Genome-wide linkage analysis and mutation analysis of hereditary congenital blepharoptosis in a Japanese family

Hereditary congenital ptosis (PTOS) is defined as drooping of the upper eyelid without any other accompanying symptoms and distinguished from syndromic blepharoptosis. Two previous linkage analyses assigned a PTOS locus (PTOS1) to 1p32-p34.1 and another (PTOS2) to Xq24-q27.1. In addition, in a sporadic case with a balanced chromosomal translocation t(1;8) (p34.3;q21.12), the ZFHX4 (zinc finger homeodomain 4) gene was found to be disrupted at the 8q21.12 breakpoint, but there was no gene at the 1p34.3 breakpoint, suggesting the existence of the third PTOS locus (PTOS1) at 8q21.12. We carried out a genome-wide linkage analysis in a Japanese PTOS family and calculated two-point and multipoint log of odds (LOD) scores with reduced penetrance. Haplotype analysis gave three candidate disease-responsible regions, i.e., 8q21.11-q22.1, 12q24.32-q24.33, and 14q21.1-q23.2. Although the family size is too small to define one of them, 8q21.11-q22.1 is a likely candidate region, because it contains the previously reported translocation breakpoint above. We thus performed mutation, Southern-blot and methylation analyses of ZFHX4 but could not find any disease-specific change in the family. Nevertheless, our data may support the localization of PTOS1.