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Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype–Phenotype Correlations

Authors

  • Donna S. Mackay,

    1. Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK
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    • These authors contributed equally to this study.

  • Arundhati Dev Borman,

    1. Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK
    2. Moorfields Eye Hospital, London, UK
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    • These authors contributed equally to this study.

  • Ruifang Sui,

    1. Ophthalmology, Peking Union Medical College Hospital, Beijing, China
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  • L. Ingeborgh van den Born,

    1. The Rotterdam Eye Hospital, Rotterdam, The Netherlands
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  • Eliot L. Berson,

    1. Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear, Boston, Massachusetts
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  • Louise A. Ocaka,

    1. Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK
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  • Alice E. Davidson,

    1. Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK
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  • John R. Heckenlively,

    1. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan
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  • Kari Branham,

    1. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan
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  • Huanan Ren,

    1. McGill Ocular Genetics Laboratory, Departments of Pediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada
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  • Irma Lopez,

    1. McGill Ocular Genetics Laboratory, Departments of Pediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada
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  • Maleeha Maria,

    1. Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
    2. Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
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  • Maleeha Azam,

    1. Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
    2. Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
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  • Arjen Henkes,

    1. Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
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  • Ellen Blokland,

    1. Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
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  • [LCA5 Study Group (see Acknowledgments for Universities),

  • Sten Andreasson,

  • Elfride de Baere,

  • Jean Bennett,

  • Gerald J. Chader,

  • Wolfgang Berger,

  • Irina Golovleva,

  • Jacquie Greenberg,

  • Anneke I. den Hollander,

  • Caroline C.W. Klaver,

  • B. Jeroen Klevering,

  • Birgit Lorenz,

  • Markus N. Preising,

  • Raj Ramesar,

  • Lisa Roberts,

  • Ronald Roepman,

  • Klaus Rohrschneider,

  • Bernd Wissinger],

  • Raheel Qamar,

    1. Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
    2. Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan
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  • Andrew R. Webster,

    1. Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK
    2. Moorfields Eye Hospital, London, UK
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  • Frans P.M. Cremers,

    1. Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
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    • These senior authors contributed equally to this study.

  • Anthony T. Moore,

    1. Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK
    2. Moorfields Eye Hospital, London, UK
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    • These senior authors contributed equally to this study.

  • Robert K. Koenekoop

    Corresponding author
    1. McGill Ocular Genetics Laboratory, Departments of Pediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada
    • Correspondence to: Robert K. Koenekoop, McGill University Health Centre, McGill Ocular Genetics Centre, 2300 Tupper, Montreal, Quebec H3H 1P3, Canada. E-mail: robkoenekoop@hotmail.com

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    • These senior authors contributed equally to this study.

Errata

This article is corrected by:

  1. Errata: Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype–Phenotype Correlations Volume 35, Issue 1, 150, Article first published online: 30 October 2013

  • Contract grant sponsor: Fight for Sight (A.R.W., A.T.M.), National Institute for Health Research UK- Moorfields Eye Hospital Biomedical Research Centre (A.R.W., A.T.M.), Foundation Fighting Blindness-USA (A.R.W., A.T.M.), Ulvercroft Foundation (A.R.W., A.T.M.), Foundation for Retinal Research (F.P.M.C., R.K.K., A.I.d.H., J.B., R.R.), Foundation Fighting Blindness-Canada (R.K.K.), CIHR (R.K.K.), NIH (R.K.K.), Reseau Vision (R.K.K.), FRSQ (R.K.K.), Retina South Africa (J.G., R.R.).

  • Communicated by Daniel F. Schorderet

  • [This article was originally published online on 17 September 2013 and appeared in the issue (vol. 34, iss. 11) on 9 October 2013. Subsequently, an error in an author's name was identified and corrected on 15 October 2013.]

ABSTRACT

This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.

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