Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2022 Dec;65(12):104643.
doi: 10.1016/j.ejmg.2022.104643. Epub 2022 Oct 14.

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

Samira Ait-El-Mkadem Saadi  1 , Elsa Kaphan  2 , Amaya Morales Jaurrieta  3 , Konstantina Fragaki  4 , Annabelle Chaussenot  4 , Sylvie Bannwarth  4 , André Maues De Paula  5 , Véronique Paquis-Flucklinger  4 , Cécile Rouzier  4
Affiliations
Free article
Case Reports

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

Samira Ait-El-Mkadem Saadi et al. Eur J Med Genet. 2022 Dec.
Free article

Abstract

Biallelic rare variants in NARS2 that encode the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes ranging from severe neurodegenerative disorders to isolated mitochondrial myopathy or deafness. To date, only a small number of patients with NARS2 variants have been reported, and possible genotype-phenotype correlations are still lacking. Here, we present three siblings who had an early-onset hearing loss, while one developed severe symptoms in adulthood associated with early intellectual impairment, refractory seizures, moderate axonal sensorimotor neuropathy, and atypical psychiatric symptoms. Biochemical analysis revealed impairment of the activity and assembly of the respiratory chain complexes in this patient's muscle and fibroblasts. Whole Exome Sequencing allowed identification of a heterozygous variant NM_024678.5(NARS2):c.822G > C (p.Gln274His) that is known to be pathogenic and to affect splicing of the NARS2 gene, but was unable to detect a second variant in this gene. Coverage analysis and Sanger sequencing led to identification of a novel intronic deletion NM_024678.5(NARS2):c.922-21_922-19del in the three siblings in trans with the c.822G > C. Functional analysis by RT-PCR showed that this deletion was causing aberrant splicing and led to exon 9 skipping in NARS2 mRNA in patient fibroblasts. Our work expands the phenotype and genotype spectrum of NARS2-related disorders. We provide evidence of the pathogenic effect of a novel intronic deletion in the NARS2 gene and report on additional adult patients with a large intrafamilial variability associated with splice variants in this gene. More specifically, we detail the phenotype of the oldest living patient to date with NARS2 variants and, for the first time, we report the psychiatric symptoms associated with this gene. Our work confirms the complexity of genotype-phenotype correlation in patients with pathogenic NARS2 variants.

Keywords: Aberrant splicing; Aminoacyl-tRNA synthetase; Genotype-phenotype; NARS2; Splice variant.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Similar articles

See all similar articles

Cited by

Publication types

LinkOut - more resources