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High Genetic Heterogeneity of Leukodystrophies in Iranian Children: The First Report of Iranian Leukodystrophy Registry Publisher Pubmed



Ashrafi M1 ; Kameli R1 ; Hosseinpour S1 ; Razmara E2 ; Zamani Z3 ; Rezaei Z1 ; Mashayekhi R1 ; Pak N4 ; Barzegar M5 ; Azizimalamiri R6 ; Kashani MR7 ; Khosroshahi N8 ; Rasulinezhad M1 ; Heidari M1 Show All Authors
Authors
  1. Ashrafi M1
  2. Kameli R1
  3. Hosseinpour S1
  4. Razmara E2
  5. Zamani Z3
  6. Rezaei Z1
  7. Mashayekhi R1
  8. Pak N4
  9. Barzegar M5
  10. Azizimalamiri R6
  11. Kashani MR7
  12. Khosroshahi N8
  13. Rasulinezhad M1
  14. Heidari M1
  15. Amanat M1
  16. Abdi A1
  17. Mohammadi B1
  18. Mohammadi M9
  19. Zamani GR9
  20. Badv RS9
  21. Omrani A10
  22. Nikbakht S1
  23. Bereshneh AH11
  24. Movahedinia M12
  25. Moghaddam HF13
  26. Ardakani HS14
  27. Akbari MG15
  28. Tousi MB16
  29. Shahi MV17
  30. Hosseini F18
  31. Amouzadeh MH19
  32. Hosseini SA20
  33. Nikkhah A21
  34. Khajeh A22
  35. Alizadeh H4
  36. Yarali B9
  37. Rohani M23
  38. Karimi P24
  39. Elahi HML14
  40. Hosseiny SMM1
  41. Sadeghzadeh MS1
  42. Mohebbi H25
  43. Moghadam MH26
  44. Aryan H27
  45. Vahidnezhad H28, 29
  46. Soveizi M30
  47. Rabbani B31
  48. Rabbani A31
  49. Mahdieh N31
  50. Garshasbi M32
  51. Tavasoli AR1, 33

Source: Neurogenetics Published:2023


Abstract

Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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