Novel TARS2 variant identified in a Chinese patient with mitochondrial encephalomyopathy and a systematic review

Abstract

Biallelic pathogenic variants in the TARS2 gene cause combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial encephalomyopathy (ME) characterized by early‐onset severe axial hypotonia, limb hypertonia, delayed psychomotor development, epilepsy, and brain anomalies. Currently, eight COXPD21 patients have been reported in the literature, and 11 pathogenic variants in TARS2 have been identified. Here, we report a 2‐year‐6‐month‐old Chinese female who presented with severe dystonia, developmental regression, absent speech, and intractable epilepsy. Laboratory examination showed persistently increased serum lactate. Brain MRI showed that the head of the caudate and partial lenticular nucleus were bilateral symmetrical T2‐weighted imaging (T2WI) hyperintense and the corpus callosum was very thin. The clinical characteristics pointed to a ME. Trio‐based whole‐exome sequencing (WES) was employed to detect the causative variants. WES revealed novel compound heterozygous variants, c.470G>C (p.Thr157Arg) and c.2051C>T (p.Arg684Gln), in TARS2 in our patient that were inherited from the mother and father, respectively. Next, we systematically reviewed the available clinical features of COXPD21 patients and noticed that the reduced fetal movement observed in our patient may be a novel phenotype of COXPD21. These findings expand the mutation spectrum of TARS2 and provide insights into the genotype–phenotype relationship in COXPD21 as well as a foundation for its genetic counseling, diagnosis and treatment.

Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder

“…11 Although 3 patients were previously reported with neurosensorial hearing loss, none of our cohort had hearing impairment. 11,18 It is possible that these features may be underestimated, considering that no affected individual had specific work-up or that they may develop hearing impairment and cardiac and rental tubular dysfunction later. A cardiological evaluation, urine analysis for tubulopathy and hearing screening is warranted in patients with biallelic TARS2 variants.…”

“…Sanger sequencing confirmed segregation of the variants with the phenotype within these (Figure 1B) with TARS2-related disorder. 17,18 The position of each variant is depicted in Figure 1C. The identified variants are rare in human population variant databases (with allele frequency ranging from 0 to 0.000424 in 1,623,000 alleles across multiple databases) and have never been observed homozygously in healthy individuals (databases are listed in Supplemental Table 1).…”

“…The The 3D model of human TARS2 is from misynpat.org. 16,18 In all models, motifs 1, 2, and 3 that build the catalytic core are colored in white. Residues found mutated are shown in stick representation and colored in red for those reported in the present study and in black for those reported elsewhere (see Figure 1 and Supplemental Table 2 for references), with the corresponding amino acid from either S. aureus or E. coli indicated in brackets.…”

“…Structural templates are indicated in light gray. The 3D model of human TARS2 is from misynpat.org 16,18. In all models, motifs 1, 2, and 3 that build the catalytic core are colored in white.…”

Expanding the Phenotypic Spectrum: Chronic Kidney Disease in a Patient with Combined Oxidative Phosphorylation Defect 21

“…The TARS2 gene (MIM# 612805) encodes mitochondrial threonyl tRNA-synthetase. To the best of our knowledge, less than 30 patients of this particular mitochondrial disorder have been reported on to date ( 2 , 3 ). The main clinical features of COXPD21 include failure to thrive/growth retardation, developmental delay, axial hypotonia, hypertonus of the limbs, dystonia, seizures, and laboratory findings of lactic acidosis and elevated plasma alanine ( 1 , 2 , 3 , 4 ).…”