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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

(2019) HUMAN MUTATION. 40(6). p.765-787
Author
Organization
Abstract
Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in similar to 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, STATIONARY NIGHT BLINDNESS, MUTATION SPECTRUM, LARGE COHORT, PROBANDS, DYSTROPHY, GENOME, FAMILIES, COMPLEX, UNC80, ABCR

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MLA
Zeitz, Christina 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 40.6 (2019): 765–787. Print.
APA
Zeitz, Christina, Michiels, C., Neuillé, M., Friedburg, C., Condroyer, C., Boyard, F., Antonio, A., et al. (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. HUMAN MUTATION, 40(6), 765–787.
Chicago author-date
Zeitz, Christina, Christelle Michiels, Marion Neuillé, Christoph Friedburg, Christel Condroyer, Fiona Boyard, Aline Antonio, et al. 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.” Human Mutation 40 (6): 765–787.
Chicago author-date (all authors)
Zeitz, Christina, 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 Floch, Claire Jubin, Vincent Meyer, Helene Blanché, Anne Boland, Jean-François Deleuze, Dror Sharon, Isabelle Drumare, Sabine Defoort-Dhellemmes, Elfride De Baere, Bart Leroy, Xavier Zanlonghi, Ingele Casteels, Thorny J de Ravel, Irina Balikova, Rob K Koenekoop, Fanny Laffargue, Rebecca McLean, Irene Gottlob, Dominique Bonneau, Daniel F Schordert, Francis L Munier, Martin McKibbin, Katrina Prescott, Valerie Pelletier, Helene Dollfuss, Yaumara Perdomo-Trujillo, Celine Faure, Charlotte Reiff, Bernd Wissinger, Isabelle Meunier, Susanne Kohl, Eyal Banin, Eberhart Zrenner, Bernhard Jurklies, Birgit Lorenz, Jose-Alain Sahel, and Isabelle Audo. 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.” Human Mutation 40 (6): 765–787.
Vancouver
1.
Zeitz C, Michiels C, Neuillé M, Friedburg C, Condroyer C, Boyard F, 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):765–87.
IEEE
[1]
C. Zeitz 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, vol. 40, no. 6, pp. 765–787, 2019.
@article{8608131,
  abstract     = {{Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in similar to 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.}},
  author       = {{Zeitz, Christina and Michiels, Christelle and Neuillé, Marion and Friedburg, Christoph and Condroyer, Christel and Boyard, Fiona and Antonio, Aline and Bouzidi, Nassima and Milicevic, Diana and Veaux, Robin and Tourville, Aurore and Zoumba, Axelle and Seneina, Imene and Foussard, Marine and Andrieu, Camille and Preising, Markus N and Blanchard, Steven and Saraiva, Jean-Paul and Mesrob, Lilia and Le Floch, Edith and Jubin, Claire and Meyer, Vincent and Blanché, Helene and Boland, Anne and Deleuze, Jean-François and Sharon, Dror and Drumare, Isabelle and Defoort-Dhellemmes, Sabine and De Baere, Elfride and Leroy, Bart and Zanlonghi, Xavier and Casteels, Ingele and de Ravel, Thorny J and Balikova, Irina and Koenekoop, Rob K and Laffargue, Fanny and McLean, Rebecca and Gottlob, Irene and Bonneau, Dominique and Schordert, Daniel F and Munier, Francis L and McKibbin, Martin and Prescott, Katrina and Pelletier, Valerie and Dollfuss, Helene and Perdomo-Trujillo, Yaumara and Faure, Celine and Reiff, Charlotte and Wissinger, Bernd and Meunier, Isabelle and Kohl, Susanne and Banin, Eyal and Zrenner, Eberhart and Jurklies, Bernhard and Lorenz, Birgit and Sahel, Jose-Alain and Audo, Isabelle}},
  issn         = {{1059-7794}},
  journal      = {{HUMAN MUTATION}},
  keywords     = {{CACNA1F,gene defect,icCSNB,intronic variants,IRD,minigene approach,synonymous variants,STATIONARY NIGHT BLINDNESS,MUTATION SPECTRUM,LARGE COHORT,PROBANDS,DYSTROPHY,GENOME,FAMILIES,COMPLEX,UNC80,ABCR}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{765--787}},
  title        = {{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}},
  url          = {{http://dx.doi.org/10.1002/humu.23735}},
  volume       = {{40}},
  year         = {{2019}},
}

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