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, Christelle Michiels, Marion Neuillé, Christoph Friedburg, Christel Condroyer, Fiona Boyard, Aline Antonio, Nassima Bouzidi, Diana Milicevic, Robin Veaux, Aurore Tourville, Axelle Zoumba, Imene Seneina, Marine Foussard, Camille Andrieu, Markus N Preising, Steven Blanchard, Jean-Paul Saraiva, Lilia Mesrob, Edith Le FlochClaire Jubin, Vincent Meyer, Hélène Blanché, Anne Boland, Jean-François Deleuze, Dror Sharon, Isabelle Drumare, Sabine Defoort-Dhellemmes, Elfride De Baere, Bart P Leroy, Xavier Zanlonghi, Ingele Casteels, Thomy J de Ravel, Irina Balikova, Rob K Koenekoop, Fanny Laffargue, Rebecca McLean, Irene Gottlob, Dominique Bonneau, Daniel F Schorderet, Francis L Munier, Martin McKibbin, Katrina Prescott, Valerie Pelletier, Hélène Dollfus, Yaumara Perdomo-Trujillo, Céline Faure, Charlotte Reiff, Bernd Wissinger, Isabelle Meunier, Susanne Kohl, Eyal Banin, Eberhart Zrenner, Bernhard Jurklies, Birgit Lorenz, José-Alain Sahel, Isabelle Audo

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)765-787
Number of pages23
JournalHuman Mutation
Issue number6
Publication statusPublished - Jun 2019

Bibliographical note

© 2019 Wiley Periodicals, Inc.


  • Calcium Channels, L-Type/genetics
  • Eye Diseases, Hereditary/genetics
  • Genetic Diseases, X-Linked/genetics
  • Genetic Predisposition to Disease
  • Hemizygote
  • Humans
  • Introns
  • Male
  • Mutation
  • Myopia/genetics
  • Night Blindness/genetics
  • Pedigree
  • RNA Splicing
  • Sequence Analysis, DNA/methods
  • Silent Mutation


Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this