Li et al. BMC Medical Genetics(2020) 21:217
https://doi.org/10.1186/s12881-020-01149-0

CASE REPORTOpen Access

Novel compound heterozygous TARS2
variants in a Chinese family withmitochondrial encephalomyopathy: acase report
Xiaojing Li†, Bingwei Peng†, Chi Hou†, Jinliang Li, Yiru Zeng, Wenxiao Wu, Yinting Liao, Yang Tian and
Wen-Xiong Chen*

Abstract
Background: Mitochondrial encephalomyopathy caused by bi-allelic deleterious variants in TARS2 is rare. To date, only
two pedigrees were reported in the literature and the connection between the gene and disease needs further study.
Case presentation: We report one infant who presented with limb hypertonia, epilepsy, developmental delay, andincreased serum lactate from a non-consanguineous Chinese family. Whole-genome sequencing was performed tohelp to underlie the cause. We identified compound heterozygous variants c.470C > G, p.Thr157Arg and c.2143G > A,
p.Glu715Lys in TARS2 and the variants were confirmed by Sanger sequencing. The patient was diagnosed withcombined oxidative phosphorylation deficiency 21 according to the Online Mendelian Inheritance in Man (OMIM)
database based on the clinical data and the deleterious effect of the two variants in TARS2 predicted by in silico tools.
Conclusions: We presented one case diagnosed with combined oxidative phosphorylation deficiency 21 based on clinicalcharacteristics and genetic analysis. This is the first case in China and the fourth case in the world based on our document
retrieval. This study facilitates the understanding of combined oxidative phosphorylation deficiency disease anddemonstrates that the next-generation sequencing has a high potential to study inherited disease with high phenotypic
heterogeneity and genetic heterogeneity including mitochondrial diseases such as combined oxidative phosphorylation
deficiency.
Keywords: Mitochondrial diseases, Encephalomyopathy, TARS2, Whole genome sequencing, Case report

Background
Mitochondrial diseases are a group of genetic disorders
with high heterogeneous that are characterized by dysfunctional mitochondria [1]. The minimum prevalence of
all mitochondrial diseases is 1:5000 [2] and the clinicalmanifestations may present at any age [3]. Most of the* Correspondence: gzchcwx@126.com†
Xiaojing Li, Bingwei Peng and Chi Hou are co-first author and contributed
equally to this work.
Department of Neurology, Guangdong Province, Guangzhou Women andChildren’s Medical Center, Guangzhou Medical University, 9# Jin Sui Road,
510623 Guangzhou, People’s Republic of China

mitochondrial disease patients harbor a defect in the oxidative phosphorylation system (OXPHS) which is the coreand very important step for energy production [4].
TARS2 (*MIM 612,805) gene was first described by
Bonnefond and mapped the gene to chromosome 1 in2005 [5]. The gene encodes a mitochondrial aminoacyltRNA synthetase, a group of ubiquitous ‘house-keeping’
enzymes that perform an integral step in the initiation oftranslation by charging tRNAs with their cognate aminoacids [6]. The enzymes are connected to many kinds ofspecific diseases including cancer, neuronal pathologies,© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Li et al. BMC Medical Genetics(2020) 21:217

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A

B

C

D

E

F

G

H

Fig. 1 3T Brain MRI of the patient: a to d were performed when he was first transfer to our hospital at 4-month-old. a and b: axial T2WI showedarc-shaped subdural empyema was seen in bilateral frontotemporal parietal lobes. c: axial T2 Flair showed arc-shaped subdural empyema andbilateral cerebral hemisphere atrophy. d: Coronal T1WI enhanced scanning showed bilateral frontotemporal parietal dura enhanced which wascalled Mercedes-Benz sign. e to h was reexamined 7 days after hospitalization. e and f: axial T2WI showed new symmetrical hypersignal lesions inbilateral basal ganglia, thalamus and cerebral peduncle. g: the lesions had a slightly higher signal on T2Flair. h: the lesions had no obvious
enhancement on T2Flairautoimmune disorder, and disrupted metabolic conditions [7]. Many disease-causing mutations have been reported [8–11]. The first and the only report connecting
TARS2 with the disease was published in 2014. Diodato
et al. identified two compound heterozygous mutationsin 2 siblings by whole-exome sequencing (WES) who
presented with axial hypertonia, limb hypertonia, psychomotor delay, and increased serum lactate. Both ofthem died a few months after birth because of a metabolic crisis [12].
Nowadays, next-generation sequencing (NGS) or massively parallel sequencing has emerged as a powerful tool
for testing genetically heterogeneous conditions including
mitochondrial disorders [13–16]. The Mitochondrial

Medicine Society demonstrated that this technology shouldbe the preferred methodology when testing mtDNA andshould be performed when mitochondrial disease is suspected [17]. Here we presented a patient with combinedoxidative phosphorylation deficiency 21 who was diagnosed
through clinical and molecular investigation.

Case presentation
The proband was a 4-month-old boy at the time of admission. He was born at full-term in an uneventful pregnancy. His birth weight, height, and head circumference
were 2200 g (3th percentile), 48 cm (15th percentile),
33 cm (5th percentile) respectively. He had no so much
cry after birth and was first referred to the local hospitalFig. 2 Electroencephalogram: a: abnormal background activity with diffuse low and moderate amplitude slow activity of 1.5-2 Hz. b the posterior
head was dominated by frequent multi-focal sharp wave, spike wave, and slow spike wave, with medium voltage suppression of 1–2 s

Li et al. BMC Medical Genetics(2020) 21:217

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Fig. 3 The compound heterozygous variants were detected by whole-genome sequencing and confirmed by Sanger sequencing

because of afebrile convulsion about four times a day
1 month before he came to our hospital. The seizuresoften lasted for one minute and were characterized bystaring, motion arrest, cyanosis, and rigidity of the extremities. The lactic acid level was elevated above thenormal level (8.7 mmol/L, normal range < 2.0 mmol/L)and no obvious abnormalities were found in the routine
examination for cerebrospinal fluid (CSF) and blood.
The seizure wasn’t controlled with valproate (VPA,
21 mg/kg/d) and his parents stopped the treatment on
their own after discharge. He had a fever 20 days ago.
The seizures were more frequent than before accompanied by poor mental response and the lactic acid level was
still higher than normal level (3.2 mmol/L). After cephalosporin treatment in the local hospital, his temperature
returned to normal, but seizures were not relieved andhis mental reaction was still poor.
He was then referred to our hospital. The global development delay with the parameters including the headcircumference: 38 cm (3rd percentile), body length:
56 cm (3rd percentile), and weight: 5.1 kg (5th percentile)
were revealed. His vital signs were still stable, although
he had poor eye-eye contact and poor responses, and increased muscle tone of the limbs. The lactic acid levelremained high (3.6 mmol/L) at initial admission, while
CSF with mild polycytosis (white blood cell count = 30 ×
106/L), mild increased protein level (0.66/L), normal glucose and chloride levels were detected. The CSF cultures
were negative. Blood routine test, C-reactive protein andorgans function were generally normal. Blood procalcitonin was 0.845 ng/ml, and sputum culture was positive
for klebsiella pneumoniae. Plasma amino acid analysis

showed an increase in alanine and proline content, indicating a metabolic disorder of lactate-pyruvate. Analysisof acyl-carnitine showed a significant increase in C2 andC4-OH, suggesting ketosis. The brain magnetic resonance imaging (MRI) showed an atrophy-like changes inthe bilateral hemisphere and subdural effusion in thefrontotemporal (Fig. 1). Electroencephalogram showedabnormal background activity with diffuse low and moderate amplitude slow activity of 1.5–2 Hz. The posterior
head was dominated by frequent multi-focal sharp wave,
spike wave, and slow spike wave, with medium voltage
suppression of 1–2 s (Fig. 2). Brainstem auditory evoked
potential revealed no obvious differentiation of bilateral
I, III and V waves and bilateral auditory response thresholds were not differentiated. Echocardiography showed
left to right shunt in the horizontal chamber, with adiameter about 3.5 mm. The initial diagnosis was suspected bacterial meningoencephalitis, epilepsy and psychomotor delay. After antibiotic therapy and antiepileptic treatment (topiramate), the baby still had frequent seizures. Repeated examination of brain MRI
showed abnormal symmetry signals in bilateral basal
ganglia, thalamus and pedunculus cerebri. There was no
significant changes in bilateral hemispheric atrophy andsubdural effusion (Fig. 1). Mitochondrial energy metabolism disorders were considered and cocktail therapy
was administrated including intravenous L-carnionc andoral coenzyme Q10, folic acid, vitamin B1, B2 and E. Antiepileptic treatment with levetiracetam was then added.
The seizure reduced significantly and mental reaction
improved. He was well fed and then discharged. Twomonths after discharge, he was readmitted to ourTable 1 The analysis of pathogenicity of the variants in TARS2
Gene Transcript Mutation

Variant
originMAF
gnomAD(EAS AC)

ExAC
1000(EAS AC) Genomes

0.000163

0.000116 NE

22.6

5.23

D

PD

D

D

NE

25.7

5.25

D

PD

D

D

TARS2 NM_
025150.4

c.470C > G
p.Thr157Arg

paternal

TARS2 NM_
025150.4

c.2143G > A
p.Glu715Lys

maternal NE

CADD GERP + + SIFT PolyPhen Mutation Taster PROVEANNE

MAF minor allele frequency, NE not exist, D disease causing or deleterious or damaging, PD possibly damaging, EAS AC East Asian ExACLi et al. BMC Medical Genetics(2020) 21:217

Page 4 of 6

Fig. 4 The variants region is conserved among human, Chimp, Rhesus, Mouse, Dog, Elephant, MANLE, Frog, and Chameleon. Mut., mutant;
MANLE, Mandrillus leucophaeus

hospital for poor mental response, during which he developed recurrent apnea with cyanosis and the heart rate
below 60 beats/min. Despite adequate treatment of
cocktail therapy, the apnea became progressively worse,and eventually the parents gave up the further treatment.
The patient was followed up for 6 months after discharge and only levetiracetam was used during thisperiod. At the last follow-up, he still had frequent seizures, and could not eat independently and remained restricted growth and development.
Genomic DNA was extracted from whole bloodusing QIAamp Blood Mini Kit (Qiagen, Hilden,
Germany) and then sequenced on Illumina HiSeq X
Ten platform (Illumina, Inc., San Diego, CA,
USA). The reads were analyzed and annotated by an
in-house pipeline. According to the biological significance of the mutation site, combined with the resultsof HGMD, ClinVar disease database and various protein function prediction software for analysis, priority
is given to candidate variables related to diseasephenotype. The putative mutation was further confirmed by Sanger DNA sequencing. All variant pathogenicity assessments are based on the joint consensus
recommendation of the American College of Medical
Genetics and Genomics (ACMG) and the Association
for Molecular Pathology [18]. For copy number variants (CNV) analysis, we focused on the ultra-rareones which were not been recorded in the Databaseof Genomic Variants (DGV) and the size which beyond 500 kb.
Finally, together with inheritance model analysis, two
promising variants in TARS2 (c.470C > G and c.2143G >A) that were inherited from their parents, respectively,
draw our attention after strict filtering. Also, the twovariants were further validated by Sanger sequencing(Fig. 3). These two variants have not been reported in
Pubmed, nor have they been cited by HGMD and
ClinVar database. The minor allele frequency (MAF) of
these two mutations in the gnomAD, ExAC and 1000
Genomes database is very low or non-existent and multiple lines of computational evidence support a deleterious effect on the gene or gene product (Table 1). The
two residues are conserved among species, including
humans, Chimp, Rhesus, Mouse, Dog, and Elephant respectively (Fig. 4). These two variants were interpreted
as likely pathogenic based on ACMG guidelines (PM1,
PM2, PP1 and PP4).

Discussion and Conclusions
COXPD-21(Phenotype MIM number: 615918) is raremitochondrial encephalomyopathy caused by mutation of
the TARS2 gene on chromosome 1q21.2. The first pedigree was reported in 2014 by Diodato. They identified
compound heterozygous variants c.845C > T p. Pro282Leu
and c.695 + 3A > G in two siblings with early-onset mitochondrial encephalopathies by whole-exome sequencing.

Table 2 Cases with TARS2 mutations including reported and the case in our study
Pedigree patient

Pathogenic mutation

Reference

Family 1

Two siblings Axial hypotonia, limb hypertonia, psychomotor delay, high levels(Female/Male) of blood lactate, both died a few months after birth of ametabolic crisis

Clincal phenotype

NM_025150.4:c.845C> T(p.Pro282Leu),
Maternal / NM_025150.4:c.695 + 3A > G,
Paternal[12]

Family 2

Not available

Hypotonia, cerebellar atrophy, psychomotor delay, and increased
blood‐lactate

Not available[20]

Family 3

Male

Limb hypertonia, epilepsy, psychomotor delay, and high levels ofblood lactate

NM_025150.4:c.470C > (p. Thr157Arg),
Maternal / c.2143G > A p. Glu715Lys,
Paternal[This
Study]

Li et al. BMC Medical Genetics(2020) 21:217

The two variants segregated within the family and theamount of TARS2 proteins and threonyl-tRNA levels wasdecreased in samples of afflicted patients according to thegenetic defect. Wang et al. further analyzed the mechanism of the p.Pro282Leu mutation and clarified the molecular consequence of the mutation [19]. They found thatthe mutation induced both structural and functional defects by vitro and vivo analyses.
A PubMed search for reported cases of TARS2 and
COXPD-21 yield no result but we find one abstract through
Google Scholar search. Lucas Bartl et al. (2018) reported one
pediatric patient with a putative splice-site mutation and missense mutation in TARS2 who present with hypotonia, cerebellar atrophy, psychomotor delay, and increased bloodlactate underwent whole-exome sequencing [20]. Both thetwo variants are predicted to cause loss of mtThrRS function
and the author demonstrated that the two mutations cause
mitochondrial dysfunction and are therefore causal for thedisorder. Unfortunately, there were no further details about
the two variants in this abstract.
TARS2 gene encodes a 718 length protein that belongs
to mitochondrial aminoacyl-tRNA syntheses. This
protein family has been associated with diverse clinicalpresentations such as hypertrophic cardiomyopathy,
leukoencephalopathy with brain stem, and spinal cord
involvement and lactate elevation(LBSL), Pontocerebellar hypoplasia type 6, progressive sensorineural hearing
loss and ovarian dysgenesis and Charcot-Marie-Tooth
disease [9, 10, 21–24]. As reviewed by González-Serrano
et al., the majority of clinical manifestations are in thecentral nervous system [25]. Unfortunately, the pathogenic mechanism is not fairly well understood.
Here we described one infant suspected with congenital metabolic disease. By WGS analysis, we identified
two putative variants in TARS2 and no other promisingvariant was identified. These two variants were noveland classified as likely pathogenic according to ACMG
guidelines. Certainly, further study, such as measuring
the enzyme activity of mitochondrial respiratory chain
complex, is required to understand functional and structural changes of these two variants. Including our case,until now, there were 4 patients with TARS2 mutations
reported, and they are summarized in Table 2.
In summary, this is the fourth case with COXPD-21
disease worldwide and the first in China which was diagnosed by a clinical and molecular investigation. We expand the mutation spectrum of combined oxidative
phosphorylation deficiency. This contributes to the understanding of the connections between tRNA synthetase function and health. Besides, this study alsosuggests that WGS is a powerful technology that permits
researchers to study the disease with highly phenotypic
heterogeneity and will become more widely used in clinical settings.

Page 5 of 6

Abbreviations
WGS: Whole-genome sequencing; NGS: Next-generation sequencing;
CSF: Cerebrospinal fluid; MRI: Magnetic resonance imaging; ACMG: American
College of Medical Genetics and Genomics; HGMD: The Human Gene
Mutation Database; MAF: Minor allele frequency; MIM: Mendelian Inheritancein ManAcknowledgements
The authors are very grateful to the participating family for their courtesy
and humanity.
Authors’ contributions
Study Design, Analysis and Revision of the Manuscript, WC; Follow-up of Patient’s Information, XL, BP and CH; Original Draft Preparation, XL, BP and CH;
Reanalysis of WGS Data, JL; Collection of Clinical and WGS Data, YZ, YL, WW
and YT; Literature Search and Sanger Sequencing, YZ, YL, WW and YT. All authors have read and agreed to the published version of the manuscript.
Funding
Not applicable.
Availability of data and materials
Sanger sequencing data of the variant in TARS2 was deposited in the DDBJ
database (Project ID: 5f7de96aa3c8820eeb82a9df). Human reference genome
used in this study (UCSC hg19) can be downloaded at the following url:
https://hgdownload.soe.ucsc.edu/downloads.html. All other data andmaterials mentioned in this manuscript, except patient’s private information,
can be promptly available to readers by a reasonable request to thecorresponding author.
Ethics approval and consent to participate
This research was approved by the Ethics Committee of Guangzhou Womenand Children’s Medical Center, conforming to the Helsinki Declaration.
Informed written consent for clinical and genetic analyses was obtained
from the patient's parents.
Consent for publication
Written informed consent was obtained from the parents for publication ofthis case report and any accompanying tables/images.
Competing interests
The authors declare that they have no competing interests.
Received: 6 August 2020 Accepted: 15 October 2020

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