Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Genetics in Medicine Year : 2021

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

R Walsh , N Lahrouchi , R Tadros , F Kyndt , C Glinge , Pg Postema , As Amin , Ea Nannenberg , Js Ware , N Whiffin , F Mazzarotto , D Škorić-Milosavljević , C Krijger , E Arbelo , D Babuty , H Barajas-Martinez , Bm Beckmann , S Bézieau , Jm Bos , J Breckpot , O Campuzano , S Castelletti , C Celen , S Clauss , A Corveleyn , L Crotti , F Dagradi , C de Asmundis , I Denjoy , S Dittmann , Pt Ellinor , Cg Ortuño , C Giustetto , Jb Gourraud , D Hazeki , M Horie , T Ishikawa , H Itoh , Y Kaneko , Jk Kanters , H Kimoto , Mc Kotta , Ipc Krapels , M Kurabayashi , J Lazarte , A Leenhardt , Bl Loeys , C Lundin , T Makiyama , J Mansourati , Rp Martins , A Mazzanti , S Mörner , C Napolitano , K Ohkubo , M Papadakis , B Rudic , Ms Molina , F Sacher , H Sahin , G Sarquella-Brugada , R Sebastiano , S Sharma , Mn Sheppard , K Shimamoto , Mb Shoemaker , B Stallmeyer , J Steinfurt , Y Tanaka , Dj Tester , K Usuda , Pa van der Zwaag , S van Dooren , L van Laer , A Winbo , Bg Winkel , K Yamagata , S Zumhagen , Pga Volders , Sa Lubitz , C Antzelevitch , Pg Platonov , Ke Odening , Dm Roden , Jd Roberts , Jr Skinner , J Tfelt-Hansen , Mp van den Berg , Ms Olesen , Pd Lambiase , M Borggrefe , K Hayashi , A Rydberg , T Nakajima , M Yoshinaga , Jb Saenen , S Kääb , P Brugada , T Robyns , Df Giachino , Mj Ackerman , R Brugada , J Brugada , Jr Gimeno , C Hasdemir , P Guicheney (1) , Sg Priori , E Schulze-Bahr , N Makita , Pj Schwartz , W Shimizu , T Aiba , Jj Schott , R Redon , S Ohno , Er Behr , J Barc , Cr Bezzina
R Walsh
  • Function : Author
N Lahrouchi
  • Function : Author
R Tadros
  • Function : Author
F Kyndt
  • Function : Author
C Glinge
  • Function : Author
Pg Postema
  • Function : Author
As Amin
  • Function : Author
Ea Nannenberg
  • Function : Author
Js Ware
  • Function : Author
N Whiffin
  • Function : Author
F Mazzarotto
  • Function : Author
D Škorić-Milosavljević
  • Function : Author
C Krijger
  • Function : Author
E Arbelo
  • Function : Author
D Babuty
  • Function : Author
H Barajas-Martinez
  • Function : Author
Bm Beckmann
  • Function : Author
S Bézieau
  • Function : Author
Jm Bos
  • Function : Author
J Breckpot
  • Function : Author
O Campuzano
  • Function : Author
S Castelletti
  • Function : Author
C Celen
  • Function : Author
S Clauss
  • Function : Author
A Corveleyn
  • Function : Author
L Crotti
  • Function : Author
F Dagradi
  • Function : Author
C de Asmundis
  • Function : Author
I Denjoy
  • Function : Author
S Dittmann
  • Function : Author
Pt Ellinor
  • Function : Author
Cg Ortuño
  • Function : Author
C Giustetto
  • Function : Author
Jb Gourraud
  • Function : Author
D Hazeki
  • Function : Author
M Horie
  • Function : Author
T Ishikawa
  • Function : Author
H Itoh
  • Function : Author
Y Kaneko
  • Function : Author
Jk Kanters
  • Function : Author
H Kimoto
  • Function : Author
Mc Kotta
  • Function : Author
Ipc Krapels
  • Function : Author
M Kurabayashi
  • Function : Author
J Lazarte
  • Function : Author
A Leenhardt
  • Function : Author
Bl Loeys
  • Function : Author
C Lundin
  • Function : Author
T Makiyama
  • Function : Author
J Mansourati
  • Function : Author
Rp Martins
  • Function : Author
A Mazzanti
  • Function : Author
S Mörner
  • Function : Author
C Napolitano
  • Function : Author
K Ohkubo
  • Function : Author
M Papadakis
  • Function : Author
B Rudic
  • Function : Author
Ms Molina
  • Function : Author
F Sacher
  • Function : Author
H Sahin
  • Function : Author
G Sarquella-Brugada
  • Function : Author
R Sebastiano
  • Function : Author
S Sharma
  • Function : Author
Mn Sheppard
  • Function : Author
K Shimamoto
  • Function : Author
Mb Shoemaker
  • Function : Author
B Stallmeyer
  • Function : Author
J Steinfurt
  • Function : Author
Y Tanaka
  • Function : Author
Dj Tester
  • Function : Author
K Usuda
  • Function : Author
Pa van der Zwaag
  • Function : Author
S van Dooren
  • Function : Author
L van Laer
  • Function : Author
A Winbo
  • Function : Author
Bg Winkel
  • Function : Author
K Yamagata
  • Function : Author
S Zumhagen
  • Function : Author
Pga Volders
  • Function : Author
Sa Lubitz
  • Function : Author
C Antzelevitch
  • Function : Author
Pg Platonov
  • Function : Author
Ke Odening
  • Function : Author
Dm Roden
  • Function : Author
Jd Roberts
  • Function : Author
Jr Skinner
  • Function : Author
J Tfelt-Hansen
  • Function : Author
Mp van den Berg
  • Function : Author
Ms Olesen
  • Function : Author
Pd Lambiase
  • Function : Author
M Borggrefe
  • Function : Author
K Hayashi
  • Function : Author
A Rydberg
  • Function : Author
T Nakajima
  • Function : Author
M Yoshinaga
  • Function : Author
Jb Saenen
  • Function : Author
S Kääb
  • Function : Author
P Brugada
  • Function : Author
T Robyns
  • Function : Author
Df Giachino
  • Function : Author
Mj Ackerman
  • Function : Author
R Brugada
  • Function : Author
J Brugada
  • Function : Author
Jr Gimeno
  • Function : Author
C Hasdemir
  • Function : Author
Sg Priori
  • Function : Author
E Schulze-Bahr
  • Function : Author
N Makita
  • Function : Author
Pj Schwartz
  • Function : Author
W Shimizu
  • Function : Author
T Aiba
  • Function : Author
Jj Schott
  • Function : Author
R Redon
  • Function : Author
S Ohno
  • Function : Author
Er Behr
  • Function : Author
J Barc
  • Function : Author
Cr Bezzina
  • Function : Author

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 Nterminus (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.
Fichier principal
Vignette du fichier
Walsch R rare varainst interpretation Gen Med 2021.pdf (2.17 Mo) Télécharger le fichier
Origin Files produced by the author(s)

Dates and versions

inserm-04021331 , version 1 (09-03-2023)

Identifiers

Cite

R Walsh, N Lahrouchi, R Tadros, F Kyndt, C Glinge, et al.. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genetics in Medicine, 2021, ⟨10.1038/s41436-020-00946-5⟩. ⟨inserm-04021331⟩
6 View
18 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More