Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy |
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| Authors: | M. Tétreault L.T. Tran N. Webb M. Srour J.J. Mitchell C. Brunel‐Guitton J. Majewski V. Long S. Keller M.J. Gambello C. Simons CareRare Canada Consortium A. Vanderver G. Bernard |
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| Affiliation: | 1. Department of Human Genetics, McGill University, Montreal, Canada;2. McGill University and Genome Quebec Innovation Centre, Montreal, Canada;3. Department of Neurology and Neurosurgery, McGill University, Montreal, Canada;4. Department of Pediatrics, McGill University, Montreal, Canada;5. Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada;6. Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Canada;7. Division of Medical Genetics, Department of Pediatrics, CHU Sainte‐Justine and Université de Montréal, Montreal, Canada;8. Montreal Neurological Institute, McGill University, Montreal, Canada;9. Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia;10. Department of Pediatrics, Division of Pediatric Neurology, Emory University School of Medicine, Atlanta, Georgia;11. Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia;12. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;13. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania |
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| Abstract: | Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report 2 patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole‐exome sequencing revealed a homozygous mutation in NDUFA2 (c.134A>C, p.Lys45Thr). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole‐exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c.134A>C, p.Lys45Thr; c.225del, p.Asn76Metfs*4). Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2. |
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| Keywords: | complex I deficiency leukodystrophy leukoencephalopathy
NDUFA2 whole‐exome sequencing |
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