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Four pedigrees with aminoacyl-tRNA synthetase abnormalities

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Abstract

Aminoacyl tRNA synthetases (ARSs) are highly conserved enzymes that link amino acids to their cognate tRNAs. Thirty-seven ARSs are known and their deficiencies cause various genetic disorders. Variants in some ARSs are associated with the autosomal dominant inherited form of axonal neuropathy, including Charcot-Marie-Tooth (CMT) disease. Variants of genes encoding ARSs often cause disorders in an autosomal recessive fashion. The clinical features of cytosolic ARS deficiencies are more variable, including systemic features. Deficiencies of ARSs localized in the mitochondria are often associated with neurological disorders including Leigh and early-onset epileptic syndromes. Whole exome sequencing (WES) is an efficient way to identify the genes causing various symptoms in patients. We identified 4 pedigrees with novel compound heterozygous variants in ARS genes (WARS1, MARS1, AARS2, and PARS2) by WES. Some unique manifestations were noted. The number of patients with ARSs has been increasing since the application of WES. Our findings broaden the known genetic and clinical spectrum associated with ARS variants.

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Acknowledgements

We are grateful to Dr. Manami Iso for Sanger sequencing of AARS2 and PARS2.

Funding

This study was supported in part by grants of the Initiative on Rare and Undiagnosed Diseases in Pediatrics (IRUD-P) (16ek0109166h0002) (TK) from the Japanese Agency for Medical Research and Development (AMED), JSPS KAKENHI Grant Number JP18K07863 (TK), and JSPS KAKENHI Grant Number JP16K07211 (FM) from Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Izumi, Osaka, Japan

    Nobuhiko Okamoto

  2. Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    Fuyuki Miya & Tatsuhiko Tsunoda

  3. Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Fuyuki Miya & Tatsuhiko Tsunoda

  4. Medical Science Mathematics, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan

    Fuyuki Miya & Tatsuhiko Tsunoda

  5. Department of Neurosurgery, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Yonehiro Kanemura

  6. Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Yonehiro Kanemura

  7. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Shinji Saitoh

  8. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan

    Mitsuhiro Kato

  9. Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan

    Kumiko Yanagi & Tadashi Kaname

  10. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan

    Kenjiro Kosaki

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  1. Nobuhiko Okamoto
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  2. Fuyuki Miya
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  9. Kenjiro Kosaki
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Correspondence to Nobuhiko Okamoto.

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Ethical approval and informed consent

All procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and Helsinki Declaration of 1975, as revised in 2000. The study was approved by the institutional review board of Osaka Women’s and Children’s Hospital, and appropriate written informed consent was obtained.

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The authors declare no competing interests.

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Okamoto, N., Miya, F., Tsunoda, T. et al. Four pedigrees with aminoacyl-tRNA synthetase abnormalities. Neurol Sci 43, 2765–2774 (2022). https://doi.org/10.1007/s10072-021-05626-z

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