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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

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@article{85780886d35c4b78a949f8a8ba7b683f,
title = "Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls",
abstract = "PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.",
keywords = "ACMG/AMP guidelines, Brugada, LQTS, variant interpretation",
author = "Roddy Walsh and Najim Lahrouchi and Rafik Tadros and Florence Kyndt and Charlotte Glinge and Postema, {Pieter G} and Amin, {Ahmad S} and Nannenberg, {Eline A} and Ware, {James S} and Nicola Whiffin and Francesco Mazzarotto and Doris {\v S}kori{\'c}-Milosavljevi{\'c} and Christian Krijger and Elena Arbelo and Dominique Babuty and Hector Barajas-Martinez and Beckmann, {Britt M} and St{\'e}phane B{\'e}zieau and Bos, {J Martijn} and Jeroen Breckpot and Oscar Campuzano and Silvia Castelletti and Candan Celen and Sebastian Clauss and Anniek Corveleyn and Lia Crotti and Federica Dagradi and {de Asmundis}, Carlo and Isabelle Denjoy and Sven Dittmann and Ellinor, {Patrick T} and Ortu{\~n}o, {Cristina Gil} and Carla Giustetto and Jean-Baptiste Gourraud and Daisuke Hazeki and Minoru Horie and Taisuke Ishikawa and Hideki Itoh and Yoshiaki Kaneko and Kanters, {J{\o}rgen K} and Hiroki Kimoto and Maria-Christina Kotta and Krapels, {Ingrid P C} and Masahiko Kurabayashi and Julieta Lazarte and Antoine Leenhardt and Loeys, {Bart L} and Winkel, {Bo G} and Jacob Tfelt-Hansen and Olesen, {Morten S} and {Nantes Referral Center for inherited cardiac arrhythmia}",
year = "2021",
month = jan,
doi = "10.1038/s41436-020-00946-5",
language = "English",
volume = "23",
pages = "47--58",
journal = "Genetics In Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams & Wilkins",
number = "1",

}

RIS

TY - JOUR

T1 - Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

AU - Walsh, Roddy

AU - Lahrouchi, Najim

AU - Tadros, Rafik

AU - Kyndt, Florence

AU - Glinge, Charlotte

AU - Postema, Pieter G

AU - Amin, Ahmad S

AU - Nannenberg, Eline A

AU - Ware, James S

AU - Whiffin, Nicola

AU - Mazzarotto, Francesco

AU - Škorić-Milosavljević, Doris

AU - Krijger, Christian

AU - Arbelo, Elena

AU - Babuty, Dominique

AU - Barajas-Martinez, Hector

AU - Beckmann, Britt M

AU - Bézieau, Stéphane

AU - Bos, J Martijn

AU - Breckpot, Jeroen

AU - Campuzano, Oscar

AU - Castelletti, Silvia

AU - Celen, Candan

AU - Clauss, Sebastian

AU - Corveleyn, Anniek

AU - Crotti, Lia

AU - Dagradi, Federica

AU - de Asmundis, Carlo

AU - Denjoy, Isabelle

AU - Dittmann, Sven

AU - Ellinor, Patrick T

AU - Ortuño, Cristina Gil

AU - Giustetto, Carla

AU - Gourraud, Jean-Baptiste

AU - Hazeki, Daisuke

AU - Horie, Minoru

AU - Ishikawa, Taisuke

AU - Itoh, Hideki

AU - Kaneko, Yoshiaki

AU - Kanters, Jørgen K

AU - Kimoto, Hiroki

AU - Kotta, Maria-Christina

AU - Krapels, Ingrid P C

AU - Kurabayashi, Masahiko

AU - Lazarte, Julieta

AU - Leenhardt, Antoine

AU - Loeys, Bart L

AU - Winkel, Bo G

AU - Tfelt-Hansen, Jacob

AU - Olesen, Morten S

AU - Nantes Referral Center for inherited cardiac arrhythmia

PY - 2021/1

Y1 - 2021/1

N2 - PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

AB - PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

KW - ACMG/AMP guidelines

KW - Brugada

KW - LQTS

KW - variant interpretation

UR - http://www.scopus.com/inward/record.url?scp=85090223596&partnerID=8YFLogxK

U2 - 10.1038/s41436-020-00946-5

DO - 10.1038/s41436-020-00946-5

M3 - Journal article

C2 - 32893267

VL - 23

SP - 47

EP - 58

JO - Genetics In Medicine

JF - Genetics In Medicine

SN - 1098-3600

IS - 1

ER -

ID: 62374439