September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Novel mutations in SLC24A1 leading to congenital stationary night blindness (CSNB)
Author Affiliations & Notes
  • Marion Neuille
    Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France
  • Sivasankar Malaichamy
    SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India
  • Maria Vadala
    Department of Experimental Medicine and Clinical Neuroscience, Ophthalmology Section, University of Palermo, Palermo, Italy
  • Ramya Sachidanandam
    Department of Optometry, Medical Research Foundation, Chennai, India
  • Tharigopala Arokiasamy
    SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India
  • Jose Sahel
    Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision; CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC; Fondation Ophtalmologique Adolphe de Rothschild; Académie des Sciences–Institut de France, Paris, France
    University College of London, Institute of Ophthalmology, London, United Kingdom
  • Parveen Sen
    Department of Vitreo-Retinal Services, Medical Research Foundation, Chennai, India
  • Isabelle S Audo
    Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision; CHNO des Quinze-Vingts, DHU Sight Restore, INSERM- DHOS CIC, Paris, France
    University College of London, Institute of Ophthalmology, London, United Kingdom
  • Nagasamy Soumittra
    SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India
  • Christina Zeitz
    Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France
  • Footnotes
    Commercial Relationships   Marion Neuille, None; Sivasankar Malaichamy, None; Maria Vadala, None; Ramya Sachidanandam, None; Tharigopala Arokiasamy, None; Jose Sahel, None; Parveen Sen, None; Isabelle Audo, None; Nagasamy Soumittra, None; Christina Zeitz, None
  • Footnotes
    Support  Fondation Voir et Entendre (CZ), Prix Dalloz for “la recherche en ophtalmologie” (CZ), Fondation pour la Recherche Médicale (FRM DVS20131228918) in partnership with Fondation Roland Bailly (CZ), Fédération des Aveugles et Amblyopes de France (MN), Ville de Paris and Région Ile de France, LABEX LIFESENSES [reference ANR-10-LABX-65] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir programme [ANR-11-IDEX-0004-0], Foundation Fighting Blindness center grant [C-CMM-0907-0428-INSERM04] and the Indian Council of Medical Research and INSERM (France), an Indo-French collaborative program (No: 53/1/Indo-Foreign/Oph/10-NCD-II)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 658. doi:
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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)

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Abstract

Purpose : 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.

Methods : 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.

Results : 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.

Conclusions : 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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