Systemic inflammatory syndrome in children with FARSA deficiency

Area of Science:

• Genetics
• Molecular Biology
• Immunology

Background:

• Aminoacyl-tRNA synthetase (ARS) gene variants are linked to various inherited human diseases.
• Phenylalanyl-tRNA synthetase (PheRS), encoded by FARSA and FARSB, is crucial for protein synthesis. PheRS deficiency typically presents with brain abnormalities, lung disease, and facial dysmorphism.

Purpose of the Study:

• To investigate the genetic and clinical features of four children from two families with homozygous variants in the FARSA gene.
• To characterize the functional impact of these FARSA variants on PheRS activity.
• To identify novel clinical manifestations associated with PheRS deficiency.

Main Methods:

• Genetic sequencing to identify variants in the FARSA gene.
• Biochemical assays to measure PheRS-mediated aminoacylation activity.
• Clinical evaluation of patients, including assessment of inflammatory markers and interferon scores.
• Analysis of treatment response to JAK inhibition.

Main Results:

• Four children presented with two novel homozygous missense variants in FARSA, leading to significantly reduced PheRS aminoacylation activity.
• Beyond the core ARS-phenotype, all patients exhibited an inflammatory profile, including autoimmunity and elevated interferon scores.
• One patient showed improvement in lung disease following JAK inhibition therapy.

Conclusions:

• The study expands the known genetic and clinical spectrum of FARSA-related diseases.
• Novel homozygous variants in FARSA can cause a distinct inflammatory and autoimmune phenotype in addition to core ARS disease.
• JAK inhibition may be a potential therapeutic strategy for the lung disease associated with FARSA deficiency.