Isfahan University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share By
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

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