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The first Korean cases of combined oxidative phosphorylation deficiency 35 with two novel TRIT1 mutations in two siblings confirmed by clinical and molecular investigation

  • Author Footnotes
    1 Sukdong Yoo https://orcid.org/0000-0003-2365-9134.
    Sukdong Yoo
    Footnotes
    1 Sukdong Yoo https://orcid.org/0000-0003-2365-9134.
    Affiliations
    Department of Pediatrics, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University, Yangsan Hospital, Republic of Korea
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  • Young A. Kim
    Affiliations
    Department of Pediatrics, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University, Yangsan Hospital, Republic of Korea
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  • Ju Young Yoon
    Affiliations
    Department of Pediatrics, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University, Yangsan Hospital, Republic of Korea
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  • Go Hun Seo
    Affiliations
    3Billion, Inc., Seoul, Republic of Korea
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  • Changwon Keum
    Affiliations
    3Billion, Inc., Seoul, Republic of Korea
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  • Author Footnotes
    2 Chong Kun Cheon https://orcid.org/0000-0002-8609-5826.
    Chong Kun Cheon
    Correspondence
    Corresponding author at: Division of Medical Genetics and Metabolism, Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine, Geumo-ro 20, Yangsan 50612, Korea.
    Footnotes
    2 Chong Kun Cheon https://orcid.org/0000-0002-8609-5826.
    Affiliations
    Department of Pediatrics, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University, Yangsan Hospital, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    1 Sukdong Yoo https://orcid.org/0000-0003-2365-9134.
    2 Chong Kun Cheon https://orcid.org/0000-0002-8609-5826.
Published:September 15, 2020DOI:https://doi.org/10.1016/j.braindev.2020.08.016

      Abstract

      Background

      Combined oxidative phosphorylation deficiency 35 (COXPD 35) is a very rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the TRIT1 gene on chromosome 1p34. Only six cases of COXPD 35 and six allelic variants of TRIT1 gene mutations have been reported worldwide.
      Case description: We describe two siblings who presented with similar clinical features including severe intellectual disability and epilepsy with onset of symptom in early infancy.

      Results

      The whole exome sequencing results revealed a compound heterozygous novel variant, c.979G > A (p.Glu327Lys) and c.682 + 2 T > C, on TRIT1 exon 8 and intron 5, respectively, which was confirmed by Sanger sequencing. Protein structure analysis revealed that the p.Glu327Lys variant disrupts the conformation and electrostatic charge of the zinc-finger motif in the tRNA isopentenyltransferase (IPT), impairing binding of the mutant IPT to specific DNA sequences.

      Conclusion

      This is the first report of two Korean siblings with COXPD 35 with two novel variants in TRIT1. This study will help to understand the various phenotypic spectra in patients with COXPD 35 and to expand knowledge on the mechanisms of the disease based on genetic features.

      Abbreviations:

      ASD (atrial septal defect), COXPD (combined oxidative phosphorylation deficiency), EEG (electroencephalogram), HSF (human splicing finder), IPT (isopentenyltransferase), LP (likely pathogenic), MRI (magnetic resonance imaging), PVWM (periventricular white matter around temporal horn), VSD (ventricular septal defect), VUS (variant of uncertain significance), WES (whole-exome sequencing), WT (wild-type)

      Keywords

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