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. 2011:17:2706-16.
Epub 2011 Oct 19.

RDH12 retinopathy: novel mutations and phenotypic description

Donna S Mackay  1 , Arundhati Dev Borman, Phillip Moradi, Robert H Henderson, Zheng Li, Genevieve A Wright, Naushin Waseem, Mamatha Gandra, Dorothy A Thompson, Shomi S Bhattacharya, Graham E Holder, Andrew R Webster, Anthony T Moore
Affiliations

RDH12 retinopathy: novel mutations and phenotypic description

Donna S Mackay et al. Mol Vis. 2011.

Abstract

Purpose: To identify patients with autosomal recessive retinal dystrophy caused by mutations in the gene, retinal dehydrogenase 12 (RDH12), and to report the associated phenotype.

Methods: After giving informed consent, all patients underwent full clinical evaluation. Patients were selected for mutation analysis based upon positive results from the Asper Ophthalmics Leber congenital amaurosis arrayed primer extansion (APEX) microarray screening, linkage analysis, or their clinical phenotype. All coding exons of RDH12 were screened by direct Sanger sequencing. Potential variants were checked for segregation in the respective families and screened in controls, and their pathogenicity analyzed using in silico prediction programs.

Results: Screening of 389 probands by the APEX microarray and/or direct sequencing identified bi-allelic mutations in 29 families. Seventeen novel mutations were identified. The phenotype in these patients presented with a severe early-onset rod-cone dystrophy. Funduscopy showed severe generalized retinal pigment epithelial and retinal atrophy, which progressed to dense, widespread intraretinal pigment migration by adulthood. The macula showed severe atrophy, with pigmentation and yellowing, and corresponding loss of fundus autofluorescence. Optical coherence tomography revealed marked retinal thinning and excavation at the macula.

Conclusions: RDH12 mutations account for approximately 7% of disease in our cohort of patients diagnosed with Leber congenital amaurosis and early-onset retinal dystrophy. The clinical features of this disorder are highly characteristic and facilitate candidate gene screening. The term RDH12 retinopathy is proposed as a more accurate description.

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Figures

Figure 1
Figure 1
RDH12 gene structure showing the locations of the mutations identified in this study. Novel mutations are shown in red.
Figure 2
Figure 2
Phenotype associated with retinal dehydrogenase 12 (RDH12) retinopathy. A: Fundus appearance in adults and older children shows dense intraretinal pigment migration, severe retinal pigment epithelium atrophy, and arteriolar attenuation, with a severe atrophic pigmentary maculopathy (family 12, age 20 years). B: Para-arteriolar sparing of the intraretinal pigmentation was evident in six of 32 patients (white arrows, family 22, age 17.5 years). C: In children, retinal pigment epithelium atrophy with macular atrophy and minimal intraretinal pigmentation predominated (family 17, age 8.5 years). D: Macular atrophy was often associated with striking yellow deposits (family 3, age 27 years). E: No detectable macular autofluorescence was visible on fundus autofluorescence imaging, corresponding to the severe macular atrophy (family 11, age 11). F: Spectral domain optical coherence tomography demonstrated severe macular thinning, excavation, and distortion of the laminar architecture (white arrow, family 22, age 17.5 years).
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