Splicing variants in NARS2 are associated with milder phenotypes and intra-familial variability

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Biallelic rare variants in NARS2, encoding mitochondrial asparaginyl-tRNA synthetase, are linked to diverse clinical phenotypes, including neurodegenerative disorders, mitochondrial myopathy, and deafness.
• Limited patient data and genotype-phenotype correlations exist for NARS2-related disorders.

Observation:

• Three siblings presented with early-onset hearing loss; one developed severe adult-onset symptoms including intellectual impairment, seizures, neuropathy, and psychiatric issues.
• Biochemical analyses revealed impaired respiratory chain complex activity and assembly in the affected patient.
• Whole Exome Sequencing identified a known pathogenic heterozygous variant (c.822G>C) and a novel intronic deletion (c.922-21_922-19del) in NARS2.

Findings:

• The novel intronic deletion in NARS2 was found to cause aberrant splicing and exon skipping in patient fibroblasts.
• This expands the known spectrum of NARS2 variants and associated phenotypes.
• The study details the phenotype of the oldest reported patient with NARS2 variants, including novel psychiatric symptoms.

Implications:

• This research broadens the understanding of NARS2-related disorders, highlighting a novel pathogenic deletion and its functional consequences.
• It underscores the complexity of genotype-phenotype correlations in NARS2 variants, particularly splice variants.
• The findings contribute to improved diagnosis and potential therapeutic strategies for patients with mitochondrial disorders linked to NARS2.