Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for...

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Aminoacyl-tRNA synthetases (ARSs) are crucial enzymes for protein synthesis.
• Variants in ARS genes can lead to diverse human diseases with various inheritance patterns.
• Tryptophanyl-tRNA synthetase 1 (WARS1) variants are linked to dominant neuropathies, but biallelic effects are poorly understood.

Purpose of the Study:

• To investigate the role of biallelic WARS1 variants in human neurodevelopmental disorders.
• To characterize the clinical phenotypes associated with biallelic WARS1 disruption.
• To establish and validate animal models for studying WARS1-related diseases.

Main Methods:

• Clinical evaluation of three individuals from two families with biallelic WARS1 variants.
• Genetic analysis to identify and confirm WARS1 variants.
• Phenotypic analysis in Caenorhabditis elegans with knocked-down wars-1.
• Generation and analysis of a WARS1 knockout vertebrate model.

Main Results:

• Identified biallelic WARS1 variants (p.Met1? and p.(Asp419Asn)) in affected individuals.
• Observed variable neurodevelopmental phenotypes including intellectual disability, microcephaly, and brain abnormalities.
• WARS1 depletion in C. elegans caused germ cell development defects.
• WARS1 knockout model recapitulated human phenotypes, including hearing impairment, supporting pathogenicity.

Conclusions:

• Biallelic disruption of WARS1 is causally linked to an autosomal recessive neurodevelopmental syndrome.
• The study provides evidence for WARS1 variants impacting hearing, potentially due to exon disruption.
• Developed a vertebrate model that effectively mimics patient phenotypes, aiding further research into WARS1-related disorders.