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Ditta Zobor, Britta Feldhaus, Nicole Weisschuh, Fadi Nasser, Eberhart Zrenner, Susanne Kohl; CEP290 mutation spectrum in Germany and delineation of the associated phenotype. Invest. Ophthalmol. Vis. Sci. 2018;59(9):23.
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© ARVO (1962-2015); The Authors (2016-present)
Gene therapy for Leber congenital amaurosis (LCA) is becoming available. Therefore, genetic testing and clinical characterization of patients are crucial. We report the spectrum of CEP290 mutations in the largest German cohort and delineate the associated phenotype.
Twenty-four patients from 22 families with genetically confirmed mutations in CEP290 were included. Genomic DNA was analyzed by Sanger sequencing or by high-throughput sequencing for all RP-related genes and segregation analysis in a research or diagnostic-genetic set-up. All patients underwent ophthalmological examination including psychophysical tests and electrophysiology, where possible. Additionally, fundus autofluorescence (FAF) and spectral domain optical coherence tomography (SD-OCT) were performed.
In 24 patients (12 m, 12 f; mean age 31±18.7 years, range 4-72 years), 15 different CEP290 genotypes and 19 mutations were revealed. The most frequent mutation was c.2991+1655A>G, found in 80% (19/24) of patients. Seven patients carried the mutation in a homozygous, fourteen in a compound heterozygous state. The most common clinical diagnosis was LCA (16/24) followed by retinitis pigmentosa (RP, 7/24) and cone dystrophy (CD, 1/24). BCVA was severely reduced: 8/24 had no (NLP) or residual light perception (LP), and 6/24 had only hand motion vision (HM). Exceptions were 3 patients with BCVA of 0.8 (Snellen). All patients showed severely reduced or no measurable visual fields. ERG was typically undetectable, 3 patients with RP had preserved photopic responses. SD-OCT revealed centrally preserved photoreceptors in the milder RP cases and a complete photoreceptor loss in LCA and CD patients. Central foveal thickness was reduced (mean: 177µm ± 47µm), as well as outer nuclear layer (ONL) thickness (mean: 105 ± 27µm). Additional findings were nystagmus (75%), cataract (58%), keratoconus (17%), strabismus (38%) and the oculo-digital sign (17%). Interestingly, in patients with homozygous c.2991+1655A>G genotype, as well as in some compound heterozygous cases, FAF was absent.
c.2991+1655A>G is the most frequent mutation in CEP290 patients originating from Germany. A homozygous c.2991+1655A>G genotype was associated with the least favorable phenotype, however, clinical variability was observed. For future therapies, the affected gene as well as the presence of photoreceptors in SD-OCT might be most important to look out for.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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