Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

Nunn, Laurence; Lopes, Luís Rocha; Syrris, Petros; Murphy, Cian; Plagnol, Vincent; Firman, Eileen; Dalageorgou, Chrysoula; Zorio, Esther; Domingo, Diana; Murday, Victoria; Findlay, Iain; Duncan, Alexis E.; Carr‐White, Gerry; Robert, Leema; Bueser, Teofila; Langman, Caroline; Fynn, Simon P.; Goddard, Martin; White, Anne; Bundgaard, Henning; Ferrero-Miliani, Laura; Wheeldon, Nigel; Suvarna, S. Kim; O'Beirne, Aliceson; Löwe, Martin; McKenna, William J.; Elliott, Perry; Lambiase, Pier D.

doi:10.1093/europace/euv285

Cited by 66 publications

(35 citation statements)

References 34 publications

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“…Our higher percentage may be due to a comprehensive genetic analysis including both genes associated with channelopathies and genes associated with cardiomyopathies, recently associated with arrhythmic pathologies without any structural alteration [52, 53]. In concordance with our results, recent studies performed in post-mortem samples using NGS technology showed percentages of rare variants potentially pathogenic in 30%-40% of samples analyzed [24–26, 54–58]. …”

Section: Discussionsupporting

confidence: 90%

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

et al. 2016

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BackgroundSudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases.Methods and FindingsOur cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively.ConclusionsCardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk.

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Section: Discussionsupporting

confidence: 90%

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

et al. 2016

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“…Targeted sequencing of large gene panels in sudden unexplained death victims <50 years with a structural normal heart show a yield of 21-32%. [4][5][6] Moreover, extensive genetic screening with whole exome or genome sequencing has identified several causative mutations in IVF patients, for example the Dutch DPP6 risk haplotype, CALM1, a novel RYR2 mutation that causes ventricular fibrillation in rest, and IRX3 that is associated with short-coupled Torsade De Pointes. [7][8][9][10] The detection of these causative mutations has facilitated the identification and improved the clinical management of asymptomatic IVF family members.…”

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing of a large gene panel in patients initially diagnosed with idiopathic ventricular fibrillation

et al. 2017

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“…Actin filament length did not show any obvious alteration in individual 2 or 3 ( Figure S7 Figure S8). 19,[26][27][28] These include 21 missense mutations, 19,26,[29][30][31] two nonsense mutations, 19 and one 1-bp deletion, 26 and most of them were suspected to have dominant-negative effects ( Figures S8 and S9, row 2). 19,26,32 Among the three possible truncating mutations, two (c.1585C>T [p.Gln529*] and c.2653C>T [p.Arg885*]) are located within the 50-bp region upstream of each exon junction, implying the possible escape from NMD, and the truncated MYPD might cause the dominant-negative effect.…”

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confidence: 99%

Biallelic Mutations in MYPN , Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy

Miyatake

Mitsuhashi

Hayashi

et al. 2017

The American Journal of Human Genetics

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Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.

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Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

Abstract: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution.

Cited by 66 publications

References 34 publications

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

Next-generation sequencing of a large gene panel in patients initially diagnosed with idiopathic ventricular fibrillation

Biallelic Mutations in MYPN , Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy

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