title: Leber congenital amaurosis associated with AIPL1: challenges in ascribing disease causation, clinical findings, and implications for gene therapy.
abstract: Leber Congenital Amaurosis (LCA) and Early Childhood Onset Severe Retinal Dystrophy are clinically and genetically heterogeneous retinal disorders characterised by visual impairment and nystagmus from birth or early infancy. We investigated the prevalence of sequence variants in AIPL1 in a large cohort of such patients (n = 392) and probed the likelihood of disease-causation of the identified variants, subsequently undertaking a detailed assessment of the phenotype of patients with disease-causing mutations. Genomic DNA samples were screened for known variants in the AIPL1 gene using a microarray LCA chip, with 153 of these cases then being directly sequenced. The assessment of disease-causation of identified AIPL1 variants included segregation testing, assessing evolutionary conservation and in silico predictions of pathogenicity. The chip identified AIPL1 variants in 12 patients. Sequencing of AIPL1 in 153 patients and 96 controls found a total of 46 variants, with 29 being novel. In silico analysis suggested that only 6 of these variants are likely to be disease-causing, indicating a previously unrecognized high degree of polymorphism. Seven patients were identified with biallelic changes in AIPL1 likely to be disease-causing. In the youngest subject, electroretinography revealed reduced cone photoreceptor function, but rod responses were within normal limits, with no measurable ERG in other patients. An increasing degree and extent of peripheral retinal pigmentation and degree of maculopathy was noted with increasing age in our series. AIPL1 is significantly polymorphic in both controls and patients, thereby complicating the establishment of disease-causation of identified variants. Despite the associated phenotype being characterised by early-onset severe visual loss in our patient series, there was some evidence of a degree of retinal structural and functional preservation, which was most marked in the youngest patient in our cohort. This data suggests that there are patients who have a reasonable window of opportunity for gene therapy in childhood.
authors.affiliation: Department of Genetics, Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Mei Hong
authors.initials: MH
authors.lastname: Tan
authors.forename: Donna S
authors.initials: DS
authors.lastname: Mackay
authors.forename: Jill
authors.initials: J
authors.lastname: Cowing
authors.forename: Hoai Viet
authors.initials: HV
authors.lastname: Tran
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Wright
authors.forename: Arundhati
authors.initials: A
authors.lastname: Dev-Borman
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henderson
authors.forename: Phillip
authors.initials: P
authors.lastname: Moradi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Russell-Eggitt
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacLaren
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Thompson
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005136:Eye Proteins / Q000235:genetics*; D005451:Fluorescein Angiography; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D009154:Mutation; D022821:RNA Splice Sites; D055815:Young Adult
chemical_list: C403625:AIPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D005136:Eye Proteins; D022821:RNA Splice Sites