Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors

Bennett, Jeffrey S.; McBride, Kim L.; Zmuda, Erik; Kertesz, Naomi J.; Garg, Vidu; Fitzgerald-Butt, Sara; Kamp, Anna

doi:10.1007/s00246-019-02203-2

Cited by 33 publications

(32 citation statements)

References 32 publications

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“…This data reinforces the need for clinical data in genetic diagnoses; a complete clinical history contributes to variant classification and helps to clarify the role of a variant in each patient. Recently, a study focused on the reclassification of VUS in IAS concluded that disease-specific phenotypes significantly increase the accuracy of classification [10]. Interestingly, we determined that many missense variants changed their classification from LP to VUS after reanalysis; this modification is mainly due to the increase of items used in ACMG recommendations.…”

Section: Discussionmentioning

confidence: 77%

“…In 2018, a reclassification of rare variants previously considered deleterious in Brugada Syndrome was performed; only 37% were classified as P or LP following current ACMG recommendations [8]. A recent study identified a modification in 52% of rare variants classified as VUS seven years ago [10]. Therefore, the evidence supports the periodic reclassification of the rare variants in IAS despite lack of data concerning the time of re-evaluation.…”

Section: Discussionmentioning

confidence: 96%

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Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

et al. 2020

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A B S T R A C TBackground: Accurate interpretation of rare genetic variants is a challenge for clinical translation. Updates in recommendations for rare variant classification require the reanalysis and reclassification. We aim to perform an exhaustive re-analysis of rare variants associated with inherited arrhythmogenic syndromes, which were classified ten years ago, to determine whether their classification aligns with current standards and research findings. Methods: In 2010, the rare variants identified through genetic analysis were classified following recommendations available at that time. Nowadays, the same variants have been reclassified following current American College of Medical Genetics and Genomics recommendations. Findings: Our cohort included 104 cases diagnosed with inherited arrhythmogenic syndromes and 17 postmortem cases in which inherited arrhythmogenic syndromes was cause of death. 71.87% of variants change their classification. While 65.62% of variants were classified as likely pathogenic in 2010, after reanalysis, only 17.96% remain as likely pathogenic. In 2010, 18.75% of variants were classified as uncertain role but nowadays 60.15% of variants are classified of unknown significance. Interpretation: Reclassification occurred in more than 70% of rare variants associated with inherited arrhythmogenic syndromes. Our results support the periodical reclassification and personalized clinical translation of rare variants to improve diagnosis and adjust treatment.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 96%

Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

et al. 2020

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“…Importantly, all classifications are performed according to the data available at the time of interpretation. Therefore, predictions regarding BrS are not immutable, and classifications of analyzed variants should be revised periodically as new data can be available [ 56 , 57 ]. New data included in the final classification may modify the role of a variant, with potential clinical implications.…”

Section: Genetic Interpretation/classificationmentioning

confidence: 99%

Update on Genetic Basis of Brugada Syndrome: Monogenic, Polygenic or Oligogenic?

Campuzano

Sarquella‐Brugada

César

et al. 2020

IJMS

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Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the SCN5A gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome.

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“…American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines classify all variants associated with arrhythmogenic diseases and SCD [ 29 ]. However, more than 50% of rare variants recently changed classification according to updated ACMG guidelines due to modifications performed in the current guidelines [ 30 , 31 ]. Genetic alterations with potential deleterious roles, classified as pathogenic (P) or likely pathogenic (LP), in an individual diagnosed with IAS, allow familial screening via cascade testing to identify at-risk individuals.…”

Section: Genetic Translationmentioning

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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Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors

Cited by 33 publications

References 32 publications

Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

Update on Genetic Basis of Brugada Syndrome: Monogenic, Polygenic or Oligogenic?

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

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