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Biallelic Variation in the Choline and Ethanolamine Transporter Flvcr1 Underlies a Severe Developmental Disorder Spectrum Publisher Pubmed



Calame DG1, 2, 3 ; Wong JH4 ; Panda P4 ; Nguyen DT4 ; Leong NCP4 ; Sangermano R5 ; Patankar SG5 ; Abdelhamid MS6 ; Alabdi L7 ; Safwat S8, 9 ; Flannery KP9 ; Dardas Z3 ; Fatih JM3 ; Murali C3 Show All Authors
Authors
  1. Calame DG1, 2, 3
  2. Wong JH4
  3. Panda P4
  4. Nguyen DT4
  5. Leong NCP4
  6. Sangermano R5
  7. Patankar SG5
  8. Abdelhamid MS6
  9. Alabdi L7
  10. Safwat S8, 9
  11. Flannery KP9
  12. Dardas Z3
  13. Fatih JM3
  14. Murali C3
  15. Kannan V1
  16. Lotze TE1
  17. Herman I1, 2, 3, 10
  18. Ammouri F10, 11
  19. Rezich B12
  20. Efthymiou S13
  21. Alavi S13
  22. Murphy D14
  23. Firoozfar Z15
  24. Nasab ME16, 17
  25. Bahreini A18, 19
  26. Ghasemi M20
  27. Haridy NA21
  28. Goldouzi HR22
  29. Eghbal F23
  30. Karimiani EG24
  31. Begtrup A25
  32. Elloumi H25
  33. Srinivasan VM26
  34. Gowda VK26
  35. Du H3
  36. Jhangiani SN27
  37. Cobanakdemir Z3, 28
  38. Marafi D3, 29
  39. Rodan L30, 31
  40. Isikay S32
  41. Rosenfeld JA3, 33
  42. Ramanathan S34
  43. Staton M34
  44. Oberg KC35
  45. Clark RD34
  46. Wenman C36
  47. Loughlin S36
  48. Saad R37
  49. Ashraf T37
  50. Male A37
  51. Tadros S37, 38
  52. Boostani R39
  53. Abdelsalam GMH40
  54. Zaki M40
  55. Mardi A41
  56. Hashemigorji F42
  57. Abdalla E8
  58. Manzini MC9
  59. Pehlivan D1, 2, 3
  60. Posey JE3
  61. Gibbs RA3, 27
  62. Houlden H13
  63. Alkuraya FS7, 43
  64. Bujakowska K5
  65. Maroofian R13
  66. Lupski JR2, 3, 27, 44
  67. Nguyen LN4, 45, 46, 47, 48
Show Affiliations
Authors Affiliations
  1. 1. Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
  2. 2. Texas Children's Hospital, Houston, TX, United States
  3. 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
  4. 4. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  5. 5. Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, United States
  6. 6. Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
  7. 7. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  8. 8. Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
  9. 9. Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ, United States
  10. 10. Boys Town National Research Hospital, Boys Town, NE, United States
  11. 11. The University of Kansas Health System, Westwood, KS, United States
  12. 12. Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, United States
  13. 13. Department of Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom
  14. 14. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, United Kingdom
  15. 15. Palindrome, Isfahan, Iran
  16. 16. Meybod Genetic Research Center, Yazd, Iran
  17. 17. Yazd Welfare Organization, Yazd, Iran
  18. 18. KaryoGen, Isfahan, Iran
  19. 19. Department of Human Genetics, University of Pittsburgh, PA, United States
  20. 20. Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran
  21. 21. Department of Neurology, Faculty of Medicine, Assiut University, Assiut, Egypt
  22. 22. Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  23. 23. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
  24. 24. Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom
  25. 25. GeneDx, Gaithersburg, MD, United States
  26. 26. Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
  27. 27. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
  28. 28. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States
  29. 29. Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait
  30. 30. Department of Neurology, Boston Children's Hospital, Boston, MA, United States
  31. 31. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States
  32. 32. Gaziantep Islam Science and Technology University, Medical Faculty, Department of Pediatric Neurology, Gaziantep, Turkiye
  33. 33. Baylor Genetics Laboratories, Houston, TX, United States
  34. 34. Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, United States
  35. 35. Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, United States
  36. 36. Rare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
  37. 37. North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
  38. 38. Genetics and Genomic Medicine Department, University College London, United Kingdom
  39. 39. Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran
  40. 40. Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
  41. 41. Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  42. 42. Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  43. 43. Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
  44. 44. Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
  45. 45. Immunology Program, Life Sciences Institute, National University of Singapore, Singapore
  46. 46. Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore
  47. 47. Cardiovascular Disease Research (CVD) Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  48. 48. Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Source: Genetics in Medicine Published:2025


Abstract

Purpose: FLVCR1 encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although Flvcr1−/− mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa. Methods: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants. Results: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (z-score −2.5 to −10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits, including macrocytic anemia and skeletal malformations, with Flvcr1−/− mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing. Conclusion: These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield. © 2024 American College of Medical Genetics and Genomics