Purpose: The present study was designed to elucidate the molecular genetic basis of a congenital stationary cone dysfunction characterized by congenital nystagmus, moderate visual impairment, and markedly disparate color vision deficiencies between two affected cousins.
Methods: Ophthalmic examinations with emphasis on color vision and electrophysiology. Molecular genetic analysis of the X-linked cone opsin genes, mutation screening of the CNGA3, CNGB3, and GNAT2 genes, and heterologous splicing experiments.
Results: Whereas the proband was found to carry a homozygous frameshift mutation (Tyr95fs) in GNAT2, her cousin was compound heterozygous for the Tyr95fs and a new intronic mutation c.461 + 24G-->A. Heterologous expression in COS7 cells showed that the latter causes a splicing defect that results in early translation termination. Yet, this mutation is leaky, giving rise to small amounts of correctly spliced transcripts and offer an explanation for the diverging clinical findings in the cousins, one best described as incomplete achromatopsia and the other with oligocone trichromacy.
Conclusions: The cases presented broaden the phenotypic spectrum of GNAT2 mutations and underline the increasing importance of molecular genetics in the clinical diagnosis of atypical ophthalmic phenotypes.