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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 
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.

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Soumis le : lundi 25 mai 2020 - 04:41:56
Dernière modification le : vendredi 5 août 2022 - 10:39:42

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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, Wiley, 2019, 40 (6), pp.765-787. ⟨10.1002/humu.23735⟩. ⟨hal-02616948⟩



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