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Genetic Analysis of Arrhythmogenic Diseases in the Era of NGS: The Complexity of Clinical Decision-Making in Brugada Syndrome
Allegue, Catarina; Coll, Monica; Matés Ramírez, Jesús; Campuzano Larrea, Oscar; Iglesias, Anna; Sobrino, Beatriz; Brion, Maria; Amigo, Jorge; Carracedo, Angel; Brugada Terradellas, Pedro; Brugada Terradellas, Josep; Brugada, Ramon
BackgroundThe use of next-generation sequencing enables a rapid analysis of many genes associatedwith sudden cardiac death in diseases like Brugada Syndrome. Genetic variation is identifiedand associated with 30–35% of cases of Brugada Syndrome, with nearly 20–25%attributable to variants in SCN5A, meaning many cases remain undiagnosed genetically.To evaluate the role of genetic variants in arrhythmogenic diseases and the utility of nextgenerationsequencing, we applied this technology to resequence 28 main genes associatedwith arrhythmogenic disorders.Materials and MethodsA cohort of 45 clinically diagnosed Brugada Syndrome patients classified as SCN5Anegativewas analyzed using next generation sequencing. Twenty-eight genes were resequenced:AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP,GPD1L, HCN4, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNQ1,NOS1AP, PKP2, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, and TMEM43. A total of85 clinically evaluated relatives were also genetically analyzed to ascertain familialsegregation.Results and DiscussionTwenty-two patients carried 30 rare genetic variants in 12 genes, only 4 of which were previouslyassociated with Brugada Syndrome. Neither insertion/deletion nor copy number variationwere detected. We identified genetic variants in novel candidate genes potentiallyassociated to Brugada Syndrome. These include: 4 genetic variations in AKAP9 including a de novo genetic variation in 3 positive cases; 5 genetic variations in ANK2 detected in 4 cases; variations in KCNJ2 together with CASQ2 in 1 case; genetic variations in RYR2,including a de novo genetic variation and desmosomal proteins encoding genes includingDSG2, DSP and JUP, detected in 3 of the cases. Larger gene panels or whole exomesequencing should be considered to identify novel genes associated to Brugada Syndrome.However, application of approaches such as whole exome sequencing would difficult theinterpretation for clinical purposes due to the large amount of data generated. The identificationof these genetic variants opens new perspectives on the implications of genetic backgroundin the arrhythmogenic substrate for research purposes.ConclusionsAs a paradigm for other arrhythmogenic diseases and for unexplained sudden death, ourdata show that clinical genetic diagnosis is justified in a family perspective for confirmationof genetic causality. In the era of personalized medicine using high-throughput tools, clinicaldecision-making is increasingly complex
Cor -- Malalties
Heart -- Diseases
Cor -- Malalties -- Aspectes genètics
Heart -- Diseases -- Genetic aspects
Attribution 3.0 Spain
Public Library of Science (PLoS)

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