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A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension

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Abstract

The VARS2 gene encodes a mitochondrial valyl-transfer RNA synthetase which is used in mitochondrial translation. To date, several patients with VARS2 pathogenic variants have been described in the literature. These patients have features of lactic acidosis with encephalomyopathy. We present a case of an infant with lactic acidosis, failure to thrive, and severe primary pulmonary hypertension who was found to be a compound heterozygote for two novel VARS2 variants (c.1940C>T, p.(Thr647Met) and c.2318G>A, p.(Arg773Gln)). The patient was treated with vitamin supplements and a carbohydrate-restricted diet. The lactic acidosis and failure to thrive resolved, and he showed good growth and development. Functional studies and molecular analysis employed a yeast model system and the VAS1 gene (yeast homolog of VARS2). VAS1 genes harboring either one of two mutations corresponding to the two novel variants in the VARS2 gene, exhibited partially reduced function in haploid yeast strains. A combination of both VAS1 variant alleles in a diploid yeast cell exhibited a more significant decrease in oxidative metabolism-dependent growth and in the oxygen consumption rate (reminiscent of the patient who carries two mutant VARS2 alleles). Our results demonstrate the pathogenicity of the biallellic novel VARS2 variants.

Key messages

• A case of an infant who is a compound heterozygote for two novel VARS2 variants.

• This infant displayed lactic acidosis, failure to thrive, and pulmonary hypertension.

• Treatment of the patient with a carbohydrate-restricted diet resulted in good growth and development.

• Studies with the homologous yeast VAS1 gene showed reduced function of corresponding single mutant in haploid yeast strains.

• A combination of both VAS1 variant alleles in diploid yeast exhibited a more significant decrease in function, thereby confirming the pathogenicity of the biallellic novel VARS2 variants.

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Acknowledgments

We would like to thank the patient and his family for allowing us to discuss their case.

Funding

This study was supported, in part, by a MMID-2 SHARE grant, CREATE, National Research Foundation (NRF) of Singapore to OP, HLC, and CKH; Telethon GGP15041 to CD and EB and DIP; ISF, Pakula family grants to OP.

Author information

Authors and Affiliations

  1. Khoo Teck Puat-National University Children’s Medical Institute, National University Health Systems (NUHS), Singapore, Singapore

    Hui-Lin Chin, Denise Li-Meng Goh, Furene Sijia Wang, Stacey Kiat Hong Tay & Chew Kiat Heng

  2. Department of Pediatrics, Yong Loo Lin School of Medicine, National University Hospital, National University of Singapore, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore

    Hui-Lin Chin, Denise Li-Meng Goh, Furene Sijia Wang, Stacey Kiat Hong Tay & Chew Kiat Heng

  3. Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124, Parma, Italy

    Claudia Donnini & Enrico Baruffini

  4. Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Ophry Pines

  5. NUS-HUJ-CREATE Program and the Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Ophry Pines

Authors
  1. Hui-Lin Chin
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  2. Denise Li-Meng Goh
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  3. Furene Sijia Wang
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  6. Claudia Donnini
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  7. Enrico Baruffini
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  8. Ophry Pines
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Corresponding authors

Correspondence to Hui-Lin Chin or Enrico Baruffini.

Ethics declarations

Informed consent from the patient’s parents was obtained. The requirement for ethics approval was waived as functional testing was not done on patient samples. The patient’s growth chart was plotted on charts developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). http://www.cdc.gov.sg/growthcharts.

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The authors declare that they have no conflict of interests.

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Chin, HL., Goh, D.LM., Wang, F.S. et al. A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension. J Mol Med 97, 1557–1566 (2019). https://doi.org/10.1007/s00109-019-01834-5

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  • DOI: https://doi.org/10.1007/s00109-019-01834-5

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