Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations.
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.
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Donna S
DS
Mackay
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.|Moorfields Eye Hospital, London, UK.
Arundhati Dev
AD
Borman
Ophthalmology, Peking Union Med College Hosp, Beijing, China.
Ruifang
R
Sui
The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
L Ingeborgh
LI
van den Born
Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear, Boston, Massachusetts, USA.
Eliot L
EL
Berson
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Louise A
LA
Ocaka
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Alice E
AE
Davidson
Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan.
John R
JR
Heckenlively
Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan.
Kari
K
Branham
McGill Ocular Genetics Laboratory, Departments of Pediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
Huanan
H
Ren
McGill Ocular Genetics Laboratory, Departments of Pediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
Irma
I
Lopez
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.
Maleeha
M
Maria
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.
Maleeha
M
Azam
Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
Arjen
A
Henkes
Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
Ellen
E
Blokland
Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.|Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.
Raheel
R
Qamar
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.|Moorfields Eye Hospital, London, UK.
Andrew R
AR
Webster
Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
Frans P M
FPM
Cremers
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.|Moorfields Eye Hospital, London, UK.
Anthony T
AT
Moore
McGill Ocular Genetics Laboratory, Departments of Pediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
Robert K
RK
Koenekoop
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Sten
S
Andreasson
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Elfride
E
de Baere
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Jean
J
Bennett
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Gerald J
GJ
Chader
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Wolfgang
W
Berger
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Irina
I
Golovleva
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Jacquie
J
Greenberg
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Anneke I
AI
den Hollander
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Caroline C W
CCW
Klaver
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
B Jeroen
BJ
Klevering
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Birgit
B
Lorenz
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Markus N
MN
Preising
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Raj
R
Ramsear
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Lisa
L
Roberts
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Ronald
R
Roepman
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Klaus
K
Rohrschneider
Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.
Bernd
B
Wissinger
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005451:Fluorescein Angiography; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D057130:Leber Congenital Amaurosis / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
D005136:Eye Proteins; C522405:LCA5 protein, human; D008869:Microtubule-Associated Proteins
LCA; LCA5; RP; blindness; lebercilin; retinal dystrophy