title: Blepharospasm in a multiplex African-American pedigree.
abstract: BACKGROUND
  Isolated blepharospasm (BSP) is a late-onset focal dystonia characterized by involuntary contractions of the orbicularis oculi muscles. Genetic studies of BSP have been limited by the paucity of large multiplex pedigrees. Although sequence variants (SVs) in THAP1 have been reported in rare cases of BSP, the genetic causes of this focal dystonia remain largely unknown. Moreover, in the absence of family history and strong in silico or in vitro evidence of deleteriousness, the pathogenicity of novel SVs in THAP1 and other dystonia-associated genes can be indeterminate.
  
  
  METHODS
  A large African-American pedigree with BSP was phenotypically characterized and screened for mutations in THAP1, TOR1A and GNAL with Sanger sequencing. Whole-exome sequencing of the proband was used to examine other dystonia-associated genes for potentially pathogenic SVs. In silico and co-segregation analyses were performed for a novel THAP1 SV identified in the proband.
  
  
  RESULTS
  Seven family members exhibited increased blinking and/or stereotyped bilateral and synchronous orbicularis oculi spasms with age of onset ranging from early childhood to late adult life (7 to 54 years). The proband was found to harbor a novel THAP1 SV (c.314T>C, p.L105S). However, the p.L105S SV did not co-segregate with blepharospasm in the pedigree. Moreover, in silico analyses suggest that p.L105S is benign. No pathogenic or likely pathogenic SVs in other dystonia-associated genes were identified with whole-exome sequencing.
  
  
  CONCLUSIONS
  Blepharospasm can be familial and may be hereditary in African-Americans. A comprehensive array of in silico tools, and, if possible, co-segregation analysis should be used to classify SVs in dystonia-associated genes.
authors.affiliation: Departments of Neurology, and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Departments of Neurology, and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Misty M
authors.initials: MM
authors.lastname: Thompson
authors.affiliation: Departments of Neurology, and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Satya R
authors.initials: SR
authors.lastname: Vemula
authors.affiliation: Departments of Neurology, and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: mledoux@uthsc.edu.
authors.forename: Mark S
authors.initials: MS
authors.lastname: LeDoux
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American; D017668:Age of Onset; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001764:Blepharospasm / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics; D004421:Dystonia / Q000150:complications; D005192:Family Health; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D020869:Gene Expression Profiling; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D044385:GTP-Binding Protein alpha Subunits; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C474080:THAP1 protein, human; C108175:TOR1A protein, human; C084618:olfactory G protein subunit alpha olf
keywords: African-American; Blepharospasm; Dystonia; Sequence variant; THAP1