Most mitochondrial and
cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear
genes. Syndromic disorders resulting from mutation of aaRSs genes
display significant phenotypic heterogeneity. We expand aaRSs-related
phenotypes through characterization of the clinical and molecular basis
of a novel autosomal-recessive syndrome manifesting severe mental
retardation, ataxia, speech impairment, epilepsy, short stature,
microcephaly, hypogonadism, and growth hormone deficiency.
A G>A variant in exon 29 of VARS2
(c.3650G>A) (NM_006295) was identified in the index case. This
homozygous variant was confirmed by Sanger sequencing and segregated
with disease in the family studied. The c.3650G>A change results in
alteration of arginine to histidine at residue 1217 (R1217H) of the
mature protein and is predicted to be pathogenic.
These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.