Programmpunkt

14:45–15:00

Titel: Biallelic variants in YRDC cause a developmental disorder with progeroid features
ID: W9-004
Art: Invited talk
Redezeit: 15 min
Session: Workshop 9
Monogenic Syndromes

Referent: Julia Schmidt (Göttingen/DE)


Abstract - Text

Abstract-Text

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 analyses of patient-derived dermal fibroblasts revealed that mutant YRDC results in aberrant tRNA modification mainly caused by reduced t6A modifications. 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 primary patient cells and detected an overall increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect, affecting both homologous recombination and non-homologous end joining in the patient cells. 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 novel progeroid syndrome and might be linked to increased genomic instability and telomere shortening.