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A Phenotype-Enhanced Variant Classification Framework to Decrease the Burden of Missense Variants of Uncertain Significance in Type 1 Long QT Syndrome

  • Author Footnotes
    ∗ Ms. Bains, Mr. Dotzler, and Mr. Krijger are co-equal first authors.
    Sahej Bains
    Footnotes
    ∗ Ms. Bains, Mr. Dotzler, and Mr. Krijger are co-equal first authors.
    Affiliations
    Medical Scientist Training Program, Mayo Clinic, Rochester, MN

    Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
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  • Author Footnotes
    ∗ Ms. Bains, Mr. Dotzler, and Mr. Krijger are co-equal first authors.
    Steven M. Dotzler
    Footnotes
    ∗ Ms. Bains, Mr. Dotzler, and Mr. Krijger are co-equal first authors.
    Affiliations
    Medical Scientist Training Program, Mayo Clinic, Rochester, MN

    Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
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  • Author Footnotes
    ∗ Ms. Bains, Mr. Dotzler, and Mr. Krijger are co-equal first authors.
    Christian Krijger
    Footnotes
    ∗ Ms. Bains, Mr. Dotzler, and Mr. Krijger are co-equal first authors.
    Affiliations
    Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
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  • John R. Giudicessi
    Affiliations
    Department of Cardiovascular Medicine (Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic), Mayo Clinic, Rochester, MN
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  • Dan Ye
    Affiliations
    Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
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  • Hennie Bikker
    Affiliations
    Department of Human Genetics, University of Amsterdam, Amsterdam University Medical Center, Amsterdam, Netherlands
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  • Ram K. Rohatgi
    Affiliations
    Department of Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), Mayo Clinic, Rochester, MN
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  • David J. Tester
    Affiliations
    Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN

    Department of Cardiovascular Medicine (Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic), Mayo Clinic, Rochester, MN

    Department of Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), Mayo Clinic, Rochester, MN
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  • J. Martijn Bos
    Affiliations
    Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN

    Department of Cardiovascular Medicine (Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic), Mayo Clinic, Rochester, MN

    Department of Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), Mayo Clinic, Rochester, MN
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  • Arthur A.M. Wilde
    Affiliations
    Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands

    Department of Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
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  • Michael J. Ackerman
    Correspondence
    Reprints and correspondence: Michael J. Ackerman, MD, PhD, Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic, Rochester, MN 55905 ,
    Affiliations
    Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN

    Department of Cardiovascular Medicine (Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic), Mayo Clinic, Rochester, MN

    Department of Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), Mayo Clinic, Rochester, MN
    Search for articles by this author
  • Author Footnotes
    ∗ Ms. Bains, Mr. Dotzler, and Mr. Krijger are co-equal first authors.
Published:November 16, 2021DOI:https://doi.org/10.1016/j.hrthm.2021.11.017

      ABSTRACT

      Background

      Pathogenic/likely pathogenic (P/LP) variants in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). Despite the revamped 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNQ1 variants of uncertain significance (VUS) in patients with LQTS remains ∼30%.

      Objective

      To determine whether a phenotype-enhanced (PE) variant classification approach could reduce the VUS burden in LQTS genetic testing.

      Methods

      Retrospective analysis was performed on 79 KCNQ1 missense variants in 356 patients from Mayo Clinic and an independent cohort of 42 variants in 225 patients from Amsterdam UMC. Each variant was classified initially using the ACMG guidelines and then re-adjudicated using a PE-ACMG framework that incorporated the LQTS clinical diagnostic Schwartz score plus four “LQT1-Defining Features”: broad-based/slow upstroke T-waves, syncope/seizure during exertion, swimming-associated events, and a maladaptive LQT1 treadmill stress test.

      Results

      According to ACMG guidelines, Mayo Clinic variants were classified as follows: 17/79 (22%) P, 34/79 (43%) LP, and 28/79 (35%) VUS. Similarly, for Amsterdam UMC, the variant distribution was 9/42 (22%) P, 14/42 (33%) LP, and 19/42 (45%) VUS. Following PE-ACMG re-adjudication, the total VUS burden decreased significantly from 28 (35%) to 13 (16%, p=0.0007) for Mayo Clinic and from 19 (45%) to 12 (29%, p=0.02) for Amsterdam UMC.

      Conclusions

      Phenotype-guided variant adjudication decreased significantly the VUS burden of LQT1 case-derived KCNQ1 missense variants in two independent cohorts. This study demonstrates the value of incorporating LQT1-specific phenotype/clinical data to aid in interpretation of KCNQ1 missense variants identified during genetic testing for LQTS.

      Keywords

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      REFERENCES

        • Ackerman M.J.
        Genetic purgatory and the cardiac channelopathies: Exposing the variants of uncertain/unknown significance issue.
        Heart Rhythm. 2015; 12: 2325-2331
        • Giudicessi J.R.
        • Ackerman M.J.
        Genotype- and phenotype-guided management of congenital long QT syndrome.
        Curr Probl Cardiol. 2013; 38: 417-455
        • Kapa S.
        • Tester D.J.
        • Salisbury B.A.
        • et al.
        Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.
        Circulation. 2009; 120: 1752-1760
        • Richards 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. 2015; 17: 405-424
        • Ackerman M.J.
        • Tester D.J.
        • Jones G.S.
        • Will M.L.
        • Burrow C.R.
        • Curran M.E.
        Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.
        Mayo Clin Proc. 2003; 78: 1479-1487
        • Giudicessi J.R.
        • Kapplinger J.D.
        • Tester D.J.
        • et al.
        Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.
        Circ Cardiovasc Genet. 2012; 5: 519-528
        • Mattivi C.L.
        • Bos J.M.
        • Bagnall R.D.
        • et al.
        Clinical utility of a phenotype enhanced MYH7-specific variant classification framework in hypertrophic cardiomyopathy genetic testing.
        Circ Genom Precis Med. 2020;
        • Giudicessi 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.
        Circ Genom Precis Med. 2019; 12 (e002510)
        • Porta-Sanchez A.
        • Spillane D.R.
        • Harris L.
        • et al.
        T-wave morphology analysis in congenital long QT syndrome discriminates patients from healthy individuals.
        JACC Clin Electrophysiol. 2017; 3: 374-381
        • Schwartz P.J.
        • Moss A.J.
        • Vincent G.M.
        • Crampton R.S.
        Diagnostic criteria for the long QT syndrome. An update.
        Circulation. 1993; 88: 782-784
        • Horner J.M.
        • Horner M.M.
        • Ackerman M.J.
        The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome.
        Heart Rhythm. 2011; 8: 1698-1704
        • Malfatto G.
        • Beria G.
        • Sala S.
        • Bonazzi O.
        • Schwartz P.J.
        Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome.
        J Am Coll Cardiol. 1994; 23: 296-301
        • Narravula A.
        • Garber K.B.
        • Askree S.H.
        • Hegde M.
        • Hall P.L.
        Variants of uncertain significance in newborn screening disorders: implications for large-scale genomic sequencing.
        Genet Med. 2017; 19: 77-82
        • Berg J.S.
        Exploring the importance of case-level clinical information for variant interpretation.
        Genet Med. 2017; 19: 3-5
        • Van Driest S.L.
        • Wells Q.S.
        • Stallings S.
        • et al.
        Association of arrhythmia-related genetic variants with phenotypes documented in electronic medical records.
        JAMA. 2016; 315: 47-57
        • Vanoye C.G.
        • Desai R.R.
        • Fabre K.L.
        • et al.
        High-throughput functional evaluation of KCNQ1 decrypts variants of unknown significance.
        Circ Genom Precis Med. 2018; 11 (e002345)
        • Gelb B.D.
        • Cave H.
        • Dillon M.W.
        • et al.
        ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.
        Genet Med. 2018; 20: 1334-1345
        • Tester D.J.
        • Will M.L.
        • Haglund C.M.
        • Ackerman M.J.
        Effect of clinical phenotype on yield of long QT syndrome genetic testing.
        J Am Coll Cardiol. 2006; 47: 764-768
        • Paquin A.
        • Ye D.
        • Tester D.J.
        • Kapplinger J.D.
        • Zimmermann M.T.
        • Ackerman M.J.
        Even pore-localizing missense variants at highly conserved sites in KCNQ1-encoded Kv7.1 channels may have wild-type function and not cause type 1 long QT syndrome: Do not rely solely on the genetic test company's interpretation.
        HeartRhythm Case Rep. 2018; 4: 37-44
        • Bartos D.C.
        • Anderson J.B.
        • Bastiaenen R.
        • et al.
        A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation.
        J Cardiovasc Electrophysiol. 2013; 24: 562-569