Novel mutations in c2orf71 causing an early onset form of cone-rod dystrophy: A molecular diagnosis after 20 years of clinical follow-up

Abstract

Purpose: Cone rod-dystrophies (CRDs) are pigmentary retinopathies mainly involving cones. CRDs typically present with decreased visual acuity and loss of sensitivity in the central visual field, reflecting the primary dysfunction of cones associated with night blindness and concentric visual field loss due to rod dysfunction. We describe the phenotype, natural history, and molecular analysis results of an early onset form of CRD.

Methods: An otherwise healthy 25-year-old man from Sardinia, Italy, initially presented with subacute visual loss and central scotoma in both eyes. He underwent a complete ophthalmic examination, electrophysiologic testing, and genetic counseling. We first applied a candidate gene approach on ABCA4 to detect mutations; then, we performed exome sequencing (WES) on all family members to identify causative mutations.

Results: The ophthalmic examination was unremarkable except the fundus examination, which revealed a well-circumscribed ring-shaped area of choroidal and RPE atrophy surrounding the fovea in the left eye and small white patches of atrophy around the fovea in the right eye. The ocular features and medical history were consistent with a diagnosis of CRD. Twenty years later, he showed a marked impairment in visual function, secondary to severe atrophic maculopathy associated with sparse pigmentary deposits. Molecular analysis identified two novel frameshift mutations in C2orf71: c.3039dupC: p.Ser1014Leufs*93 and c.1804_1805delAG:p. His603Argfs*77.

Conclusions: The mutations in C2orf71 reported in this study comprise protein truncation mutations, which are likely to be involved in the pathogenesis of this severe form of early onset CRD.

Figure 1

Genetic testing results. A: Pedigree of the family under study. All the members were recruited for whole exome analysis. Mutation status of C2orf71 is shown under the symbols for each subject (+/−, heterozygous carriers). B: Sanger sequencing confirmation: Chromatographs obtained with Sanger sequencing for all family members. The arrow indicates the frameshift start. Sanger sequencing that identified the mutation c.1804_1805delAG was performed using a reverse primer.

Figure 2

Multimodal imaging evaluation and visual fields, at baseline. A: Color fundus photography reveals small white patches of atrophy around the fovea in the right eye and a well-circumscribed ring-shaped area of choroidal and RPE atrophy surrounding the fovea in the left eye. A, E: In both eyes, there is a pale optic disc, but no pigment deposits are visible. A punctate retinal pigment epitheliopathy can be seen in the midperipheral retina bilaterally, more evident on fluorescein angiography, which also reveals hyperfluorescent macular lesions suggestive of bull’s-eye maculopathy (B, C, F, G). D, H: In both eyes, visual field testing showed an absolute paracentral ring scotoma, surrounded by a relative annular scotoma extending 15° from the fovea bilaterally.

Figure 3

Fundus autofluorescence, fluorescein angiography, and visual fields, 20 years later. A, F: In both eyes, fundus autofluorescence shows a central round area of decreased autofluorescence corresponding to the area of macular atrophy, surrounded by a ring of relatively increased autofluorescence. In the mid-peripheral retina, several roundish areas of reduced autofluorescence, suggestive of patchy atrophy, can be seen. B, C, G, H: In both eyes, fluorescein angiography frames reveal a severe macular atrophy surrounded by a ring of preserved retinal pigment epithelium. The mid-peripheral retina is extensively atrophic with some sparse pigmentary deposits (white arrow in H). D, I: Bilateral visual field extinction. E: In the right eye, simultaneous infrared and spectral domain optical coherence tomography show an ovoid tubular structure with a partial hyperreflective border and hyporreflective material inside, suggestive of an outer retina tabulation (white arrow) while (J) in the left eye reveal a severe retinal thinning secondary to the atrophy of the external retinal layers with backscattering.