BioProject

Biallelic variants in NARS2 that encode the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes. More...

Biallelic variants in NARS2 that encode the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes. Herein, we report on two siblings with different phenotypes carrying the same compound heterozygous missense mutations in NARS2, to improve the understanding of the phenotypic heterogeneity of NARS2 variants.

Case presentation

The two probands, a 2-year-old female (patient 1) and a 10-month-old male (patient 2), harbor identical compound heterozygous missense mutations in NARS2 (c.1253G>A/p.Arg418His and c.1163C>T/p.Thr388Met), yet they manifest distinct phenotypes. This observation enhances our understanding of the phenotypic heterogeneity attributed to NARS2 variants. Genetic evaluations were conducted utilizing whole exome sequencing and Sanger sequencing methodologies. Notably, the siblings presented with disparate clinical presentations; one exhibited psychomotor retardation, early-onset generalized epilepsy with myoclonic seizures, and radiological findings on brain magnetic resonance imaging(MR) consistent with cerebral atrophy and hypomyelination, resembling the features of Combined Oxidative Phosphorylation Deficiency 24 (COXPD24). In contrast, the other sibling solely manifested focal seizures and a regression in motor development, accompanied by abnormal signal intensities bilaterally in the putamen on brain MRI.

Conclusions

Our findings contribute to the broadening of the NARS2 mutation spectrum and associated phenotypic variability, emphasizing the crucial role of NARS2 in epilepsy and neurodevelopment. For pediatric patients with refractory epilepsy, early genetic testing represents a pivotal step in enhancing the precision of diagnostic evaluation and prognosis assessment, ultimately guiding more informed prognostic predictions and optimized medical management approaches. Less...