Spectrum, frequency, and genotype-phenotype of mutations in .

PURPOSE

To describe the mutation spectrum of and associated ocular phenotypes.

METHODS

As part of a continuing examination of the genetic basis of inherited ophthalmic diseases, sequencing variations in were identified in sequencing data from 5,090 probands. Mutations in were identified in 12 Chinese patients from ten families. Family history and clinical data were examined in detail in these patients. To evaluate possible gene-specific fundus changes, the results were combined with data from 66 patients from 50 families previously reported in the literature.

RESULTS

Seven homozygous or compound heterozygous mutations, including two novel mutations (c.367C>T, p.Q123* and c.1083-2A>G) and five known mutations in , were identified in ten families, including six families with Leber congenital amaurosis (LCA), three families with juvenile retinitis pigmentosa, and one family with early-onset high myopia. These families accounted for approximately 2.2% (6/269) of LCA and 0.4% (10/2,252) of inherited retinal dystrophies in this case series. A combined analysis of data from the present study and data from 60 families reported in the literature showed that 93.3% (112/120) of mutant alleles were truncation mutations, whereas only about 5.0% were missense mutations, and 1.7% were non-frameshift indels. Common -associated fundus changes, including narrow arterioles, a relatively well-preserved macular region, and widespread RPE atrophy resulting in diffuse mottled hypopigmentation in the midperipheral retina, were identified in this cohort and in patients in the literature. Missense mutations were not associated with specific phenotypic features or severity.

CONCLUSIONS

Narrow arterioles, a relatively well-preserved macular region, and widespread RPE atrophy resulting in diffuse mottling hypopigmentation in the midperipheral retina may be considered early and common fundus changes specific to -associated retinopathy. The fact that similar mutations result in varied phenotypes points to the existence of other potential modifiers of the disease. Uncovering the identity of these modifiers might aid the development of novel treatments.