Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTOR signaling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions. We report a cohort of twelve individuals with biallelic SZT2 variants and phenotypes consistent with SZT2-related neurodevelopmental disorder. The majority of this cohort contained one or more SZT2 variants of uncertain significance (VUS). We developed a novel individualized platform to functionally characterize SZT2 VUSs. We identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis determined this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Overall, we present a FACS-based rapid assay to distinguish pathogenic variants from VUSs in SZT2, using an approach that is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1/2, MTOR and NPRL2/3.

中文翻译：

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确定不确定意义的变体的致病性并鉴定癫痫相关基因SZT2中的奠基者变体

SZT2中的双等位基因致病变异导致具有共同特征的神经发育障碍，包括早发性癫痫，发育迟缓，大头畸形和call体异常。SZT2是mTOR信号传导途径的氨基酸传感臂中的关键支架蛋白。由于其大小大（3432个氨基酸），缺乏晶体结构和功能域，因此难以确定SZT2错义和框内缺失的致病性。我们报告了队列的十二个人与SZT2相关的神经发育障碍的双等位基因SZT2变体和表型。该队列中的大多数包含一个或多个不确定重要性（VUS）的SZT2变体。我们开发了一个新颖的个性化平台来对SZT2 VUS进行功能表征。我们鉴定出复发的框内缺失（SZT2 p.Val1984del），其被确定为功能丧失的变异体，因此可能是致病的。单倍型分析确定该单个框内缺失是阿什肯纳兹犹太血统的创始人变异。总体而言，我们提出了一种基于FACS的快速检测方法，以区分SZT2中VUSs的致病变体，该方法广泛适用于其他mTORopathies，包括局灶性遗传性癫痫的最常见原因，DEPDC5，TSC1 / 2，MTOR和NPRL2 / 3。