title: Primary familial brain calcification linked to deletion of 5' noncoding region of SLC20A2.
abstract: OBJECTIVE
  Primary familial brain calcification (PFBC) is a rare neurological disease often inherited as a dominant trait. Mutations in four genes (SLC20A2, PDGFB, PDGFRB, and XPR1) have been reported in patients with PFBC. Of these, point mutations or small deletions in SLC20A2 are most common. Thus far, only one large deletion covering entire SLC20A2 and several smaller, exonic deletions of SLC20A2 have been reported. The aim of this study was to identify the causative gene defect in a Finnish PFBC family with three affected patients.
  
  
  METHODS
  A Finnish family with three PFBC patients and five unaffected subjects was studied. Sanger sequencing was used to exclude mutations in the coding and splice site regions of SLC20A2, PDGFRB, and PDGFB. Whole-exome (WES) and whole-genome sequencing (WGS) were performed to identify the causative mutation. A SNP array was used in segregation analysis.
  
  
  RESULTS
  Copy number analysis of the WGS data revealed a heterozygous deletion of ~578 kb on chromosome 8. The deletion removes the 5' UTR region, the noncoding exon 1 and the putative promoter region of SLC20A2 as well as the coding regions of six other genes.
  
  
  CONCLUSIONS
  Our results support haploinsufficiency of SLC20A2 as a pathogenetic mechanism in PFBC. Analysis of copy number variations (CNVs) is emerging as a crucial step in the molecular genetic diagnostics of PFBC, and it should not be limited to coding regions, as causative variants may reside in the noncoding parts of known disease-associated genes.
authors.affiliation: Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.|Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Pasanen
authors.affiliation: Department of Neurology, Tampere University Hospital, Tampere, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Mäkinen
authors.affiliation: Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Myllykangas
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, Aveiro, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, Aveiro, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Bras
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Valori
authors.affiliation: Department of Geriatrics, University of Turku, Turku, Finland.|Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Viitanen
authors.affiliation: Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: P J
authors.initials: PJ
authors.lastname: Tienari
authors.affiliation: Department of Clinical Genetics, Helsinki University Central Hospital and Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Pöyhönen
authors.affiliation: Department of Neurology and Clinical Neurophysiology, Lapland Central Hospital, Rovaniemi, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Baumann
mesh_terms: D024506:5' Flanking Region; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics*; D002114:Calcinosis / Q000175:diagnosis / Q000235:genetics*; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000235:genetics*; D000089842:Xenotropic and Polytropic Retrovirus Receptor
chemical_list: C493589:SLC20A2 protein, human; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; C000715267:XPR1 protein, human; D000089842:Xenotropic and Polytropic Retrovirus Receptor
keywords: SLC20A2; deletion; primary familial brain calcification; promoter