Prognostic Value of Multiplexed Assays of Variant Effect and Automated Patch-clamping for KCNH2-LQTS Risk Stratification
Background: Long QT syndrome (LQTS) is a lethal arrhythmia condition, frequently caused by rare loss-of-function variants in the cardiac potassium channel encoded by KCNH2. Variant-based risk stratification is complicated by heterogenous clinical data, incomplete penetrance, and low-throughput functional data.
Objective: To test the utility of variant-specific features, including high-throughput functional data, to predict cardiac events among KCNH2 variant heterozygotes.
Methods: We quantified cell-surface trafficking of 18,323 variants in KCNH2 and recorded potassium current densities for 506 KCNH2 variants. Next, we deeply phenotyped 1150 KCNH2 missense variant patients, including ECG features, cardiac event history (528 total cardiac events), and mortality. We then assessed variant functional, in silico, structural, and LQTS penetrance data to stratify event-free survival for cardiac events in the study cohort.
Results: Variant-specific current density (HR 0.28 [0.13-0.60]) and estimates of LQTS penetrance incorporating MAVE data (HR 3.16 [1.59-6.27]) were independently predictive of severe cardiac events when controlling for patient-specific features. Risk prediction models incorporating these data significantly improved prediction of 20 year cardiac events (AUC 0.79 [0.75-0.82]) over patient-only covariates (QTc and sex) (AUC 0.73 [0.70-0.77]).
Conclusion: We show that high-throughput functional data, and other variant-specific features, meaningfully contribute to both diagnosis and prognosis of a clinically actionable monogenic disease.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
medRxiv : the preprint server for health sciences - (2024) vom: 05. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
O'Neill, Matthew J [VerfasserIn] |
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| Anmerkungen: |
Date Revised 26.02.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2024.02.01.24301443 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368608212 |
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| 100 | 1 | |a O'Neill, Matthew J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Prognostic Value of Multiplexed Assays of Variant Effect and Automated Patch-clamping for KCNH2-LQTS Risk Stratification |
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| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Background: Long QT syndrome (LQTS) is a lethal arrhythmia condition, frequently caused by rare loss-of-function variants in the cardiac potassium channel encoded by KCNH2. Variant-based risk stratification is complicated by heterogenous clinical data, incomplete penetrance, and low-throughput functional data | ||
| 520 | |a Objective: To test the utility of variant-specific features, including high-throughput functional data, to predict cardiac events among KCNH2 variant heterozygotes | ||
| 520 | |a Methods: We quantified cell-surface trafficking of 18,323 variants in KCNH2 and recorded potassium current densities for 506 KCNH2 variants. Next, we deeply phenotyped 1150 KCNH2 missense variant patients, including ECG features, cardiac event history (528 total cardiac events), and mortality. We then assessed variant functional, in silico, structural, and LQTS penetrance data to stratify event-free survival for cardiac events in the study cohort | ||
| 520 | |a Results: Variant-specific current density (HR 0.28 [0.13-0.60]) and estimates of LQTS penetrance incorporating MAVE data (HR 3.16 [1.59-6.27]) were independently predictive of severe cardiac events when controlling for patient-specific features. Risk prediction models incorporating these data significantly improved prediction of 20 year cardiac events (AUC 0.79 [0.75-0.82]) over patient-only covariates (QTc and sex) (AUC 0.73 [0.70-0.77]) | ||
| 520 | |a Conclusion: We show that high-throughput functional data, and other variant-specific features, meaningfully contribute to both diagnosis and prognosis of a clinically actionable monogenic disease | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Ng, Chai-Ann |e verfasserin |4 aut | |
| 700 | 1 | |a Aizawa, Takanori |e verfasserin |4 aut | |
| 700 | 1 | |a Sala, Luca |e verfasserin |4 aut | |
| 700 | 1 | |a Bains, Sahej |e verfasserin |4 aut | |
| 700 | 1 | |a Denjoy, Isabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Winbo, Annika |e verfasserin |4 aut | |
| 700 | 1 | |a Ullah, Rizwan |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Qianyi |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Chek-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Kozek, Krystian |e verfasserin |4 aut | |
| 700 | 1 | |a Vanags, Loren R |e verfasserin |4 aut | |
| 700 | 1 | |a Mitchell, Devyn W |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Alex |e verfasserin |4 aut | |
| 700 | 1 | |a Wada, Yuko |e verfasserin |4 aut | |
| 700 | 1 | |a Kashiwa, Asami |e verfasserin |4 aut | |
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| 700 | 1 | |a Bos, J Martijn |e verfasserin |4 aut | |
| 700 | 1 | |a Giudicessi, John R |e verfasserin |4 aut | |
| 700 | 1 | |a Bledsoe, Xavier |e verfasserin |4 aut | |
| 700 | 1 | |a Lancaster, Megan |e verfasserin |4 aut | |
| 700 | 1 | |a Glazer, Andrew M |e verfasserin |4 aut | |
| 700 | 1 | |a Roden, Dan M |e verfasserin |4 aut | |
| 700 | 1 | |a Leenhardt, Antoine |e verfasserin |4 aut | |
| 700 | 1 | |a Salem, Joe-Elie |e verfasserin |4 aut | |
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| 700 | 1 | |a Johnson, Christopher N |e verfasserin |4 aut | |
| 700 | 1 | |a Horie, Minoru |e verfasserin |4 aut | |
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