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Biallelic Variants in Ogdh Encoding Oxoglutarate Dehydrogenase Lead to a Neurodevelopmental Disorder Characterized by Global Developmental Delay, Movement Disorder, and Metabolic Abnormalities Publisher Pubmed



Whittle EF1 ; Chilian M2 ; Karimiani EG1, 3 ; Progri H2 ; Buhas D4 ; Kose M5, 6 ; Ganetzky RD6, 7 ; Toosi MB8, 9 ; Torbati PN10 ; Badv RS11 ; Shelihan I12 ; Yang H13 ; Elloumi HZ13 ; Lee S14 Show All Authors
Authors
  1. Whittle EF1
  2. Chilian M2
  3. Karimiani EG1, 3
  4. Progri H2
  5. Buhas D4
  6. Kose M5, 6
  7. Ganetzky RD6, 7
  8. Toosi MB8, 9
  9. Torbati PN10
  10. Badv RS11
  11. Shelihan I12
  12. Yang H13
  13. Elloumi HZ13
  14. Lee S14
  15. Jamshidi Y1
  16. Pittman AM1
  17. Houlden H15
  18. Ignatius E16
  19. Rahman S17
  20. Maroofian R1, 15
  21. Yoon WH2
  22. Carroll CJ1
Show Affiliations
Authors Affiliations
  1. 1. Genetics Section, Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom
  2. 2. Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
  3. 3. Innovative Medical Research Centre, Faculty of Medicine, Islamic Azad University-Mashhad Branch, Mashhad, Iran
  4. 4. Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Center, Department of Human Genetics, McGill University, Montreal, Canada
  5. 5. Division of Inborn Errors of Metabolism, Department of Pediatrics, Izmir Katip Celebi University Faculty of Medicine, Izmir, Turkey
  6. 6. Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
  7. 7. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
  8. 8. Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  9. 9. Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
  10. 10. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
  11. 11. Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
  12. 12. Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Canada
  13. 13. GeneDx, Gaithersburg, MD, United States
  14. 14. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, United States
  15. 15. Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London, United Kingdom
  16. 16. Division of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  17. 17. Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom

Source: Genetics in Medicine Published:2023


Abstract

Purpose: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities. Methods: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells. Results: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells. Conclusion: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities. © 2022 The Authors
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