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Novel compound heterozygous TARS2 variants in a Chinese family with mitochondrial encephalomyopathy: a case 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, and increased serum lactate from a non-consanguineous Chinese family. Whole-genome sequencing was performed to help 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 with combined 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 clinical characteristics 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 and demonstrates 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 clinical manifestations may present at any age [3]. Most of the * Correspondence: [email protected] † Xiaojing Li, Bingwei Peng and Chi Hou are co-first author and contributed equally to this work. Department of Neurology, Guangdong Province, Guangzhou Women and Children’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 core and very important step for energy production [4]. TARS2 (*MIM 612,805) gene was first described by Bonnefond and mapped the gene to chromosome 1 in 2005 [5]. The gene encodes a mitochondrial aminoacyltRNA synthetase, a group of ubiquitous ‘house-keeping’ enzymes that perform an integral step in the initiation of translation by charging tRNAs with their cognate amino acids [6]. The enzymes are connected to many kinds of specific diseases including cancer, neuronal pathologies,

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