Biallelic variants in YRDC cause a developmental disorder with progeroid features

Area of Science:

• Genetics and Molecular Biology
• Cell Biology
• Developmental Biology

Background:

• The YrdC domain-containing protein (YRDC) is crucial for tRNA modification, interacting with the KEOPS complex to ensure accurate protein synthesis.
• The KEOPS complex is known to be involved in telomere maintenance and genome integrity.
• Genetic defects in YRDC can lead to severe developmental disorders.

Observation:

• A newborn presented with a severe neonatal progeroid phenotype, including growth retardation, microcephaly, and premature death.
• Trio whole-exome sequencing identified a novel homozygous missense mutation (c.662T>C, p.Ile221Thr) in the YRDC gene.
• Patient-derived fibroblasts showed impaired YRDC function and reduced t6A tRNA modifications.

Findings:

• The YRDC mutation led to significant telomere shortening in patient cells, as revealed by 3-D Q-FISH analysis.
• Single-cell RNA sequencing demonstrated transcriptome-wide changes in YRDC-mutant fibroblasts, particularly in DNA repair-associated genes.
• Patient fibroblasts exhibited increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect.

Implications:

• Biallelic YRDC variants cause a developmental disorder characterized by progeroid features.
• YRDC plays a significant role in maintaining genomic stability.
• These findings highlight the link between tRNA modification, telomere maintenance, and DNA repair in human development.