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2019 - High-throughput phenotyping of heteromeric human ether-à-go-go-related gene potassium channel variants can discriminate pathogenic from rare benign variants

icon sp96   SyncroPatch 384PE (a predecessor model of SyncroPatch 384i) publication in Heart Rhythm (2019)

Ng C-A., Perry M.D., Liang W., Smith N.J., Foo B., Shrier A., Lukacs G.L., Hill A.P., Vandenberg J.I.

Heart Rhythm (2019) In Press. doi.org/10.1016/j.hrthm.2019.09.020


KCNH2 encodes the human ether-à-go-go-related gene (hERG) potassium channel, which passes the rapid delayed rectifier potassium current, IKr. Loss-of-function variants in KCNH2 cause long QT syndrome type 2 (LQTS2) which is associated with a markedly increased risk of cardiac arrhythmias. The majority of rare KCNH2 variants however are likely to be benign.

To develop a high-throughput assay for discriminating between pathogenic and benign KCNH2 variants.

Nonsynonymous homozygous KCNH2 variants stably expressed in Flp-In human embryonic kidney 293 (HEK293) cell lines were phenotyped using an automated patch-clamp platform (SyncroPatch 384PE) and a cell surface ELISA assay. Functional phenotyping of heterozygous KCNH2 variants stably expressed in Flp-In HEK293 using a bicistronic vector was performed using SyncroPatch 384PE.

In homozygous KCNH2 variant cell lines, discrepancies between current density and cell surface expression levels measured by ELISA can be explained by changes in gating properties of the variant channels. Amongst 30 heterozygous KCNH2 variant cell lines studied, the assay correctly predicted the ClinVar ascribed classification for 17/17 pathogenic/likely pathogenic/benign variants. Of 13 pore-domain variants studied, 11 had a dominant-negative expression defect whilst the remaining two had enhanced inactivation gating resulting in a dominant-negative phenotype.

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.

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