The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. By trio whole-exome sequencing, we identified a novel homozygous missense mutation, c.662T > C, in YRDC affecting an evolutionary highly conserved amino acid (p.Ile221Thr). Functional characterization of patient-derived dermal fibroblasts revealed that this mutation impairs YRDC function and consequently results in reduced t⁶A modifications of tRNAs. Furthermore, we established and performed a novel and highly sensitive 3-D Q-FISH analysis based on single-telomere detection to investigate the impact of YRDC on telomere maintenance. This analysis revealed significant telomere shortening in YRDC-mutant cells. Moreover, single-cell RNA sequencing analysis of YRDC-mutant fibroblasts revealed significant transcriptome-wide changes in gene expression, specifically enriched for genes associated with processes involved in DNA repair. We next examined the DNA damage response of patient’s dermal fibroblasts and detected an increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect. Thus, our data suggest that YRDC may affect the maintenance of genomic stability. Together, our findings indicate that biallelic variants in YRDC result in a developmental disorder with progeroid features and might be linked to increased genomic instability and telomere shortening.

高度保守的含有 YrdC 结构域的蛋白质 (YRDC) 与描述良好的 KEOPS 复合物相互作用，调节特定的 tRNA 修饰以确保准确的蛋白质合成。先前的研究已将 KEOPS 复合体与促进端粒维持和控制基因组完整性的作用联系起来。在这里，我们报告了一个具有严重新生儿早衰表型的新生儿，包括皮下脂肪的全身性损失、小头畸形、生长迟缓、皮肤皱纹、肾功能衰竭和 12 天时过早死亡。通过三重全外显子组测序，我们在 YRDC 中发现了一个新的纯合错义突变 c.662T > C影响进化高度保守的氨基酸（p.Ile221Thr）。源自患者的真皮成纤维细胞的功能表征表明，这种突变会损害 YRDC 功能，从而导致 t ⁶tRNA 的一种修饰。此外，我们建立并执行了一种基于单端粒检测的新型高灵敏度 3-D Q-FISH 分析，以研究 YRDC 对端粒维持的影响。该分析揭示了 YRDC 突变细胞中显着的端粒缩短。此外，YRDC 突变成纤维细胞的单细胞 RNA 测序分析揭示了基因表达的显着转录组范围的变化，特别是与 DNA 修复过程相关的基因富集。我们接下来检查了患者皮肤成纤维细胞的 DNA 损伤反应，并检测到对基因毒性剂的敏感性增加和全局 DNA 双链断裂修复缺陷。因此，我们的数据表明 YRDC 可能会影响基因组稳定性的维持。总之，我们的研究结果表明双等位基因变体在YRDC导致具有早衰特征的发育障碍，可能与基因组不稳定性增加和端粒缩短有关。