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Novel Disease-Causing Variants in a Cohort of Iranian Patients With Metachromatic Leukodystrophy and in Silico Analysis of Their Pathogenicity Publisher Pubmed



Mahdieh N1, 2 ; Sharifi A1 ; Rabbani A1 ; Ashrafi M1, 3 ; Tavasoli AR3 ; Badv RS3 ; Bonkowsky JL4, 5 ; Rabbani B1
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Authors Affiliations
  1. 1. Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
  3. 3. Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Division of Pediatric Neurology, Department of Pediatrics, Salt Lake City, UT, United States
  5. 5. Center for Personalized Medicine, Primary Children's Hospital, Salt Lake City, UT, United States

Source: Clinical Neurology and Neurosurgery Published:2021


Abstract

Objective: Metachromatic leukodystrophy (MLD) is an autosomal recessive leukodystrophy caused by deficiency of aryl sulfatase A (ASA) activity affecting the nervous system. MLD and mutations in ARSA have not been widely studied in non-European cohorts. The genotype-phenotype spectrum of MLD patients was investigated in this study of a cohort of Iranian leukodystrophy patients. In silico analysis was performed to investigate the pathogenicity of the variants. Methods: Genetic analysis for 25 patients was performed with direct sequencing of the ARSA gene. The missense variants underwent in silico analysis to characterize the pathogenicity based on predicted structural and stability changes. Results: 19 patients had variants in ARSA genes, including 18 homozygotes and one compound heterozygote individual. In 6 individuals no mutations were found in ARSA gene, suggesting an alternative cause of their leukodystrophy. We found 5 novel disease causing variants: p.Phe64Ile, p.Ser292Alafs*34, p.Arg99Profs*35, p.Phe400Leu and p.Leu429Pro. 32 % of the patients had p.Gly311Ser substitution and resulted in juvenile MLD type. Different in silico analysis showed variable pathogenic effect for the variants. Conclusion: c.931 G > A (p.Gly311Ser) and c.465 + 1 G > A variants are the most frequent alleles among Iranian MLD patients and five mutations appear to be confined to the Iranian patients. Population screening for these variants may be helpful to reduce the burden of the disease in this part of the world. © 2020 Elsevier B.V.
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