Article dans une revue

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

Christina Zeitz ¹ Christelle Michiels ¹ Marion Neuillé ² Christoph Friedburg ³ Christel Condroyer ¹ Fiona Boyard ¹ Aline Antonio ¹ Nassima Bouzidi ¹ Diana Milicevic Robin Veaux Aurore Tourville Axelle Zoumba Imene Seneina Marine Foussard ¹ Camille Andrieu ⁴ Markus Preising ³ Steven Blanchard ⁵ Jean-Paul Saraiva ⁶ Lilia Mesrob ⁷ Edith Le Floch ⁸ Claire Jubin ⁹ Vincent Meyer ¹⁰ Hélène Blanché ¹¹ Anne Boland ^{12, 10} Jean-François Deleuze ¹² Dror Sharon ¹³ Isabelle Drumare ¹⁴ Sabine Defoort-Dhellemmes ¹⁴ Elfride de Baere ¹⁵ Bart Leroy ^{16, 17, 18} Xavier Zanlonghi ¹⁹ Ingele Casteels ²⁰ Thomy de Ravel ²¹ Irina Balikova ²² Rob Koenekoop Fanny Laffargue ²³ Rebecca Mclean Irene Gottlob Dominique Bonneau ²⁴ Daniel Schorderet Francis Munier Martin Mckibbin Katrina Prescott ²⁵ Valérie Pelletier ²⁶ Hélène Dollfus ^{27, 28} Yaumara Perdomo-Trujillo Celine Faure ²⁹ Charlotte Reiff Bernd Wissinger ³⁰ Isabelle Meunier ³¹ Susanne Kohl ³⁰ Eyal Banin ¹³ Eberhart Zrenner ³² Bernhard Jurklies ³³ Birgit Lorenz ³ José-Alain Sahel ^{4, 34, 1, 35} Isabelle Audo ^{1, 4, 36}

1 Institut de la Vision

2 Institut de la Vision

3 JLU - Justus-Liebig-Universität Gießen = Justus Liebig University

4 CHNO - Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts

5 IntegraGen SA

6 Génopole [Evry]

7 U894 / UMS 1266 - Institut de psychiatrie et neurosciences

8 CNRGH - Centre National de Recherche en Génomique Humaine

9 GENOSCOPE - Genoscope - Centre national de séquençage [Evry]

10 JACOB - Institut de Biologie François JACOB

11 Fondation Jean Dausset CEPH

12 CNG - Centre National de Génotypage

13 Hadassah Hebrew University Medical Center [Jerusalem]

14 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]

15 Center for Medical Genetics [Ghent]

16 Ghent University Hospital

17 UGENT - Universiteit Gent = Ghent University [Belgium]

18 CHOP - Children’s Hospital of Philadelphia

19 Service Exploration Fonctionnelle de la Vision

20 Department of Ophthalmology

21 University Hospitals Leuven [Leuven]

22 Centre for Human Genetics

23 Service de Génétique Médicale [CHU Clermont-Ferrand]

24 MITOVASC - Physiopathologie Cardiovasculaire et Mitochondriale

25 Department of Clnical Genetics, Chapel Allerton Hospital

26 CARGO - Centre de référence pour les affections ophtalmologiques héréditaires

27 LGM - Laboratoire de Génétique Médicale

28 Laboratoire de Génétique Médicale

29 UVHC - Université de Valenciennes et du Hainaut-Cambrésis

30 Centre for Ophthalmology - Institute for Ophthalmic Research [Tübingen, Germany]

31 INM - Institut des Neurosciences de Montpellier

32 Centre for Ophthalmology

33 Department of Ophthalmology [Essen, Germany]

34 Rothschild Ophthalmology Foundation Hospital [Paris]

35 Department of Ophthalmology [Pittsburgh, PA, États-Unis]

36 UCL - University College of London [London]

Abstract :

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.

Keywords : CACNA1F gene defect icCSNB intronic variants IRD minigene approach synonymous variants

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio]

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https://hal.univ-angers.fr/hal-02616948
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Soumis le : lundi 25 mai 2020 - 04:41:56
Dernière modification le : vendredi 5 août 2022 - 10:39:42