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Christina Zeitz, Isabelle Audo, ; Genotyping strategy for congenital stationary night blindness (CSNB): conclusion from a comprehensive study and meta-analysis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):404.
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CSNB is a genetically and clinically heterogeneous retinal disease caused by mutations in 17 identified genes. The purpose of this study was to establish phenotype-genotype correlations, prevalence, and genotyping strategies for CSNB based on meta-analyses on our cohort and a literature search.
Detailed phenotypic characterization was performed on a large CSNB cohort consisting of 350 index patients. To detect mutations, we used Sanger sequencing, microarray analysis, next generation targeted (NGS) and whole exome sequencing (WES). An exhaustive literature search was used to include all described CSNB causing mutations.
Most of the patients from our CSNB cohort have a Schubert-Bornschein-type electroretinogram (ERG) with complete (c) and incomplete (ic) phenotype. We identified novel mutations in NYX (15), TRPM1 (15), GRM6 (2), and GPR179 (3) in patients with cCSNB, and in CACNA1F (38) and CABP4 (1) in icCSNB patients. A few cases in this cohort do not harbour mutations in known genes. Compiling our data with those from the literature, we found 67 different mutations associated with gene defects affecting the phototransduction cascade and leading to CSNB with a Riggs-type ERG (RHO = 4, GNAT1 =3, PDE6B = 1, SLC24A1 = 1), or to CSNB with fundus abnormalities as in Oguchi disease (SAG = 6 and GRK1 = 9) and Fundus Albipunctatus (RDH5 = 38, RLBP1 = 3 and RPE65 = 2). Similarly, 293 different mutations have been identified in gene defects affecting the signalling from photoreceptors to bipolar cells, of which 132 occurred in cases with icCSNB (CACNA1F = 126, CABP4 = 5 and CACNA2D4 = 1) and 161 in cases with cCSNB (NYX = 69, GRM6 = 23, TRPM1 = 51, GPR179 = 14 and LRIT3 = 4). Taking into account founder mutations the following prevalence for CSNB was established: RHO>GNAT1>SLC24A1≥PDE6B in cases with a Riggs-type ERG, RDH5>SAG>GRK1>RLBP1>RPE65 in cases with fundus abnormalities, CACNA1F>CABP4>CACNA2D4 in cases with icCSNB and NYX>TRPM1>GRM6>GPR179>LRIT3 in cases with cCSNB.
Although CSNB is a heterogeneous disease, precise clinical examination is a useful first step toward gene-specific sequencing to identify disease causing mutations. In this context, Sanger sequencing seems to be the gold standard. WES should identify the missing gene defects underlying unsolved CSNB cases.
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