Abstract

This study aims to identify gene defects in pediatric cardiomyopathy and early-onset brain disease with oxidative phosphorylation (OXPHOS) deficiencies. We applied whole-exome sequencing in three patients with pediatric cardiomyopathy and early-onset brain disease with OXPHOS deficiencies. The brain pathology was studied by MRI analysis. In consanguineous patient 1, we identified a homozygous intronic variant (c.850-3A > G) in the QRSL1 gene, which was predicted to cause abnormal splicing. The variant segregated with the disease and affected the protein function, which was confirmed by complementation studies, restoring OXPHOS function only with wild-type QRSL1. Patient 2 was compound heterozygous for two novel affected and disease-causing variants (c.[253G > A];[938G > A]) in the MTO1 gene. In patient 3, we detected one unknown affected and disease-causing variants (c.2872C > T) and one known disease-causing variant (c.1774C > T) in the AARS2 gene. The c.1774C > T variant was present in the paternal copy of the AARS2 gene, the c.2872C > T in the maternal copy. All genes were involved in translation of mtDNA-encoded proteins. Defects in mtDNA-encoded protein translation lead to severe pediatric cardiomyopathy and brain disease with OXPHOS abnormalities. This suggests that the heart and brain are particularly sensitive to defects in mitochondrial protein synthesis during late embryonic or early postnatal development, probably due to the massive mitochondrial biogenesis occurring at that stage. If both the heart and brain are involved, the prognosis is poor with a likely fatal outcome at young age.

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Additional information

Jo M. Vanoevelen and Hubert J. M. Smeets contributed equally to this work.

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Acknowledgements

We acknowledge the patients and their families for their contribution to this study. Elvira N. Mulder-Den Hartog (Erasmus MC, Rotterdam) for clinical information, and Ralph W. Gottschalk (MUMC+, Maastricht) for the diagnostic analyses. This work was supported by a grant from the Princes Beatrix Spierfonds (W.OR11‐24) and Metakids.

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Author notes

    Affiliations

    1. Department of Genetics and Cell Biology, Maastricht University, Maastricht, The Netherlands

      • Rick Kamps
      • , Radek Szklarczyk
      • , Tom E. Theunissen
      • , Jo M. Vanoevelen
      •  & Hubert J. M. Smeets
    2. School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands

      • Rick Kamps
      •  & Hubert J. M. Smeets
    3. Department of Clinical Genetics, MUMC, Maastricht, The Netherlands

      • Debby M. E. I. Hellebrekers
      • , Suzanne C. E. H. Sallevelt
      • , Iris B. Boesten
      • , Bart de Koning
      • , Bianca J. van den Bosch
      •  & Jo M. Vanoevelen
    4. Department of Clinical Chemistry, VU University Medical Center/Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

      • Gajja S. Salomons
      •  & Marisa Simas-Mendes
    5. Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands

      • Rob Verdijk
    6. Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands

      • Kees Schoonderwoerd
    7. Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands

      • Irenaeus F. M. de Coo

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    The authors declare that they have no conflict of interest.

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    All procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 2000.

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    Correspondence to Hubert J. M. Smeets.

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    https://doi.org/10.1038/s41431-017-0058-2