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; 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

doi:10.1038/s41436-020-00946-5

Journal Articles Genetics in Medicine Year : 2021

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

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , (1) , , , , , , , , , , , ,

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

P Guicheney

Function : Author

Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases

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.

Keywords

variant interpretation LQTS Brugada ACMG/AMP guidelines variant interpretation LQTS Brugada ACMG/AMP guidelines

Domains

Life Sciences [q-bio]

Fichier principal

Walsch R rare varainst interpretation Gen Med 2021.pdf (2.17 Mo)

Origin : Files produced by the author(s)

Pascale Guicheney : Connect in order to contact the contributor

https://www.hal.inserm.fr/inserm-04021331

Submitted on : Thursday, March 9, 2023-1:23:49 PM

Last modification on : Saturday, March 18, 2023-4:13:34 AM

Dates and versions

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

Identifiers

HAL Id : inserm-04021331 , version 1
DOI : 10.1038/s41436-020-00946-5

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⟩

Export

BibTeX TEI Dublin Core DC Terms EndNote Datacite

Collections

INSERM ICAN SORBONNE-UNIVERSITE SU-MEDECINE IHU_ICAN

4 View

8 Download

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

Abstract

Keywords

Domains

Dates and versions

Identifiers

Cite

Export

Collections

Altmetric

Share