Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome.

Pauline Le Tanno,Julien Fauré,Michel Vivaudou,Alexandre Janin,Laurence Faivre,Gabriel Laurent,Pascal Amedro,Jean Revilloud,Gilles Millat,Nathalie Roux-Buisson,Mathilde Folacci,Lucile Pinson

doi:10.3389/fgene.2021.773177

Abstract

Andersen-Tawil Syndrome (ATS) is a rare disease defined by the association of cardiac arrhythmias, periodic paralysis and dysmorphic features, and is caused by KCNJ2 loss-of-function mutations. However, when extracardiac symptoms are atypical or absent, the patient can be diagnosed with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a rare arrhythmia at high risk of sudden death, mostly due to RYR2 mutations. The identification of KCNJ2 variants in CPVT suspicion is very rare but important because beta blockers, the cornerstone of CPVT therapy, could be less efficient. We report here the cases of two patients addressed for CPVT-like phenotypes. Genetic investigations led to the identification of p. Arg82Trp and p. Pro186Gln de novo variants in the KCNJ2 gene. Functional studies showed that both variants forms of Kir2.1 monomers act as dominant negative and drastically reduced the activity of the tetrameric channel. We characterize here a new pathogenic variant (p.Pro186Gln) of KCNJ2 gene and highlight the interest of accurate cardiologic evaluation and of attention to extracardiac signs to distinguish CPVT from atypical ATS, and guide therapeutic decisions. We also confirm that the KCNJ2 gene must be investigated during CPVT molecular analysis.

Highlights

Andersen Tawil Syndrome (ATS) is characterized by a triad of symptoms: periodic paralysis, distinctive clinical features, and cardiac arrhythmias
In the case of atypical arrhythmia, ATS or Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) diagnosis may both be evoked. In such cases the identification of the mutated gene is of uppermost importance because first line treatment of RYR2 mutation-induced CPVT is based on beta blockers that can be less efficient on KCNJ2 mutated cases (Hayashi et al, 2009; Priori et al, 2013; Manzatti et al 2020)
We report here 2 novel cases of atypical ATS initially referred for suspicion of CPVT leading to the identification of KCNJ2 pathogenic variants

Summary

Introduction

Andersen Tawil Syndrome (ATS) is characterized by a triad of symptoms: periodic paralysis (episodic flaccid muscle weakness), distinctive clinical features (such as low-set ears, broad forehead, small palpebral fissures, hypertelorism, broad nasal root, bulbous nose, thin upper lip, maxillary, malar and mandibular hypoplasia, abnormal extremities), and cardiac arrhythmias. Pathogenic variants in KCNJ2 were first associated with Andersen Tawil Syndrome (ATS) in 2001 (Plaster et al, 2001) and until now account for 80% of the cases (Zhang et al, 2005; Haruna et al, 2007). KCNJ2 variants are associated in rare familial forms of atrial fibrillation type 9, short QT syndrome type 3 and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (Tester et al, 2006). In the case of atypical arrhythmia, ATS or CPVT diagnosis may both be evoked In such cases the identification of the mutated gene is of uppermost importance because first line treatment of RYR2 mutation-induced CPVT is based on beta blockers that can be less efficient on KCNJ2 mutated cases (Hayashi et al, 2009; Priori et al, 2013; Manzatti et al 2020)

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