Non-missense variants ofKCNH2show better outcomes in type 2 long QT syndrome

Author:

Aizawa Takanori1ORCID,Wada Yuko23ORCID,Hasegawa Kanae34ORCID,Huang Hai1ORCID,Imamura Tomohiko1ORCID,Gao Jingshan1ORCID,Kashiwa Asami1ORCID,Kohjitani Hirohiko1ORCID,Fukuyama Megumi2ORCID,Kato Koichi2ORCID,Kato Eri Toda1ORCID,Hisamatsu Takashi5ORCID,Ohno Seiko6ORCID,Makiyama Takeru1,Kimura Takeshi7ORCID,Horie Minoru2ORCID

Affiliation:

1. Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan

2. Department of Cardiovascular Medicine, Shiga University of Medical Science , Setatsukinowacho, Otsu, Shiga 520-2192 , Japan

3. Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1275 MRBIV, Nashville, TN 37232 , USA

4. Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui , Fukui , Japan

5. Department of Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science , Okayama , Japan

6. Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center , Osaka , Japan

7. Division of Cardiology, Hirakata Kohsai Hospital , Osaka , Japan

Abstract

AbstractAimsMore than one-third of type 2 long QT syndrome (LQT2) patients carry KCNH2 non-missense variants that can result in haploinsufficiency (HI), leading to mechanistic loss-of-function. However, their clinical phenotypes have not been fully investigated. The remaining two-thirds of patients harbour missense variants, and past studies uncovered that most of these variants cause trafficking deficiency, resulting in different functional changes: either HI or dominant-negative (DN) effects. In this study, we examined the impact of altered molecular mechanisms on clinical outcomes in LQT2 patients.Methods and resultsWe included 429 LQT2 patients (234 probands) carrying a rare KCNH2 variant from our patient cohort undergoing genetic testing. Non-missense variants showed shorter corrected QT (QTc) and less arrhythmic events (AEs) than missense variants. We found that 40% of missense variants in this study were previously reported as HI or DN. Non-missense and HI-groups had similar phenotypes, while both exhibited shorter QTc and less AEs than the DN-group. Based on previous work, we predicted the functional change of the unreported variants—whether they cause HI or DN via altered functional domains—and stratified them as predicted HI (pHI)- or pDN-group. The pHI-group including non-missense variants exhibited milder phenotypes compared to the pDN-group. Multivariable Cox model showed that the functional change was an independent risk of AEs (P = 0.005).ConclusionStratification based on molecular biological studies enables us to better predict clinical outcomes in the patients with LQT2.

Funder

Ministry of Health

Labor and Welfare of Japan

for Clinical Research on Intractable Disease

MEXT KAKENHI

Heart Rhythm Society

American Heart Association

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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