A Pair of Compound Heterozygous IARS2 Variants Manifesting West Syndrome and Electrolyte Disorders in a Chinese Patient

Abstract

Background Aminoacyl-tRNA synthetases (ARSs) are evolutionarily conserved enzymes that ensure the accuracy of the translation process. Isoleucyl-tRNA synthetase 2 (IARS2) gene is a type of ARS that encodes mitochondrial isoleucine-tRNA synthetase. Pathogenic variants in the IARS2 gene are associated with mitochondrial disease which involves several patients presenting broad clinical phenotypes. These clinical phenotypes include West syndrome, Leigh syndrome, and Cataract, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia syndrome. Only 29 cases have been reported worldwide. The patient manifested recurrent convulsions, and specific clinical manifestations included electrolyte disorders and recurrent infections.
Methods Whole-exome sequencing was performed on the child with West syndrome. Three-dimensional structure reconstruction and thermodynamic stability prediction were performed to further analyze the relationship between variation and phenotype.
Conclusion This study further expands the clinical spectrum of IARS2 pathogenic variants. The case summaries help raise clinical awareness of IARS2-associated disease and reduce misdiagnosis.
Result In this report, a 13-month-old girl was diagnosed with West syndrome and Leigh syndrome for 7 months. Compound heterozygous variants in the IARS2 gene (NM_018060.4), c.2450G>A (Arg817His) and copy number variation (NC_000001. 11: g. (220267549_220284289) del), were detected by WES. This study further expands the clinical spectrum of IARS2 pathogenic variants. The case summaries help raise clinical awareness of IARS2-associated disease and reduce misdiagnosis.

Keywords

West syndrome / CAGSSS / aminoacyl-tRNA synthetases

Data Sharing and Data Accessibility

All data relevant to the study are included in the article. The whole genome sequencing data are not publicly available as these could compromise research participant privacy. Specific variant requests or other data are available from the corresponding authors upon reasonable request.

Ethical Approval and Consent to Participate

The study protocol was approved by the Ethics Committee of Tianjin Children's Hospital. Written informed consent to participate was obtained from the patient's parents.

Authors' Contributions

F.Z. and G.Y. analyzed the data and wrote the manuscript. X.L. collected the clinical data. W.S. participated in making substantial contributions to design, drafting and revising the important intellectual content of manuscript. C.C. and D.L. conceived the project and revised the manuscript and submitted the manuscript. All authors read and approved the final manuscript.

Funding

The study was supported by the Public Health and Technology Project of Tianjin (grant number TJWJ2021ZD007); the Program of Tianjin Science and Technology Plan (21JCZDJC00390); the Key Project of Tianjin Children's Hospital (grant number Y2020003); Natural Science Foundation of Tianjin (grant number 21JCZDJC01030); the Public Health and Technology Project of Tianjin (grant number TJWJ2021MS022) and funded by Tianjin Key Medical Discipline (Specialty) Construction Project (grant number TJYXZDXK-040A). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest

None declared.

References

[1] Ibba M, Soll D.Aminoacyl-tRNA synthesis. Annu Rev Biochem 2000; 69: 617-650

[2] Ling J, Reynolds N, Ibba M.Aminoacyl-tRNA synthesis and translational quality control. Annu Rev Microbiol 2009; 63: 61-78

[3] Meyer-Schuman R, Antonellis A.Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease. Hum Mol Genet 2017; 26(R2): R114-R127

[4] Konovalova S, Tyynismaa H.Mitochondrial aminoacyl-tRNA synthetases in human disease. Mol Genet Metab 2013; 108(04) 206-211

[5] Takezawa Y, Fujie H, Kikuchi A.et al.Novel IARS2 mutations in Japanese siblings with CAGSSS, Leigh, and West syndrome. Brain Dev 2018; 40(10) 934-938

[6] Chopra SS.Infantile spasms and West syndrome - a clinician's perspective. Indian J Pediatr 2020; 87(12) 1040-1046

[7] Chugani HT.Pathophysiology of infantile spasms. Adv Exp Med Biol 2002; 497: 111-121

[8] Roux CJ, Barcia G, Schiff M.et al.Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations. Mol Genet Metab 2021; 133(02) 222-229

[9] Upadia J, Li Y, Walano N, Deputy S, Gajewski K, Andersson HC.Genotype-phenotype correlation in IARS2-related diseases: a case report and review of literature. Clin Case Rep 2022; 10(02) e05401

[10] McFarland R, Taylor RW, Turnbull DM. A neurological perspective on mitochondrial disease. Lancet Neurol 2010; 9(08) 829-840

[11] Schwartzentruber J, Buhas D, Majewski J. et al; FORGE Canada Consortium. Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in patients with cataracts, growth hormone deficiency with short stature, partial sensorineural deafness, and peripheral neuropathy or with Leigh syndrome. Hum Mutat 2014; 35(11) 1285-1289

[12] Chow J, Rahman J, Achermann JC, Dattani MT, Rahman S.Mitochondrial disease and endocrine dysfunction. Nat Rev Endocrinol 2017; 13(02) 92-104

[13] Barcia G, Pandithan D, Ruzzenente B.et al.Biallelic IARS2 mutations presenting as sideroblastic anemia. Haematologica 2021; 106(04) 1220-1225

[14] Kobayashi T, Ikeda M, Okada Y, Higurashi Y, Okugawa S, Moriya K.Clinical and microbiological characteristics of recurrent Escherichia coli bacteremia. Microbiol Spectr 2021; 9(03) e0139921

[15] Salmaninejad A, Jafari Abarghan Y, Bozorg Qomi S.et al.Common therapeutic advances for Duchenne muscular dystrophy (DMD). Int J Neurosci 2021; 131(04) 370-389

RIGHTS & PERMISSIONS

2024 Global Medical Genetics