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Marion Neuille, Sivasankar Malaichamy, Maria Vadala, Ramya Sachidanandam, Tharigopala Arokiasamy, Jose Sahel, Parveen Sen, Isabelle S Audo, Nagasamy Soumittra, Christina Zeitz; Novel mutations in SLC24A1 leading to congenital stationary night blindness (CSNB). Invest. Ophthalmol. Vis. Sci. 2016;57(12):658.
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© ARVO (1962-2015); The Authors (2016-present)
CSNB is a clinically and genetically heterogeneous retinal disorder representing rod photoreceptor dysfunction (Riggs-type) or a signal transmission defect (Schubert-Bornschein-type). The latter can be further subdivided into complete or incomplete (ic) CSNB. The aim of this study was to identify the gene defect in a previously diagnosed icCSNB family and in two other families with unclassified CSNB.
Whole exome sequencing (WES) was applied to a previously diagnosed icCSNB family, excluded for mutations in CACNA1F, CABP4, CACNA2D4 and CACNB2. Patients of two other families were clinically examined by standard methods and screened for mutations in fourteen CSNB-associated genes by targeted next-generation sequencing (NGS). Filtering using available genomic databases and in silico analyses were used to identify the disease causing variants. Sanger sequencing, co-segregation analysis and control screening were performed to confirm the most likely pathogenic variants.
In the previously diagnosed icCSNB patient, WES identified a homozygous nonsense variant in SLC24A1 (c.2401G>T [p.Glu801*]). In the two other patients, targeted NGS identified compound heterozygous deletions (c.1691_1693delTCT [p.Phe564del] and c.3291_3294delATCT [p.Val1099Glufs*31]) and a homozygous missense variant (c.2968A>C [p.Ser990Arg]) in SLC24A1. All SLC24A1 variants co-segregate with the phenotype and were absent in 200 control chromosomes screened. Upon electroretinogram (ERG), all patients had severely decreased scotopic responses, whereas photopic responses were more variable. All patients revealed no signs of reduced visual acuity, myopia or nystagmus.
In this study, we identified four novel mutations in SLC24A1 leading to CSNB. To date, only one SLC24A1 mutation in one family has been reported with the Riggs-type of CSNB, characterized by night blindness, severely decreased scotopic ERG a-wave, normal photopic responses and the absence of other clinical signs like reduced visual acuity, myopia or nystagmus. Although ERG responses of our patients were variable, all other observed phenotypes were in accordance with the Riggs-type of CSNB. This confirms that SLC24A1 mutations lead to CSNB and shows that the notion of other clinical signs in addition to ERG is very important to correctly diagnose the type of CSNB. In the absence of clear clinical diagnosis, NGS techniques are helpful to identify gene defects.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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