deaths in the same family as family history is known to be a significant risk factor (Rodríguez-Calvo et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Analysis of SNP (single nucleotide polymorphism) multiplex markers related to sudden cardiac death in Brazilian families

Braganholi

Cicarelli

2015

Genet. Mol. Res.

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ABSTRACT. Sudden cardiac death (SCD) is a major public health concern worldwide, and genetic analysis may be useful in identifying the cause of death as well as in determining the possible genetic risk factors for SCD. This study analyzed eight SNPs (single nucleotide polymorphisms) highly correlated with cardiac sudden death in samples (blood and bone) from six Brazilian families with a history of cardiovascular diseases. Individuals with no family history of cardiovascular diseases were recruited as controls. Y chromosomes and mtDNA haplogroups belonging to these subjects were verified as well. We found that SNP rs16857031 showed significant differences between the group with a family history of cardiovascular diseases and the control group. Furthermore, the data obtained were compatible with known frequencies of SNPs for the haplogroups in which the samples were classified. A possible hereditary factor was identified for SNP rs4725982 in one family. These preliminary results suggest that identification of certain SNPs could be used to assess risk factors for SCD.

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“…Potentially lethal and heritable ion channel disorders or "channelopathies" such as long QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPTV) or Brugada syndrome may be responsible for a portion of those cases. In the last years, many of the mutated genes implicated in these channelopathies have been identified and their role in the development of cardiac arrhythmias has been confirmed [6].…”

Section: Introductionmentioning

confidence: 99%

Detection of genetic variation in KCNQ1 gene by high-resolution melting analysis in a prospective-based series of postmortem negative sudden death: comparison of results obtained in fresh frozen and formalin-fixed paraffin-embedded tissues

Farrugia¹,

Keyser

Ludes

2012

Int J Legal Med

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High-resolution melting (HRM) analysis is a recently developed molecular technique proved to be applicable for detection of genetic variation, notably in sudden cardiac death. In certain circumstances, especially in postmortem genetic investigations, the formalin-fixed and paraffin-embedded (FFPE) tissues are the only DNA source available. The present study aimed to develop HRM assays, optimized for the analysis of FFPE tissues, to detect sequence variations in KCNQ1 exons in a prospective population-based series of postmortem negative sudden death and to compare the results between the paired freshly frozen and FFPE tissue samples simultaneously obtained from the same case. The analyses were conducted in each case of sudden death involving cases younger than 35 years with no significant morphological anomalies particularly with no cardiac structural disease and with negatives toxicological investigations. HRM analysis was successfully optimized for 13 of the 16 exons of the KCNQ1 gene. All mutated samples were correctly identified by HRM whatever the type of tissue tested. However, for FFPE samples, HRM indicated more positive samples than classical sequencing, used in parallel, due to the degradation of DNA by formalin fixation. This is the first postmortem study of KCNQ1 mutation detection with HRM on DNA extracted from FFPE samples with adapted protocol. Despite the false-positive detection, we concluded that the use of HRM as a screening method with FFPE samples to analyze KCNQ1 mutations can reduce the number of sequencing reactions and, thus, results in substantial time and cost savings.

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Molecular genetics of sudden cardiac death

Cited by 72 publications

References 156 publications

A new approach to long QT syndrome mutation detection by Sequenom MassARRAY^® system

A new approach to long QT syndrome mutation detection by Sequenom MassARRAY^® system

Analysis of SNP (single nucleotide polymorphism) multiplex markers related to sudden cardiac death in Brazilian families

Detection of genetic variation in KCNQ1 gene by high-resolution melting analysis in a prospective-based series of postmortem negative sudden death: comparison of results obtained in fresh frozen and formalin-fixed paraffin-embedded tissues

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Molecular genetics of sudden cardiac death

Cited by 72 publications

References 156 publications

A new approach to long QT syndrome mutation detection by Sequenom MassARRAY® system

A new approach to long QT syndrome mutation detection by Sequenom MassARRAY® system

Analysis of SNP (single nucleotide polymorphism) multiplex markers related to sudden cardiac death in Brazilian families

Detection of genetic variation in KCNQ1 gene by high-resolution melting analysis in a prospective-based series of postmortem negative sudden death: comparison of results obtained in fresh frozen and formalin-fixed paraffin-embedded tissues

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A new approach to long QT syndrome mutation detection by Sequenom MassARRAY^® system

A new approach to long QT syndrome mutation detection by Sequenom MassARRAY^® system