Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Human Mutation Année : 2019

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders

1 Institut de la Vision
2 JLU - Justus-Liebig-Universität Gießen = Justus Liebig University
3 CHNO - Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts
4 IntegraGen SA
5 Génopole [Evry]
6 U894 - Centre de Psychiatrie et Neurosciences
7 CNRGH - Centre National de Recherche en Génomique Humaine
8 GENOSCOPE - Genoscope - Centre national de séquençage [Evry]
9 JACOB - Institut de Biologie François JACOB
10 Fondation Jean Dausset CEPH
11 CNG - Centre National de Génotypage
12 Hadassah Hebrew University Medical Center [Jerusalem]
13 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
14 Center for Medical Genetics [Ghent]
15 Ghent University Hospital
16 UGENT - Universiteit Gent = Ghent University
17 CHOP - Children’s Hospital of Philadelphia
18 Service Exploration Fonctionnelle de la Vision
19 Department of Ophthalmology
20 University Hospitals Leuven [Leuven]
21 Centre for Human Genetics
22 Service de Génétique Médicale [CHU Clermont-Ferrand]
23 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
24 Department of Clnical Genetics, Chapel Allerton Hospital
25 CARGO - Centre de référence pour les affections ophtalmologiques héréditaires
26 LGM - Laboratoire de Génétique Médicale
27 Laboratoire de Génétique Médicale
28 UVHC - Université de Valenciennes et du Hainaut-Cambrésis
29 Centre for Ophthalmology - Institute for Ophthalmic Research [Tübingen, Germany]
30 INM - Institut des Neurosciences de Montpellier
31 Centre for Ophthalmology
32 Department of Ophthalmology [Essen, Germany]
33 Fondation Ophtalmologique Adolphe de Rothschild [Paris]
34 Department of Ophthalmology [Pittsburgh, PA, États-Unis]
35 UCL - University College of London [London]
Christina Zeitz
Diana Milicevic
  • Fonction : Auteur
Robin Veaux
  • Fonction : Auteur
Aurore Tourville
  • Fonction : Auteur
Axelle Zoumba
  • Fonction : Auteur
Imene Seneina
  • Fonction : Auteur
Steven Blanchard
  • Fonction : Auteur
Hélène Blanché
Jean-François Deleuze
Rob Koenekoop
  • Fonction : Auteur
Rebecca Mclean
  • Fonction : Auteur
Irene Gottlob
  • Fonction : Auteur
Daniel Schorderet
  • Fonction : Auteur
Francis Munier
  • Fonction : Auteur
  • PersonId : 1228709
Martin Mckibbin
  • Fonction : Auteur
Yaumara Perdomo-Trujillo
  • Fonction : Auteur
Charlotte Reiff
  • Fonction : Auteur
Eberhart Zrenner

Résumé

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.

Dates et versions

hal-02616948 , version 1 (25-05-2020)

Identifiants

Citer

Christina Zeitz, Christelle Michiels, Marion Neuillé, Christoph Friedburg, Christel Condroyer, et al.. Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders. Human Mutation, 2019, 40 (6), pp.765-787. ⟨10.1002/humu.23735⟩. ⟨hal-02616948⟩
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