Sudden Cardiac Death and Copy Number Variants: What Do We Know after 10 Years of Genetic Analysis?

Mates, Jesus; Mademont-Soler, Irene; Fernández-Falgueras, Anna; Sarquella‐Brugada, Georgia; César, Sergi; Arbelo, Elena; García‐Álvarez, Ana; Jordà, Paloma; Toro, Rocío; Coll, Mónica; Fiol, Victoria; Iglesias, Anna; Pérez‐Serra, Alexandra; Olmo, Bernat del; Alcalde, Mireia; Puigmulé, Marta; Pico, Fernando; López, Laura; Ferrer, Carles; Tirón, Coloma; Grassi, Simone; Oliva, Antonio; Brugada, Josép; Brugada, Ramón; Campuzano, Òscar

doi:10.1016/j.fsigen.2020.102281

Cited by 27 publications

(25 citation statements)

References 100 publications

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“…In recent years many studies on CNVs in the human genome have been published. Vast majority of them regarded clinical applications, such as the impact of CNVs on arrhythmogenic pathologies (17), autism and psychosis (18) as well as on cancer (19). However, only few studies have focussed on genome architectures underlying CNVs (20).…”

Section: Discussionmentioning

confidence: 99%

DNA sequence features underlying large-scale duplications and deletions in human

Kołomański¹,

Szyda²,

Frąszczak³

et al. 2021

Preprint

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BackgroundCopy Number Variants (CNVs) may cover up to 12% of the whole genome and have substantial impact on phenotypes. We used 5 867 duplications and 33 181 deletions available from the 1000 Genomes Project to characterize genomic regions vulnerable to CNV formation and to identify sequence features characteristic for those regions.ResultsOnly 14 CNVs contained unknown nucleotides, which reflected the high quality of the analysed data. The GC content for deletions was lower and for duplications was higher than for randomly selected regions. In regions flanking deletions and downstream of duplications content was higher than in the random sequences, but upstream of duplication content was lower. In duplications, the percentage of low complexity sequences was not different from the randomized data, but in deletions it was higher. Moreover, it was significantly higher upstream of CNVs as compared to random sequences. Conversely, it was lower downstream of duplications. The majority of CNVs intersected with genic regions - mainly with introns. ConclusionsGC content may be associated with CNV formation and CNVs, especially duplications are initiated in low complexity regions. Moreover, CNVs located or overlapped with introns indicate their role in shaping intron variability. Genic CNV regions were enriched in many essential biological processes such as cell adhesion, synaptic transmission, transport, cytoskeleton organization, immune response and metabolic mechanisms what indicates that this large-scaled variants play important biological roles.

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Section: Discussionmentioning

confidence: 99%

DNA sequence features underlying large-scale duplications and deletions in human

Kołomański¹,

Szyda²,

Frąszczak³

et al. 2021

Preprint

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show abstract

“…Finally, with regard to CNVs as being potentially responsible for FDCM, to date no structural alteration has been identified in RBM20. Only two CNVs have been associated with FDCM, one located in LMNA [66] and the other in BAG3 [67], explaining <5% of FDCM cases together [68,69].…”

Section: Rare Rbm20 Variants In Familial Dilated Cardiomyopathymentioning

confidence: 99%

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

Jordà

Toro

Díez

et al. 2021

JPM

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The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine.

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“…Technology focused on genetic panels usually obtains high coverage. This improvement allows the bioinformatic identification of other structural alterations such as rearrangements and CNVs, which are associated with 2–10% of diagnosed IASs [ 43 , 44 ]. However, WES does not provide enough coverage for exhaustive CNV analysis.…”

Section: Technical Datamentioning

confidence: 99%

“…A similar situation occurs in WGS, but with lower coverage. A genetic report including WES or WGS results from families with IAS has yet to be established [ 43 ] despite that, in the near future, both genetic approaches will be the main technologies in genetic diagnosis ( Figure 3 ). Nonetheless, panels encompassing all genes associated with IAS are the best approach for the genetic diagnosis of both living patients and postmortem cases of unexplained sudden decease with suspected arrhythmia.…”

Section: Technical Datamentioning

confidence: 99%

Genetic Variants as Sudden-Death Risk Markers in Inherited Arrhythmogenic Syndromes: Personalized Genetic Interpretation

Campuzano

Sarquella-Brugada

Arbelo

et al. 2020

JCM

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Inherited arrhythmogenic syndromes are the primary cause of unexpected lethal cardiac episodes in young people. It is possible that the first sign of the condition may be sudden death. Inherited arrhythmogenic syndromes are caused by genetic defects that may be analyzed using different technical approaches. A genetic alteration may be used as a marker of risk for families who carry the genetic alterations. Therefore, the early identification of the responsible genetic defect may help the adoption of preventive therapeutic measures focused on reducing the risk of lethal arrhythmias. Here, we describe the use of massive sequencing technologies and the interpretation of genetic analyses in inherited arrhythmogenic syndromes.

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Sudden Cardiac Death and Copy Number Variants: What Do We Know after 10 Years of Genetic Analysis?

Cited by 27 publications

References 100 publications

DNA sequence features underlying large-scale duplications and deletions in human

DNA sequence features underlying large-scale duplications and deletions in human

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

Genetic Variants as Sudden-Death Risk Markers in Inherited Arrhythmogenic Syndromes: Personalized Genetic Interpretation

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