Blepharospasm in a multiplex African-American pedigree.

Area of Science:

• Genetics
• Neurology
• Dermatology

Background:

• Isolated blepharospasm (BSP) is a focal dystonia affecting the orbicularis oculi muscles, with largely unknown genetic causes.
• Genetic studies are limited by a lack of large pedigrees, and the pathogenicity of novel sequence variants (SVs) is often indeterminate.

Purpose of the Study:

• To investigate the genetic basis of blepharospasm in a large African-American family.
• To identify pathogenic sequence variants (SVs) in known dystonia-associated genes.

Main Methods:

• Phenotypic characterization of a large African-American pedigree with blepharospasm.
• Sanger sequencing of THAP1, TOR1A, and GNAL, followed by whole-exome sequencing of the proband.
• In silico and co-segregation analyses of a novel THAP1 SV.

Main Results:

• Seven family members displayed blepharospasm symptoms with varying onset ages.
• A novel THAP1 SV (c.314T>C, p.L105S) was identified in the proband but did not co-segregate with the disease and was predicted to be benign.
• Whole-exome sequencing did not reveal other pathogenic or likely pathogenic SVs in dystonia-associated genes.

Conclusions:

• Blepharospasm can exhibit familial inheritance patterns in African-Americans.
• Accurate classification of SVs in dystonia-associated genes necessitates comprehensive in silico tools and co-segregation analysis.