Blepharospasm in a multiplex African-American pedigree
| Autor: | Jianfeng Xiao, Satya R. Vemula, Misty M. Thompson, Mark S. LeDoux |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Proband Adult Male Adolescent In silico Blepharospasm Pedigree chart Biology Severity of Illness Index Article 03 medical and health sciences symbols.namesake Young Adult 0302 clinical medicine medicine Humans Genetic Testing Age of Onset Child Genetic testing Oligonucleotide Array Sequence Analysis Genetics Sanger sequencing Dystonia Family Health medicine.diagnostic_test Gene Expression Profiling Nuclear Proteins Focal dystonia Middle Aged medicine.disease GTP-Binding Protein alpha Subunits Black or African American DNA-Binding Proteins 030104 developmental biology Neurology Mutation symbols Female Neurology (clinical) medicine.symptom Apoptosis Regulatory Proteins 030217 neurology & neurosurgery Molecular Chaperones |
| Zdroj: | Journal of the neurological sciences. 362 |
| ISSN: | 1878-5883 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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