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Patch Clamp

Patch Clamp

Many fundamental cell functions such as muscle contraction and nerve transmission rely on the electrical signals produced by the movement of positively and negatively charged ions across the cell membrane. One competent method to record current flowing across the whole cell or single ion channel is the patch-clamp technique.
In this method, a glass micropipette containing electrolyte solution is tightly sealed against a small portion of the cell membrane. As a result, a patch of the cell...

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Related Experiment Video

Updated: Jun 12, 2025

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve KCNH2-LQTS Variant Classification and

Matthew J O'Neill¹, Chai-Ann Ng², Takanori Aizawa³

¹Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN (M.J.O., X.B.).

|September 24, 2024

Summary

High-throughput functional assays improve classification of KCNH2 variants causing Long QT syndrome. Penetrance estimates and patch clamping data enhance cardiac event risk stratification in patients.

Keywords:

LQTS arrhythmias automated patch clamping multiplexed assay of variant effect risk stratification

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Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes

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Last Updated: Jun 12, 2025

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

Technical Applications of Microelectrode Array and Patch Clamp Recordings on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

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Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes

Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes

Published on: March 12, 2013

Area of Science:

Genetics and Genomics
Cardiovascular Medicine
Molecular Biology

Background:

Long QT syndrome (LQTS) is a life-threatening arrhythmia syndrome often caused by loss-of-function variants in the KCNH2 potassium channel gene.
Classifying KCNH2 variants and stratifying patient risk is challenging due to limited functional data, heterogeneous clinical information, and incomplete penetrance.

Purpose of the Study:

To evaluate if variant-specific data from high-throughput functional assays can improve the classification of KCNH2 missense variants.
To assess the utility of functional assay data in refining cardiac event risk stratification for patients with heterozygous KCNH2 missense variants.

Main Methods:

Quantified cell-surface trafficking of 18,796 KCNH2 variants using a multiplexed assay of variant effect (MAVE).
Recorded KCNH2 current density for 533 variants via automated patch clamping.
Deeply phenotyped 1458 patients with KCNH2 missense variants, correlating functional data and Bayesian LQTS penetrance estimates with clinical outcomes.

Main Results:

MAVE trafficking scores strongly correlated with automated patch clamping peak tail currents (ρ=0.69).
MAVE data provided strong evidence for severe loss-of-function variants.
Functional assays and Bayesian penetrance estimates significantly predicted cardiac events; MAVE data became non-significant when peak tail current and penetrance were included. Area under the curve improved from 0.80 to 0.86 with penetrance scores or 0.84 with patch clamping data.

Conclusions:

High-throughput MAVE data effectively contribute to large-scale KCNH2 variant classification.
LQTS penetrance estimates and automated patch clamping peak tail current measurements significantly enhance cardiac event risk stratification in patients with heterozygous KCNH2 missense variants.