Analysis of ARSA gene variant in an infant with late infantile metachromatic leukodystrophy
10.3760/cma.j.issn.1003-9406.2020.01.004
- VernacularTitle: 一例晚期婴儿型异染性脑白质营养不良病患儿的ARSA基因变异分析
- Author:
Ruohao WU
1
;
Wenting TANG
2
;
Dongfang LI
1
;
Danxia TANG
1
;
Yu LI
1
;
Xiangyang LUO
1
Author Information
1. Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
2. Department of Molecular Diagnostics, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China
- Publication Type:Journal Article
- Keywords:
ARSA gene;
Metachromatic leukodystrophy;
Compound heterozygous variant;
Nonsense variant
- From:
Chinese Journal of Medical Genetics
2020;37(1):12-16
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To detect pathogenic variant of ARSA gene in an infant with late infantile metachromatic leukodystrophy (MLD).
Methods:The male proband had an onset of walking dysfunction and seizure at 28 months. Arylsulfatase A activity of his peripheral blood leucocytes was 26.9 nmol/mg.17h, and cranial MRI showed wild symmetrical demyelination. With genomic DNA extracted from his peripheral blood sample, all coding exons and splicing sites of the ARSA gene were subjected to Sanger sequencing. PubMed Protein BLAST system was employed to analyze cross-species conservation of the mutant amino acid. Ucsf chimera software was used to analyze the impact of candidate variants on the secondary structure of the protein product. Impact of potential variants was also analyzed with software including PolyPhen-2, Mutation Taster, SIFT and PROVEAN. Whole-exome sequencing was carried out to identify additional variants which may explain the patient’s condition.
Results:The proband was found to harbor compound heterozygous variants of the ARSA gene [c.467G>A (p.Gly156Asp) and c. 960G>A (p.Trp320*)], neither of which was reported previously. As predicted by Ucsf chimera software, the c. 960G>A (p.Trp320*) variant may demolish important secondary structures including α-helix, β-strand and coil of the ARSA protein, causing serious damage to its structure and loss of function. The c. 467G>A (p.Gly156Asp) variant was predicted to be "probably damaging" by PolyPhen-2, Mutation Taster and SIFT software.
Conclusion:The patient’s condition may be attributed to the compound heterozygous c. 467G>A (p.Gly156Asp) and c. 960G>A (p.Trp320*) variants of the ARSA gene. Above results have facilitated genetic counseling and prenatal diagnosis for this family.
