Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes

Campuzano, Òscar; Sarquella‐Brugada, Georgia; Fernández-Falgueras, Anna; Coll, Mónica; Iglesias, Anna; Ferrer-Costa, Carles; César, Sergi; Arbelo, Elena; García‐Álvarez, Ana; Jordà, Paloma; Toro, Rocío; Llano, Coloma Tirón de; Grassi, Simone; Oliva, Antonio; Brugada, Josép; Brugada, Ramón

doi:10.1016/j.ebiom.2020.102732

Cited by 57 publications

(49 citation statements)

References 28 publications

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“…In 2020, Campuzano et al analyzed how many variants of genes involved in IAS had to be reclassified after 10 years [118]. The authors found that the 69.23% and the 94.11% of the variants found in, respectively, clinical and forensic cases had to be reclassified and that many of the variants previously classified as likely pathogenic were re-classified as variants of uncertain significance (VUS).…”

Section: Molecular Autopsymentioning

confidence: 99%

Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies

Grassi

Campuzano

Coll

et al. 2021

IJMS

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Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this review, the main differential diagnoses of hypertrophic cardiomyopathy (e.g., athlete’s heart, idiopathic left ventricular hypertrophy), arrhythmogenic cardiomyopathy (e.g., adipositas cordis, myocarditis) and dilated cardiomyopathy (e.g., acquired forms of dilated cardiomyopathy, left ventricular noncompaction) are discussed. Moreover, the diagnostic issues in SCD victims affected by phenotype-negative hypertrophic cardiomyopathy and the relationship between myocardial bridging and hypertrophic cardiomyopathy are analyzed. Finally, the applications/limits of virtopsy and post-mortem genetic testing in this field are discussed, with particular attention to the issues related to the assessment of the significance of the genetic variants.

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Section: Molecular Autopsymentioning

confidence: 99%

Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies

Grassi

Campuzano

Coll

et al. 2021

IJMS

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“…Other studies already pointed out the importance of reanalysis of sequencing data, especially in patients with complex genetic diseases, as genomic databases are continuously updated and adjusted based on new findings in co-segregation studies and functional analyses [44]. Accordingly, when comparing our previously published data and the results presented in this study, some variants were interpreted differently and some new variants popped up.…”

Section: Discussionmentioning

confidence: 73%

Re-evaluation of single nucleotide variants and identification of structural variants in a cohort of 45 sudden unexplained death cases

et al. 2021

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Sudden unexplained death (SUD) takes up a considerable part in overall sudden death cases, especially in adolescents and young adults. During the past decade, many channelopathy- and cardiomyopathy-associated single nucleotide variants (SNVs) have been identified in SUD studies by means of postmortem molecular autopsy, yet the number of cases that remain inconclusive is still high. Recent studies had suggested that structural variants (SVs) might play an important role in SUD, but there is no consensus on the impact of SVs on inherited cardiac diseases. In this study, we searched for potentially pathogenic SVs in 244 genes associated with cardiac diseases. Whole-exome sequencing and appropriate data analysis were performed in 45 SUD cases. Re-analysis of the exome data according to the current ACMG guidelines identified 14 pathogenic or likely pathogenic variants in 10 (22.2%) out of the 45 SUD cases, whereof 2 (4.4%) individuals had variants with likely functional effects in the channelopathy-associated genes SCN5A and TRDN and 1 (2.2%) individual in the cardiomyopathy-associated gene DTNA. In addition, 18 structural variants (SVs) were identified in 15 out of the 45 individuals. Two SVs with likely functional impairment were found in the coding regions of PDSS2 and TRPM4 in 2 SUD cases (4.4%). Both were identified as heterozygous deletions, which were confirmed by multiplex ligation-dependent probe amplification. In conclusion, our findings support that SVs could contribute to the pathology of the sudden death event in some of the cases and therefore should be investigated on a routine basis in suspected SUD cases.

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“…Similar results were obtained in other studies, which reported a prevalence of 35%-40% of new mutations, half of which were unique for a family[ 136 ]. The conclusive classification of VUS is encumbered by challenges, particularly in cases of “private” mutations, as it involves computational and population-based studies, not rarely misleading[ 137 , 138 ]. Combined use of recent technologies such as iPSC and gene editing have enabled functional annotation in specific cases.…”

Section: Modeling Variants Of Uncertain Significancementioning

confidence: 99%

Patient-specific induced pluripotent stem cells as “disease-in-a-dish” models for inherited cardiomyopathies and channelopathies – 15 years of research

Micheu¹,

Rosca²

2021

WJSC

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Among inherited cardiac conditions, a special place is kept by cardiomyopathies (CMPs) and channelopathies (CNPs), which pose a substantial healthcare burden due to the complexity of the therapeutic management and cause early mortality. Like other inherited cardiac conditions, genetic CMPs and CNPs exhibit incomplete penetrance and variable expressivity even within carriers of the same pathogenic deoxyribonucleic acid variant, challenging our understanding of the underlying pathogenic mechanisms. Until recently, the lack of accurate physiological preclinical models hindered the investigation of fundamental cellular and molecular mechanisms. The advent of induced pluripotent stem cell (iPSC) technology, along with advances in gene editing, offered unprecedented opportunities to explore hereditary CMPs and CNPs. Hallmark features of iPSCs include the ability to differentiate into unlimited numbers of cells from any of the three germ layers, genetic identity with the subject from whom they were derived, and ease of gene editing, all of which were used to generate “disease-in-a-dish” models of monogenic cardiac conditions. Functionally, iPSC-derived cardiomyocytes that faithfully recapitulate the patient-specific phenotype, allowed the study of disease mechanisms in an individual-/allele-specific manner, as well as the customization of therapeutic regimen. This review provides a synopsis of the most important iPSC-based models of CMPs and CNPs and the potential use for modeling disease mechanisms, personalized therapy and deoxyribonucleic acid variant functional annotation.

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Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes

Cited by 57 publications

References 28 publications

Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies

Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies

Re-evaluation of single nucleotide variants and identification of structural variants in a cohort of 45 sudden unexplained death cases

Patient-specific induced pluripotent stem cells as “disease-in-a-dish” models for inherited cardiomyopathies and channelopathies – 15 years of research

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