Purpose: We have previously reported clinical features of two siblings, a sister with complete achromatopsia (ACHM) and a brother with incomplete ACHM, in a consanguineous Japanese family. With the current study, we intended to identify a disease-causing mutation in the siblings and to investigate why the phenotypes of the siblings differed.
Methods: We performed a comprehensive ophthalmic examination for each sibling and parent. Whole-exome and Sanger sequencing were performed on genomic DNA. Molecular modeling was analyzed in an in silico study.
Results: The ophthalmic examination revealed severe macular atrophy in the older female sibling at 30 years of age and mild macular atrophy in the brother at 26 years of age. The genetic analysis identified a novel homozygous PDE6C mutation (p.E591K) as the disease-causing allele in the siblings. Each parent was heterozygous for the mutation. Molecular modeling showed that the mutation could cause a conformational change in the PDE6C protein and result in reduced phosphodiesterase activity. We also identified an OPN1SW mutation (p.G79R), which is associated with congenital tritan deficiencies, in the sister and the father but not in the brother.
Conclusions: A novel homozygous PDE6C mutation was identified as the cause of ACHM. In addition, we identified an OPN1SW mutation in the sibling with complete ACHM, which might explain the difference in phenotype (complete versus incomplete ACHM) between the siblings.
Keywords: Achromatopsia; OPN1SW; PDE6C; RHO; whole-exome sequencing.