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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.
Hum Mutat 2013; 34(11):1537-1546HM

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.

Authors+Show Affiliations

Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK. Moorfields Eye Hospital, London, UK.Ophthalmology, Peking Union Med College Hosp, Beijing, China.The Rotterdam Eye Hospital, Rotterdam, The Netherlands.Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear, Boston, Massachusetts, USA.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan.Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan.McGill Ocular Genetics Laboratory, Departments of Pediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.McGill Ocular Genetics Laboratory, Departments of Pediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands. Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands. Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan. Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK. Moorfields Eye Hospital, London, UK.Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK. Moorfields Eye Hospital, London, UK.McGill Ocular Genetics Laboratory, Departments of Pediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.No affiliation info availableDepartment of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23946133

Citation

Mackay, Donna S., et al. "Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype-phenotype Correlations." Human Mutation, vol. 34, no. 11, 2013, pp. 1537-1546.
Mackay DS, Borman AD, Sui R, et al. Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations. Hum Mutat. 2013;34(11):1537-1546.
Mackay, D. S., Borman, A. D., Sui, R., van den Born, L. I., Berson, E. L., Ocaka, L. A., ... Wissinger, B. (2013). Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations. Human Mutation, 34(11), pp. 1537-1546. doi:10.1002/humu.22398.
Mackay DS, et al. Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype-phenotype Correlations. Hum Mutat. 2013;34(11):1537-1546. PubMed PMID: 23946133.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations. AU - Mackay,Donna S, AU - Borman,Arundhati Dev, AU - Sui,Ruifang, AU - van den Born,L Ingeborgh, AU - Berson,Eliot L, AU - Ocaka,Louise A, AU - Davidson,Alice E, AU - Heckenlively,John R, AU - Branham,Kari, AU - Ren,Huanan, AU - Lopez,Irma, AU - Maria,Maleeha, AU - Azam,Maleeha, AU - Henkes,Arjen, AU - Blokland,Ellen, AU - Qamar,Raheel, AU - Webster,Andrew R, AU - Cremers,Frans P M, AU - Moore,Anthony T, AU - Koenekoop,Robert K, AU - ,, AU - Andreasson,Sten, AU - de Baere,Elfride, AU - Bennett,Jean, AU - Chader,Gerald J, AU - Berger,Wolfgang, AU - Golovleva,Irina, AU - Greenberg,Jacquie, AU - den Hollander,Anneke I, AU - Klaver,Caroline C W, AU - Klevering,B Jeroen, AU - Lorenz,Birgit, AU - Preising,Markus N, AU - Ramsear,Raj, AU - Roberts,Lisa, AU - Roepman,Ronald, AU - Rohrschneider,Klaus, AU - Wissinger,Bernd, Y1 - 2013/09/17/ PY - 2013/03/29/received PY - 2013/08/05/accepted PY - 2013/8/16/entrez PY - 2013/8/16/pubmed PY - 2014/5/9/medline KW - LCA KW - LCA5 KW - RP KW - blindness KW - lebercilin KW - retinal dystrophy SP - 1537 EP - 1546 JF - Human mutation JO - Hum. Mutat. VL - 34 IS - 11 N2 - 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. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/23946133/Screening_of_a_large_cohort_of_leber_congenital_amaurosis_and_retinitis_pigmentosa_patients_identifies_novel_LCA5_mutations_and_new_genotype_phenotype_correlations_ L2 - https://doi.org/10.1002/humu.22398 DB - PRIME DP - Unbound Medicine ER -