Application and validation of phenotype-enhanced variant classification in East Asian patients with catecholaminergic polymorphic ventricular tachycardia
Journal
Heart rhythm
Journal Volume
21
Journal Issue
3
Pages
349–351
Date Issued
2024-03
Author(s)
Hsu, Grace Chia-Yen
Yeh, Shih-Fan Sherri
Chuang, Jing-Yuan
Horie, Minoru
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) has been identified as a notable cause of sudden cardiac death in children and young adults.1Giudicessi J.R. Lieve K.V.V. Rohatgi R.K. et al.Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.Circulation: Genomic and Precision Medicine. 2019; 12e002510Crossref Scopus (35) Google Scholar Mutation of ryanodine receptor 2 (RYR2) is observed in the majority of CPVT patients and is inherited through an autosomal dominant pattern.2Shimamoto K. Ohno S. Kato K. et al.Impact of cascade screening for catecholaminergic polymorphic ventricular tachycardia type 1.Heart. May 12 2022; 108: 840-847Crossref PubMed Scopus (0) Google Scholar Genetic tests can help clinicians diagnose CPVT and identify potentially at-risk individuals so that medication can be prescribed before the onset of lethal arrhythmias.1Giudicessi J.R. Lieve K.V.V. Rohatgi R.K. et al.Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.Circulation: Genomic and Precision Medicine. 2019; 12e002510Crossref Scopus (35) Google Scholar The American College of Medical Genetics and Genomics (ACMG) published guidelines for classifying variants as pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), or benign.3Richards S. Aziz N. Bale S. et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med May. 2015; 17: 405-424Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar However, many RYR2 variants remain classified ambiguously. A previous multicenter study developed a phenotype-enhanced variant classification algorithm for CPVT, integrating the ACMG criteria and clinical data.1Giudicessi J.R. Lieve K.V.V. Rohatgi R.K. et al.Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.Circulation: Genomic and Precision Medicine. 2019; 12e002510Crossref Scopus (35) Google Scholar This CPVT score was developed using Caucasian CPVT cohorts. Whether it is applicable to other ethnicities is yet to be determined. This was an international, retrospective cohort study of 40 clinically diagnosed Taiwanese CPVT patients and 109 Japanese CPVT patients from multiple tertiary medical centers. Subject data were obtained from the Sudden Arrhythmia Death Syndrome Registry in Taiwan and two Japanese CPVT cohorts described by Shimamoto et al. in 2022 and Kawamura et al. in 2013.2Shimamoto K. Ohno S. Kato K. et al.Impact of cascade screening for catecholaminergic polymorphic ventricular tachycardia type 1.Heart. May 12 2022; 108: 840-847Crossref PubMed Scopus (0) Google Scholar,4Kawamura M. Ohno S. Naiki N. et al.Genetic Background of Catecholaminergic Polymorphic Ventricular Tachycardia in Japan.Circulation Journal. 2013; 77: 1705-1713Crossref PubMed Scopus (0) Google Scholar Data sharing agreements and local ethics approval were obtained by each center, and informed consent was obtained from all patients (IRB No. 201305043RINB). The Taiwanese CPVT patients were screened for CPVT-associated genes using capture-based targeted exon sequencing (Illumina, CA, USA), described in our previous work.5Juang J.M. Lu T.P. Lai L.C. et al.Disease-targeted sequencing of ion channel genes identifies de novo mutations in patients with non-familial Brugada syndrome.Sci Rep. Oct 23 2014; 4: 6733Crossref PubMed Scopus (48) Google Scholar The mutations were confirmed by Sanger sequencing. The genetic testing of the 2022 Japanese cohort was performed by combining the conventional Sanger method, multiplex ligation-dependent probe amplification, and next-generation sequencing using MiSeq (Illumina, San Diego, California, USA).2Shimamoto K. Ohno S. Kato K. et al.Impact of cascade screening for catecholaminergic polymorphic ventricular tachycardia type 1.Heart. May 12 2022; 108: 840-847Crossref PubMed Scopus (0) Google Scholar The 2013 Japanese cohort received CPVT-related genetic mutation analysis via Sanger sequencing when the study was published.4Kawamura M. Ohno S. Naiki N. et al.Genetic Background of Catecholaminergic Polymorphic Ventricular Tachycardia in Japan.Circulation Journal. 2013; 77: 1705-1713Crossref PubMed Scopus (0) Google Scholar Panel gene analysis was introduced afterwards, and these patients received next-generation sequencing to confirm the results. The traditional ACMG classification was determined using ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), VarsSome (https://varsome.com) and InterVar (https://wintervar.wglab.org). If discrepancies were noted between these databases during classification, the ACMG classification was determined manually, according to ACMG guidelines and a literature search for previous reports of the variants. Among the 80 different RYR2 variants detected in the largest Asian combined CPVT cohort, 46 (58%) mutations were classified as VUS while 34 (43%) mutations were classified as P/LP by the ACMG criteria. The CPVT score of the RYR2 mutation-positive CPVT patients was then calculated according to the scorecard proposed by Giudicessi et al.1Giudicessi J.R. Lieve K.V.V. Rohatgi R.K. et al.Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.Circulation: Genomic and Precision Medicine. 2019; 12e002510Crossref Scopus (35) Google Scholar The scorecard includes the patients’ symptoms such as exercise-associated cardiac arrest or syncope, exercise stress test or Holter results, genetic test results, and family history.1Giudicessi J.R. Lieve K.V.V. Rohatgi R.K. et al.Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.Circulation: Genomic and Precision Medicine. 2019; 12e002510Crossref Scopus (35) Google Scholar The phenotype-enhanced variant classification reduced the VUS rate to 16% (p<0.001) in the combined cohort (Figure 1). Thirty-three (71%) VUS were promoted to P/LP resulting in a total of 67 (84%) P/LP variants. Such a result is consistent with the study by Giudicessi et al in which the VUS rate was decreased from 48% to 7% (p<0.001) with 65% of VUS promoted to likely pathogenic.1Giudicessi J.R. Lieve K.V.V. Rohatgi R.K. et al.Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.Circulation: Genomic and Precision Medicine. 2019; 12e002510Crossref Scopus (35) Google Scholar The CPVT score proposed by Giudicessi1Giudicessi J.R. Lieve K.V.V. Rohatgi R.K. et al.Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.Circulation: Genomic and Precision Medicine. 2019; 12e002510Crossref Scopus (35) Google Scholar was generated using Caucasian CPVT cohorts. Our study showed that this score is applicable to the Asian population. The phenotype-enhanced variant classification framework decreased the VUS rate from 58% to 16% (p<0.001) in the largest Asian combined cohort. In future practice, this would be a useful tool for interpreting genetic test results that are currently classified as having unknown significance.
Subjects
Arrhythmia; Catecholaminergic polymorphic ventricular tachycardia; Sudden cardiac arrest; Sudden cardiac death
SDGs
Type
journal article