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A massively parallel assay accurately discriminates between functionally normal and abnormal variants in a hotspot domain of KCNH2.
Ng, Chai-Ann; Ullah, Rizwan; Farr, Jessica; Hill, Adam P; Kozek, Krystian A; Vanags, Loren R; Mitchell, Devyn W; Kroncke, Brett M; Vandenberg, Jamie I.
Afiliación
  • Ng CA; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Darlinghurst, NSW, Australia.
  • Ullah R; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Farr J; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; School of Computer Science and Engineering, UNSW Sydney, Kensington, NSW, Australia.
  • Hill AP; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Darlinghurst, NSW, Australia.
  • Kozek KA; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Vanags LR; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Mitchell DW; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Kroncke BM; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: brett.m.kroncke.1@vumc.org.
  • Vandenberg JI; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Darlinghurst, NSW, Australia. Electronic address: j.vandenberg@victorchang.edu.au.
Am J Hum Genet ; 109(7): 1208-1216, 2022 07 07.
Article en En | MEDLINE | ID: mdl-35688148
Many genes, including KCNH2, contain "hotspot" domains associated with a high density of variants associated with disease. This has led to the suggestion that variant location can be used as evidence supporting classification of clinical variants. However, it is not known what proportion of all potential variants in hotspot domains cause loss of function. Here, we have used a massively parallel trafficking assay to characterize all single-nucleotide variants in exon 2 of KCNH2, a known hotspot for variants that cause long QT syndrome type 2 and an increased risk of sudden cardiac death. Forty-two percent of KCNH2 exon 2 variants caused at least 50% reduction in protein trafficking, and 65% of these trafficking-defective variants exerted a dominant-negative effect when co-expressed with a WT KCNH2 allele as assessed using a calibrated patch-clamp electrophysiology assay. The massively parallel trafficking assay was more accurate (AUC of 0.94) than bioinformatic prediction tools (REVEL and CardioBoost, AUC of 0.81) in discriminating between functionally normal and abnormal variants. Interestingly, over half of variants in exon 2 were found to be functionally normal, suggesting a nuanced interpretation of variants in this "hotspot" domain is necessary. Our massively parallel trafficking assay can provide this information prospectively.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de QT Prolongado / Canales de Potasio Éter-A-Go-Go / Canal de Potasio ERG1 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de QT Prolongado / Canales de Potasio Éter-A-Go-Go / Canal de Potasio ERG1 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos