Abstract:
BACKGROUND:KCNH2 encodes the human ether-à-go-go-related gene potassium channel, which passes the rapid delayed rectifier potassium current. Loss-of-function variants in KCNH2 cause long QT syndrome type 2, which is associated with a markedly increased risk of cardiac arrhythmias. The majority of rare KCNH2 variants, however, are likely to be benign. OBJECTIVE:The purpose of this study was to develop a high-throughput assay for discriminating pathogenic from benign KCNH2 variants. METHODS:Nonsynonymous homozygous KCNH2 variants stably expressed in Flp-In human embryonic kidney 293 cell lines were phenotyped using an automated patch-clamp platform and a cell surface enzyme-linked immunosorbent assay. Functional phenotyping of heterozygous KCNH2 variants stably expressed in Flp-In human embryonic kidney 293 cell lines using a bicistronic vector was performed using an automated patch-clamp platform. RESULTS:In homozygous KCNH2 variant cell lines, discrepancies between current density and cell surface expression levels measured using an enzyme-linked immunosorbent assay can be explained by changes in gating properties of the variant channels. For the 30 heterozygous KCNH2 variant cell lines studied, the assay correctly predicted the ClinVar ascribed classification for 17/17 pathogenic/likely pathogenic/benign variants. Of the 13 pore-domain variants studied, 11 had a dominant-negative expression defect while the remaining 2 had enhanced inactivation gating, resulting in a dominant-negative phenotype. CONCLUSION:High-throughput electrophysiological phenotyping of heterozygous KCNH2 variants can accurately distinguish between dominant-negative, haploinsufficient loss-of-function, and benign variants. This assay will help with future classification of KCNH2 variants.
journal_name
Heart Rhythmjournal_title
Heart rhythmauthors
Ng CA,Perry MD,Liang W,Smith NJ,Foo B,Shrier A,Lukacs GL,Hill AP,Vandenberg JIdoi
10.1016/j.hrthm.2019.09.020subject
Has Abstractpub_date
2020-03-01 00:00:00pages
492-500issue
3eissn
1547-5271issn
1556-3871pii
S1547-5271(19)30853-7journal_volume
17pub_type
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