Four pedigrees with aminoacyl-tRNA synthetase abnormalities

Area of Science:

• Biochemistry and Molecular Biology
• Genetics and Genomics
• Neuroscience

Background:

• Aminoacyl tRNA synthetases (ARSs) are crucial enzymes for protein synthesis, conserved across species.
• Deficiencies in ARS enzymes are linked to a range of genetic disorders, including neuropathies like Charcot-Marie-Tooth disease.
• ARS deficiencies can manifest with diverse clinical features, affecting either cytosolic or mitochondrial functions, leading to systemic or neurological symptoms.

Purpose of the Study:

• To identify novel genetic variants in ARS genes responsible for unexplained genetic disorders.
• To broaden the understanding of the genetic and clinical spectrum of ARS-related diseases.
• To evaluate the utility of whole exome sequencing (WES) in diagnosing ARS deficiencies.

Main Methods:

• Whole exome sequencing (WES) was employed to analyze the genetic material of patients from four pedigrees.
• Identification and characterization of novel compound heterozygous variants in specific ARS genes (WARS1, MARS1, AARS2, PARS2).
• Clinical correlation of identified variants with patient phenotypes.

Main Results:

• Four pedigrees with novel compound heterozygous variants in ARS genes (WARS1, MARS1, AARS2, and PARS2) were identified via WES.
• Unique clinical manifestations were observed in the affected individuals.
• The application of WES has led to an increasing number of diagnosed ARS deficiency cases.

Conclusions:

• The study successfully identified novel ARS gene variants, expanding the known genetic causes of ARS-related disorders.
• The findings highlight the significant clinical variability associated with ARS deficiencies.
• WES is an effective tool for diagnosing complex genetic disorders linked to ARS variants.