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Hum Mutat. 2019 Mar 2. doi: 10.1002/humu.23735. [Epub ahead of print]

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.

Author information

1
INSERM, CNRS, Institut de la Vision, Sorbonne Université, Paris, France.
2
Department of Ophthalmology, Justus-Liebig-University Giessen, Germany.
3
CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DGOS CIC 1423, Paris, France.
4
IntegraGen SA, Genopole Campus, Evry, France.
5
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France.
6
INSERM, Sorbonne Université, Paris, France.
7
Fondation Jean Dausset-CEPH (Centre d'Etude du Polymorphisme Humain), Paris, France.
8
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
9
Service d'Exploration de la Vision et Neuro-ophtalmologie, CHRU de Lille, Lille, France.
10
Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
11
Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
12
Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
13
Clinique Jules Verne, Centre de Compétence Maladies Rares, Nantes, France.
14
Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium.
15
Centre for Human Genetics, University Hospitals Leuven, Belgium.
16
Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
17
Departments of Ophthalmology, Human Genetics, and Pediatric Surgery, Montreal Children's Hospital, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
18
Service de Génétique, CHU Clermont-Ferrand, France.
19
Department of Neuroscience, Psychology and Behaviour, Ulverscroft Eye Unit, University of Leicester, Leicester, United Kingdom.
20
Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
21
Mitovasc, UMR CNRS 6015-INSERM 1083, Université d'Angers, France.
22
Department of Ophthalmology, Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.
23
IRO-Institute for Research in Ophthalmology, Sion, Switzerland.
24
Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
25
Department of Ophthalmology, St. James's University Hospital, Leeds, United Kingdom.
26
Department of Clinical Genetics, Leeds, United Kingdom.
27
Centre de référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Hôpital Civil, Strasbourg, France.
28
Service de Génétique Médicale, Hôpital de Hautepierre, Strasbourg, France.
29
Laboratoire de Génétique Médicale, INSERM U1112, Strasbourg, France.
30
Hôpital Privé Saint Martin, Ramsay Générale de Santé, Caen, France.
31
Medical Practice Stadttheater, Freiburg, Germany.
32
Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
33
Centre de Référence Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, Montpellier, France.
34
Institute for Neurosciences of Montpellier, Montpellier University and INSERM U1051, Montpellier, France.
35
Werner Reichardt Center for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
36
Department of Ophthalmology, University of Essen, Essen, Germany.
37
Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.
38
Academie des Sciences, Institut de France, Paris, France.
39
Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
40
Institute of Ophthalmology, University College of London, London, United Kingdom.

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; IRD; gene defect; icCSNB; intronic variants; minigene approach; synonymous variants

PMID:
30825406
DOI:
10.1002/humu.23735

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