title: Unique spectrum of SPAST variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements.
abstract: BACKGROUND
  Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder that can be an autosomal-dominant, autosomal-recessive, or X-linked disease. The most common autosomal-dominant form of the disease derives from mutations in the SPAST gene.
  
  
  METHODS
  The aim of this study was to analyze 49 patients diagnosed with HSP from the Estonian population for sequence variants of the SPAST gene and to describe the associated phenotypes. Healthy control individuals (n = 100) with no family history of HSP were also analyzed. All patient samples were screened using denaturing high performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) assay. Samples with abnormal DHPLC and MLPA profiles were sequenced, with the same regions sequenced in control samples.
  
  
  RESULTS
  Sequence variants of SPAST were identified in 19/49 HSP patients (38.8%), twelve among them had pathogenic mutations. Within the latter group there was one sporadic case. Eight patients had pure, and four - complex HSP. The twelve variants were identified: seven pathogenic (c.1174-1G>C, c.1185delA, c.1276C>T, c.1352_1356delGAGAA, c.1378C>A, c.1518_1519insTC, c.1841_1842insA) and five non-pathogenic (c.131C>T, c.484G>A, c.685A>G, c.1245+202delG, c.1245+215G>C). Only 2 of these mutations had previously been described (c.131C>T, c.1245+202delG). Three mutations, c.1174-1G>C, c.1276 C>T, c.1378C>A, showed intrafamilial segregation.
  
  
  CONCLUSIONS
  This study identified new variants of the SPAST gene which included benign missense variants and short insertions/deletions. No large rearrangements were found. Based on these data, 7 new pathogenic variants of HSP are associated with clinical phenotypes.
authors.affiliation: Department of Neurology, University of Tartu, Estonia. Mark.Braschinsky@kliinikum.ee
authors.forename: Mark
authors.initials: M
authors.lastname: Braschinsky
authors.forename: Riin
authors.initials: R
authors.lastname: Tamm
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
authors.forename: Elena
authors.initials: E
authors.lastname: Sachez-Ferrero
authors.forename: Elve
authors.initials: E
authors.lastname: Raukas
authors.forename: Siiri-Merike
authors.initials: SM
authors.lastname: Lüüs
authors.forename: Katrin
authors.initials: K
authors.lastname: Gross-Paju
authors.forename: Catherine
authors.initials: C
authors.lastname: Boillot
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.forename: Sulev
authors.initials: S
authors.lastname: Haldre
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004957:Estonia; D005091:Exons; D005190:Family; D005260:Female; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012426:Russia; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin; D055815:Young Adult
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human