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Int J Mol Sci 2023 Jan 10;242:. doi: 10.3390/ijms24021350.
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Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome KCNQ1 Variants.

Rinné S , Oertli A , Nagel C , Tomsits P , Jenewein T , Kääb S , Kauferstein S , Loewe A , Beckmann BM , Decher N .

The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score.

PubMed ID: 36674868
PMC ID: PMC9865342
Article link: Int J Mol Sci

Species referenced: Xenopus laevis
Genes referenced: arfgap1 kcne1 kcnq1 mink1 scd sh2b2
GO keywords: voltage-gated potassium channel activity

Disease Ontology terms: autosomal dominant disease [+]

Article Images: [+] show captions
References [+] :
Ackerman, Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. 1999, Pubmed