一般口演26（II-OR26）
心血管発生・基礎研究

[II-OR26-03] iPS心筋を用いたQT延長症候群の表現型に基づく分類法

^○吉永 大介¹, 馬場 志郎¹, 牧山 武², 平田 拓也¹, 赤木 健太郎¹, 松田 浩一¹, 堀江 稔³, 滝田 順子¹ (1.京都大学大学院医学研究科 小児科, 2.京都大学大学院医学研究科 循環器内科, 3.滋賀医科大学 循環器内科)

キーワード：long QT syndrome, iPS, phenotype-based

Background: For long-QT syndrome (LQTS), recent progress in genome-sequencing technologies enabled the identification of rare genomic variants with diagnostic, prognostic, and therapeutic implications. However, pathogenic stratification of the identified variants remains challenging, especially in variants of uncertain significance.Objective: This study aimed to propose a phenotypic cell-based diagnostic assay for identifying LQTS to recognize pathogenic variants in a high-throughput manner suitable for screening.Methods: Disease-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were differentiated from iPSCs generated from three LQTS patients (KCNQ1 p.A344Aspl, KCNH2 p.A422T, and SCN5A p.N406K, respectively). Response to specific current blockade was evaluated by using a multi-electrode array.Results: We first investigated the response of LQT type2 (LQT2)- iPSC-CMs following I_Kr blockade, finding that the response was significantly smaller in LQT2^A422T-iPSC-CMs than in Controls. Importantly, gene correction of the A422T mutation normalized the LQT2-CM phenotype. Furthermore, evaluation of this method for other LQTS types in response to I_Ks blockade using LQT1^A344Aspl-iPSC-CMs revealed a significantly smaller response relative to Controls. Moreover, response to I_Na blockade in LQT3^N406K-iPSC-CMs was greater than in LQT3^corr- iPSC-CMs. Conclusions: The methods presented in this study allowed classification of LQTS types 1, 2 and 3. This strategy potentially represents a breakthrough in compensating for the shortcomings of genetic testing of LQTS.