title: Identification of a large intronic transposal insertion in SLC17A5 causing sialic acid storage disease.
abstract: Sialic acid storage diseases are neurodegenerative disorders characterized by accumulation of sialic acid in the lysosome. These disorders are caused by mutations in SLC17A5, the gene encoding sialin, a sialic acid transporter located in the lysosomal membrane. The most common form of sialic acid storage disease is the slowly progressive Salla disease, presenting with hypotonia, ataxia, epilepsy, nystagmus and findings of cerebral and cerebellar atrophy. Hypomyelination and corpus callosum hypoplasia are typical as well. We report a 16 year-old boy with an atypically mild clinical phenotype of sialic acid storage disease characterized by psychomotor retardation and a mixture of spasticity and rigidity but no ataxia, and only weak features of hypomyelination and thinning of corpus callosum on MRI of the brain.
  
  
  
  The thiobarbituric acid method showed elevated levels of free sialic acid in urine and fibroblasts, indicating sialic acid storage disease. Initial Sanger sequencing of SLC17A5 coding regions did not show any pathogenic variants, although exon 9 could not be sequenced. Whole exome sequencing followed by RNA and genomic DNA analysis identified a homozygous 6040 bp insertion in intron 9 of SLC17A5 corresponding to a long interspersed element-1 retrotransposon (KF425758.1). This insertion adds two splice sites, both resulting in a frameshift which in turn creates a premature stop codon 4 bp into intron 9.
  
  
  
  This study describes a novel pathogenic variant in SLC17A5, namely an intronic transposal insertion, in a patient with mild biochemical and clinical phenotypes. The presence of a small fraction of normal transcript may explain the mild phenotype. This case illustrates the importance of including lysosomal sialic acid storage disease in the differential diagnosis of developmental delay with postnatal onset and hypomyelination, as well as intronic regions in the genetic investigation of inborn errors of metabolism.
authors.affiliation: BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.|Centre for Molecular Medicine and Therapeutics, Vancouver, Canada.
authors.forename: Maja
authors.initials: M
authors.lastname: Tarailo-Graovac
authors.affiliation: BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.|Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Britt I
authors.initials: BI
authors.lastname: Drögemöller
authors.affiliation: BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.|Centre for Molecular Medicine and Therapeutics, Vancouver, Canada.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.|Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Colin J D
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ans M W
authors.initials: AM
authors.lastname: van den Ouweland
authors.affiliation: Department of Pediatrics, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Gittan
authors.initials: G
authors.lastname: Kollberg
authors.affiliation: BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada. cvankarnebeek@cw.bc.ca.|Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. cvankarnebeek@cw.bc.ca.|Department of Pediatrics, University of British Columbia, Vancouver, Canada. cvankarnebeek@cw.bc.ca.|Department of Pediatrics, Academic Medical Centre, Amsterdam, The Netherlands. cvankarnebeek@cw.bc.ca.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. maria.k.blomqvist@vgregion.se.
authors.forename: Maria
authors.initials: M
authors.lastname: Blomqvist
mesh_terms: D004251:DNA Transposable Elements / Q000235:genetics; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics*; D016133:Polymerase Chain Reaction; D029461:Sialic Acid Storage Disease / Q000235:genetics*; D012867:Skin / Q000166:cytology; D027981:Symporters / Q000235:genetics*; D000073359:Exome Sequencing / Q000379:methods
chemical_list: D004251:DNA Transposable Elements; D027361:Organic Anion Transporters; D027981:Symporters; C421224:sialic acid transport proteins; D019158:N-Acetylneuraminic Acid
keywords: SLC17A5; Salla disease; Sialic acid storage disease; Transposon insertion; Whole exome sequencing