Mutations in FARS2 and non-fatal mitochondrial dysfunction in two siblings

Area of Science:

• Genetics
• Mitochondrial Biology
• Neurology

Background:

• Mutations in FARS2, encoding mitochondrial phenylalanyl-tRNA synthetase, are linked to autosomal recessive combined oxidative phosphorylation deficiency 14.
• Previous reports associate FARS2 mutations with infantile onset epilepsy and fatal Alpers-like encephalopathy.

Purpose of the Study:

• To report two siblings with global developmental delay, dysarthria, and tremor due to compound heterozygous FARS2 abnormalities.
• To expand the phenotypic spectrum of FARS2-related mitochondrial disease.

Main Methods:

• Exome sequencing identified a heterozygous missense mutation (c.1255C>T; p.Arg419Cys).
• SNP array analysis revealed an interstitial deletion of chromosome 6p25.1, encompassing FARS2 exon 6.
• Biochemical studies confirmed a mitochondrial disorder.

Main Results:

• The siblings presented with global developmental delay, dysarthria, and tremor.
• They exhibited compound heterozygous FARS2 abnormalities: a missense mutation and a deletion.
• Despite developmental challenges, the siblings showed consistent progress, indicating a milder phenotype than previously reported.

Conclusions:

• This study broadens the understanding of FARS2-related mitochondrial disease phenotypes.
• Intragenic deletions should be considered among causative mutations for FARS2-related disorders.
• The findings highlight the variability in clinical presentation and disease severity.