title: Whole-exome sequencing identifies compound heterozygous mutations in ARSA of two siblings presented with atypical onset of metachromatic leukodystrophy from a Chinese pedigree.
abstract: BACKGROUND
  Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disorder caused mainly by variants in arylsulfatase A (ARSA) gene. MLD can be divided into three major clinical forms according to the age of onset: late infantile, juvenile, and adult. We report two siblings of late infantile MLD presenting with cerebellar ataxia as the only first clinical symptom.
  
  
  METHODS
  Because of the unspecific neurological manifestation, whole-exome sequencing (WES) was performed to find disease-causing mutations for molecular diagnosis. Then successive MRI and ARSA activity determination were performed to further confirm the diagnosis. Moreover, the prenatal diagnosis was carried out on the basis of molecular diagnosis.
  
  
  RESULTS
  The siblings exhibited compound heterozygous variants {[c.302G>T]+[c.1344dupC]} in the ARSA gene, and both of the variants have been reported as disease-causing mutations previously. The results of MRI and low ARSA activity confirmed the diagnosis of MLD. Prenatal diagnosis showed that the fetus was a heterozygous carrier.
  
  
  CONCLUSIONS
  It is recommended that WES be considered as a first line diagnostic procedure to discover potential disease-causing genetic variants in affected individuals with hereditary traits but without definite clinical diagnosis. However, the final diagnosis should be confirmed by comprehensive evaluations including biochemical, enzymatic or imaging investigations.
authors.affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Dongfang Hospital, Xiamen University Medical College, Fuzhou, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Dongfang Hospital, Xiamen University Medical College, Fuzhou, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Dongfang Hospital, Xiamen University Medical College, Fuzhou, China.
authors.forename: Dezhu
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Dongfang Hospital, Xiamen University Medical College, Fuzhou, China.
authors.forename: Aizhen
authors.initials: A
authors.lastname: Yan
authors.affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Dongfang Hospital, Xiamen University Medical College, Fuzhou, China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Tu
authors.affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Dongfang Hospital, Xiamen University Medical College, Fuzhou, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Dongfang Hospital, Xiamen University Medical College, Fuzhou, China. Electronic address: fhlan@xmu.edu.cn.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Lan
mesh_terms: D017668:Age of Onset; D044466:Asian People; D002553:Cerebroside-Sulfatase / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007966:Leukodystrophy, Metachromatic / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011296:Prenatal Diagnosis; D035781:Siblings
chemical_list: D002553:Cerebroside-Sulfatase
keywords: Arylsulfatase A; Metachromatic leukodystrophy; Mutation analysis; Whole-exome sequencing