Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects.

Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa.

A recurrent arcuate retinopathy in familial cone-rod dystrophy secondary to heterozygous CRX deletion.

Purpose: To describe an arcuate retinopathy appearance in a familial cone-rod dystrophy and the underlying genetic cause.Methods: Retrospective case series of an affected three-generation family (eight affected members, eight unaffected members)Results: The proband, a 47-year-old male, noted significant visual loss since his early thirties. In addition to central macular atrophic changes, retinal examination was notable for peripapillary atrophy and an arcuate of drusenoid deep yellow lesions in the temporal macula. Spectral-domain optical coherence tomography in the area of the lesions showed regional outer neurosensory retina loss with nasal extension (forming a ring around the central retina) but no drusen. Full-field electroretinography revealed cone-rod dysfunction with an electronegative waveform. Fifteen other available family members were examined, and seven (age range 13-71 years old) showed variable expressivity for similar phenotypic findings, most notably the arcuate lesions in all but the oldest individual who had end-stage atrophy. Exome sequencing of the proband's affected daughter uncovered a heterozygous CRX deletion [NM_000554.4: CRX: c.(100 + 1_101-1)_(c.900 + 1_?)del] that segregated with the disease.Conclusion: An unusual familial cone-rod dystrophy phenotype was associated with heterozygous CRX deletion, a pathogenic variant that had a presumed mechanism of haploinsufficiency. The consistent finding of arcuate temporal macular lesions among affected family members was striking, particularly given the variable expressivity previously associated with CRX-related retinopathy. Additional phenotypic studies are needed to assess how frequently this temporal arcuate retinopathy appearance occurs in individuals harboring a similar deletion who are not from the current family.

Bilateral Symmetry of Visual Function Loss in Cone-Rod Dystrophies.

PURPOSE: To investigate bilateral symmetry of visual impairment in cone-rod dystrophy (CRD) patients and understand the feasibility of clinical trial designs treating one eye and using the untreated eye as an internal control. METHODS: This was a retrospective study of visual function loss measures in 436 CRD patients followed at the Ophthalmology Department of the Catholic University in Rome. Clinical measures considered were best-corrected visual acuity, focal macular cone electroretinogram (fERG), and Ganzfeld cone-mediated and rod-mediated electroretinograms. Interocular agreement in each of these clinical indexes was assessed by t- and Wilcoxon tests for paired samples, structural (Deming) regression analysis, and intraclass correlation. Baseline and follow-up measures were analyzed. A separate analysis was performed on the subset of 61 CRD patients carrying likely disease-causing mutations in the ABCA4 gene. RESULTS: Statistical tests show a very high degree of bilateral symmetry in the extent and progression of visual impairment in the fellow eyes of CRD patients. CONCLUSIONS: These data contribute to a better understanding of CRDs and support the feasibility of clinical trial designs involving unilateral eye treatment with the use of fellow eye as internal control.