Blepharospasm in a multiplex African-American pedigree

Jianfeng Xiao, Misty M. Thompson, Satya R. Vemula, Mark Ledoux

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)299-303
Number of pages5
JournalJournal of the Neurological Sciences
Volume362
DOIs
StatePublished - Mar 15 2016

Fingerprint

Blepharospasm
Pedigree
African Americans
Dystonia
Computer Simulation
Exome
Dystonic Disorders
Genes
Blinking
Spasm
Age of Onset
Virulence
Muscles
Mutation

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Blepharospasm in a multiplex African-American pedigree. / Xiao, Jianfeng; Thompson, Misty M.; Vemula, Satya R.; Ledoux, Mark.

In: Journal of the Neurological Sciences, Vol. 362, 15.03.2016, p. 299-303.

Research output: Contribution to journalArticle

Xiao, Jianfeng ; Thompson, Misty M. ; Vemula, Satya R. ; Ledoux, Mark. / Blepharospasm in a multiplex African-American pedigree. In: Journal of the Neurological Sciences. 2016 ; Vol. 362. pp. 299-303.
@article{1900412ef51b4035971b5bde62cd775a,
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.",
author = "Jianfeng Xiao and Thompson, {Misty M.} and Vemula, {Satya R.} and Mark Ledoux",
year = "2016",
month = "3",
day = "15",
doi = "10.1016/j.jns.2016.02.003",
language = "English (US)",
volume = "362",
pages = "299--303",
journal = "Journal of the Neurological Sciences",
issn = "0022-510X",
publisher = "Elsevier",

}

TY - JOUR

T1 - Blepharospasm in a multiplex African-American pedigree

AU - Xiao, Jianfeng

AU - Thompson, Misty M.

AU - Vemula, Satya R.

AU - Ledoux, Mark

PY - 2016/3/15

Y1 - 2016/3/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84962288197&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962288197&partnerID=8YFLogxK

U2 - 10.1016/j.jns.2016.02.003

DO - 10.1016/j.jns.2016.02.003

M3 - Article

C2 - 26944167

AN - SCOPUS:84962288197

VL - 362

SP - 299

EP - 303

JO - Journal of the Neurological Sciences

JF - Journal of the Neurological Sciences

SN - 0022-510X

ER -