TATA‐box binding protein associated factor, RNA polymerase I subunit C (TAF1C) is a component of selectivity factor 1 belonging to RNA polymerase I (Pol I) transcription machinery. We report two unrelated patients with homozygous TAF1C missense variants and an early onset neurological phenotype with severe global developmental delay. Clinical features included lack of speech and ambulation and epilepsy. MRI of the brain demonstrated widespread cerebral atrophy and frontal periventricular white matter hyperintensity. The phenotype resembled that of a previously described variant of UBTF, which encodes another transcription factor of Pol I. TAF1C variants were located in two conserved amino acid positions and were predicted to be deleterious. In patient‐derived fibroblasts, TAF1C mRNA and protein expression levels were substantially reduced compared with healthy controls. We propose that the variants impairing TAF1C expression are likely pathogenic and relate to a novel neurological disease. This study expands the disease spectrum related to Pol I transcription machinery, associating the TAF1C missense variants with a severe neurological phenotype for the first time.

中文翻译：

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纯合 TAF1C 变异与一种新的儿童期发病的神经表型相关。

TATA 盒结合蛋白相关因子 RNA 聚合酶 I 亚基 C ( TAF1C ) 是属于 RNA 聚合酶 I (Pol I) 转录机制的选择性因子 1 的组成部分。我们报告了两名不相关的患者，他们具有纯合TAF1C错义变异和早发性神经表型，且伴有严重的整体发育迟缓。临床特征包括缺乏言语和行走以及癫痫。大脑 MRI 显示广泛的脑萎缩和额叶脑室周围白质高信号。该表型类似于先前描述的UBTF变体，它编码 Pol I 的另一个转录因子。TAF1C变体位于两个保守氨基酸位置，预计是有害的。在患者来源的成纤维细胞中，与健康对照相比， TAF1C mRNA 和蛋白质表达水平显着降低。我们认为损害TAF1C表达的变异可能是致病性的，并且与一种新型神经系统疾病有关。这项研究扩展了与 Pol I 转录机制相关的疾病谱，首次将TAF1C错义变异与严重的神经表型联系起来。