Genetic and Clinical Profile of Retinopathies Due to Disease-Causing Variants in Leber Congenital Amaurosis (LCA)-Associated Genes in a Large German Cohort

Abstract

To report the spectrum of Leber congenital amaurosis (LCA) associated genes in a large German cohort and to delineate their associated phenotype. Local databases were screened for patients with a clinical diagnosis of LCA and for patients with disease-causing variants in known LCA-associated genes independent of their clinical diagnosis. Patients with a mere clinical diagnosis were invited for genetic testing. Genomic DNA was either analyzed in a diagnostic-genetic or research setup using various capture panels for syndromic and non-syndromic IRD (inherited retinal dystrophy) genes. Clinical data was obtained mainly retrospectively. Patients with genetic and phenotypic information were eventually included. Descriptive statistical data analysis was performed. A total of 105 patients (53 female, 52 male, age 3–76 years at the time of data collection) with disease-causing variants in 16 LCA-associated genes were included. The genetic spectrum displayed variants in the following genes: CEP290 (21%), CRB1 (21%), RPE65 (14%), RDH12 (13%), AIPL1 (6%), TULP1 (6%), and IQCB1 (5%), and few cases harbored pathogenic variants in LRAT, CABP4, NMNAT1, RPGRIP1, SPATA7, CRX, IFT140, LCA5, and RD3 (altogether accounting for 14%). The most common clinical diagnosis was LCA (53%, 56/105) followed by retinitis pigmentosa (RP, 40%, 42/105), but also other IRDs were seen (cone-rod dystrophy, 5%; congenital stationary night blindness, 2%). Among LCA patients, 50% were caused by variants in CEP290 (29%) and RPE65 (21%), whereas variants in other genes were much less frequent (CRB1 11%, AIPL1 11%, IQCB1 9%, and RDH12 7%, and sporadically LRAT, NMNAT1, CRX, RD3, and RPGRIP1). In general, the patients showed a severe phenotype hallmarked by severely reduced visual acuity, concentric narrowing of the visual field, and extinguished electroretinograms. However, there were also exceptional cases with best corrected visual acuity as high as 0.8 (Snellen), well-preserved visual fields, and preserved photoreceptors in spectral domain optical coherence tomography. Phenotypic variability was seen between and within genetic subgroups. The study we are presenting pertains to a considerable LCA group, furnishing valuable comprehension of the genetic and phenotypic spectrum. This knowledge holds significance for impending gene therapeutic trials. In this German cohort, CEP290 and CRB1 are the most frequently mutated genes. However, LCA is genetically highly heterogeneous and exhibits clinical variability, showing overlap with other IRDs. For any therapeutic gene intervention, the disease-causing genotype is the primary criterion for treatment access, but the clinical diagnosis, state of the retina, number of to be treated target cells, and the time point of treatment will be crucial.

The Clinical Findings, Pathogenic Variants, and Gene Therapy Qualifications Found in a Leber Congenital Amaurosis Phenotypic Spectrum Patient Cohort

“…CEP290 was the most prevalent gene in our cohort (26%), followed by RPE65, CRB1, and GUCY2D, which each had a prevalence of 13%. In comparison, a recent study on a German cohort of 105 patients found their top causative genes to be CEP290 (21%), RPE65 (14%), CRB1 (11%), and RDH12 (8%) [31]. A Brazilian cohort of 152 patients with LCA/EOSRD reported that the top causative genes were CEP290 (21%), RPE65 (16%), CRB1 (14%), and RPGRIP1 (10%) [32].…”

“…The various global studies and their LCA-associated gene variant prevalence are presented in Figure 5. The studies included the Midwest US (our cohort), Germany [31], Brazil [32], China [33], Japan [28], and Australia [30].…”

“…Three of these had VUSs in LCA-associated genes (Figure 4b), including CEP290 and RDH12. Based on the clinical presentation, our team is suspicious that the gene variants are diagnostic; however, we would need to complete further family testing [31], Brazil [32], China [33], Japan [28], and Australia [30].…”

Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin

“…Triple knockout mice abca4(-/-)rdh8(-/-)rdh12(-/-) raised under cyclic light develop retinal degeneration at the age of 6 weeks, whereas at least 3 months are needed to demonstrate a similar level of retinal degeneration for double knockout mice abca4(-/-)rdh8(-/-) [ 113 ]. Mutations of RDH12 can cause early onset severe cone-rod dystrophy, Leber congenital amaurosis, retinitis pigmentosa, and pseudocoloboma-like maculopathy [ 114 , 115 , 116 , 117 , 118 ].…”

Characterization and AAV-mediated CRB gene augmentation in human-derived CRB1KO and CRB1KOCRB2+/− retinal organoids

“… 10 , 11 , 12 RP is a clinically and genetically heterogeneous disease where children or aged patients experience night blindness that progresses to complete loss of vision, 13 while LCA causes visual impairment in newborns. 14 , 15 There are over 200 different mutations along the CRB1 gene described to be causing early-onset RP in children or LCA without a clear genotype-phenotype correlation. 16 , 17 , 18 , 19 , 20 , 21 No treatment possibilities are available for patients with a mutation in the CRB1 gene.…”