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Journal of Medical Genetics Jun 2017Variation in the gene is causal for, or associated with, a wide range of phenotypes from early onset Mendelian retinal dystrophies to late-onset complex disorders such...
BACKGROUND
Variation in the gene is causal for, or associated with, a wide range of phenotypes from early onset Mendelian retinal dystrophies to late-onset complex disorders such as age-related macular degeneration (AMD). Despite substantial progress in determining the causal genetic variation, even complete sequencing of the entire open reading frame and splice sites of identifies biallelic mutations in only 60%-70% of cases; 20%-25% remain with one mutation and no mutations are found in 10%-15% of cases with clinically confirmed ABCA4 disease. This study was designed to identify missing causal variants specifically in monoallelic cases of ABCA4 disease.
METHODS
Direct sequencing and analysis were performed in a large familial ABCA4 disease cohort of predominately European descent (n=643). Patient phenotypes were assessed from clinical and retinal imaging data.
RESULTS
We determined that a hypomorphic variant c.5603A>T (p.Asn1868Ile), previously considered benign due to high minor allele frequency (MAF) (~7%) in the general population, accounts for 10% of the disease, >50% of the missing causal alleles in monoallelic cases, ~80% of late-onset cases and distinguishes ABCA4 disease from AMD. It results in a distinct clinical phenotype characterised by late-onset of symptoms (4th decade) and foveal sparing (85%). Intragenic modifying effects involving this variant and another, c.2588G>C (p.Gly863Ala) allele, were also identified.
CONCLUSIONS
These findings substantiate the causality of frequent missense variants and their phenotypic outcomes as a significant contribution to ABCA4 disease, particularly the late-onset phenotype, and its clinical variation. They also suggest a significant revision of diagnostic screening and assessment of variation in aetiology of retinal diseases.
Topics: ATP-Binding Cassette Transporters; Adult; Alleles; Cohort Studies; Gene Frequency; Genetic Variation; Humans; Macular Degeneration; Mutation; Phenotype; Retinal Dystrophies
PubMed: 28446513
DOI: 10.1136/jmedgenet-2017-104540 -
Molecular Therapy : the Journal of the... Feb 2021Until recently, there was no approved treatment for a retinal degenerative disease. Subretinal injection of a recombinant adeno-associated virus (AAV) delivering the... (Review)
Review
Until recently, there was no approved treatment for a retinal degenerative disease. Subretinal injection of a recombinant adeno-associated virus (AAV) delivering the normal copy of the human RPE65 cDNA led to reversal of blindness first in animal models and then in humans. This led to the first US Food and Drug Administration (FDA)-approved gene therapy product for a genetic disease, voretigene neparvovec-rzyl (Luxturna). Luxturna was then approved by the European Medicines Association and is now available in the US through Spark Therapeutics and worldwide through Novartis. Not only has treatment with Luxturna changed the lives of people previously destined to live a life of blindness, but it has fueled interest in developing additional gene therapy reagents targeting numerous other genetic forms of inherited retinal disease. This review describes many of the considerations for administration of Luxturna and describes how lessons from experience with Luxturna could lead to additional gene-based treatments of blindness.
Topics: Dependovirus; Drug Approval; Drug Development; Genetic Therapy; Genetic Vectors; Humans; Retinal Dystrophies; United States; United States Food and Drug Administration; cis-trans-Isomerases
PubMed: 33278565
DOI: 10.1016/j.ymthe.2020.11.029 -
Ophthalmology. Retina Oct 2023To analyze the clinical characteristics, natural history, and genetics of CERKL-associated retinal dystrophy in the largest series to date.
PURPOSE
To analyze the clinical characteristics, natural history, and genetics of CERKL-associated retinal dystrophy in the largest series to date.
DESIGN
Multicenter retrospective cohort study.
SUBJECTS
Forty-seven patients (37 families) with likely disease-causing CERKL variants.
METHODS
Review of clinical notes, ophthalmic images, and molecular diagnosis from 2 international centers.
MAIN OUTCOME MEASURES
Visual function, retinal imaging, and characteristics were evaluated and correlated.
RESULTS
The mean age at the first visit was 29.6 ± 13.9 years, and the mean follow-up time was 9.1 ± 7.4 years. The most frequent initial symptom was central vision loss (40%), and the most common retinal feature was well-demarcated areas of macular atrophy (57%). Seventy-seven percent of the participants had double-null genotypes, and 64% had electrophysiological assessment. Among the latter, 53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern. Patients without double-null genotypes tended to have fewer pigment deposits and included a higher proportion of older patients with a relatively mild electrophysiological phenotype. Longitudinal analysis showed that over half of the cohort lost 15 ETDRS letters or more in ≥ 1 eye during the first 5 years of follow-up.
CONCLUSIONS
The phenotype of CERKL-retinal dystrophy is broad, encompassing isolated macular disease to severe retina-wide involvement, with a range of functional phenotypes, generally not fitting in the rod-cone/cone-rod dichotomy. Disease onset is often earlier, with more severe retinal degenerative changes and photoreceptor dysfunction, in nullizygous cases.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Retrospective Studies; Retina; Photoreceptor Cells, Vertebrate; Retinal Dystrophies; Phenotype
PubMed: 37331655
DOI: 10.1016/j.oret.2023.06.007 -
Biomolecules Feb 2023Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and... (Review)
Review
Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The genes associated with these diseases, when mutated, produce altered protein products that have downstream effects in pathways critical to vision, including phototransduction, the visual cycle, photoreceptor development, cellular respiration, and retinal homeostasis. The aim of this manuscript is to provide a comprehensive review of the underlying molecular mechanisms of pathogenesis of IRDs by delving into many of the genes associated with IRD development, their protein products, and the pathways interrupted by genetic mutation.
Topics: Humans; Retinal Dystrophies; Retina; Retinal Cone Photoreceptor Cells; Mutation; Vision, Ocular
PubMed: 36830640
DOI: 10.3390/biom13020271 -
Genes Nov 2021() is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the...
() is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with -associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40's; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.
Topics: Adult; Aged; Female; Gene Frequency; Humans; Japan; Male; Middle Aged; Mutation, Missense; Peripherins; Phenotype; Retinal Dystrophies
PubMed: 34828423
DOI: 10.3390/genes12111817 -
Genes May 2022The retinal dystrophy phenotype associated with retinopathy is clinically heterogenous. In this study, we describe the clinical and molecular findings of a retinal...
The retinal dystrophy phenotype associated with retinopathy is clinically heterogenous. In this study, we describe the clinical and molecular findings of a retinal dystrophy cohort (10 patients) attributed to autosomal recessive and report novel variants in populations not previously identified with -related retinopathy. Seven patients had evaluations covering at least a three-year period. The mean age of individuals at first symptoms was 36 ± 8.5 years (range 5-45 years). Visual acuity at the last visit ranged from 20/20 to 20/2000 (mean LogMAR 0.8 or 20/125). Three clinical subgroups were identified: rod-cone dystrophy (RCD), cone-rod dystrophy (CRD), and maculopathy. Extinguished scotopic electroretinography responses were noted in the RCD patients. Macular involvement was noted in all patients and documented on color fundus photography, fundus autofluorescence, and optical coherence tomography. Notable asymmetry of the degree of macular atrophy was present in two patients. The possible association between variants and clinical findings was predicted using molecular modeling.
Topics: Cadherin Related Proteins; Cadherins; Cone-Rod Dystrophies; Electroretinography; Humans; Mutation; Nerve Tissue Proteins; Phenotype; Retinal Dystrophies
PubMed: 35627310
DOI: 10.3390/genes13050925 -
International Journal of Molecular... Sep 2023The gene plays a role in retinal development and its maintenance. When disrupted, it gives a range of phenotypes such as early-onset severe retinal dystrophy/Leber...
The gene plays a role in retinal development and its maintenance. When disrupted, it gives a range of phenotypes such as early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone-rod dystrophy (CORD) and macular dystrophy (MD). Studies in retinopathies have shown thickening and coarse lamination of retinal layers resembling an immature retina. Its role in foveal development has not yet been described; however, this retrospective study is the first to report foveal hypoplasia (FH) presence in a -related retinopathy cohort. Patients with pathogenic biallelic variants from Moorfields Eye Hospital, London, UK, were collected. Demographic, clinical data and SD-OCT analyses with FH structural grading were performed. A total of 15 (48%) patients had EOSRD/LCA, 11 (35%) MD, 3 (9%) CORD and 2 (6%) RP. FH was observed in 20 (65%; CI: 0.47-0.79) patients, all of whom were grade 1. A significant difference in BCVA between patients with FH and without was found ( = 0.014). BCVA continued to worsen over time in both groups ( < 0.001), irrespective of FH. This study reports FH in a cohort, supporting the role of in foveal development. FH was associated with poorer BCVA and abnormal retinal morphology. Nonetheless, its presence did not alter the disease progression.
Topics: Humans; Retrospective Studies; Retina; Retinal Dystrophies; Macular Degeneration; Retinitis Pigmentosa; Leber Congenital Amaurosis; Cone-Rod Dystrophies; Eye Abnormalities; Eye Proteins; Membrane Proteins; Nerve Tissue Proteins
PubMed: 37762234
DOI: 10.3390/ijms241813932 -
American Journal of Ophthalmology Feb 2023To analyze the clinical characteristics, natural history, and genetics of CRB1-associated retinal dystrophies.
PURPOSE
To analyze the clinical characteristics, natural history, and genetics of CRB1-associated retinal dystrophies.
DESIGN
Multicenter international retrospective cohort study.
METHODS
Review of clinical notes, ophthalmic images, and genetic testing results of 104 patients (91 probands) with disease-causing CRB1 variants. Macular optical coherence tomography (OCT) parameters, visual function, fundus characteristics, and associations between variables were the main outcome measures.
RESULTS
The mean age of the cohort at the first visit was 19.8 ± 16.1 (median 15) years, with a mean follow-up of 9.6 ± 10 years. Based on history, imaging, and clinical examination, 26 individuals were diagnosed with retinitis pigmentosa (RP; 25%), 54 with early-onset severe retinal dystrophy / Leber congenital amaurosis (EOSRD/LCA; 52%), and 24 with macular dystrophy (MD; 23%). Severe visual impairment was most frequent after 40 years of age for patients with RP and after 20 years of age for EOSRD/LCA. Longitudinal analysis revealed a significant difference between baseline and follow-up best-corrected visual acuity in the 3 subcohorts. Macular thickness decreased in most patients with EOSRD/LCA and MD, whereas the majority of patients with RP had increased perifoveal thickness.
CONCLUSIONS
A subset of individuals with CRB1 variants present with mild, adult-onset RP. EOSRD/LCA phenotype was significantly associated with null variants, and 167_169 deletion was exclusively present in the MD cohort. The poor OCT lamination may have a degenerative component, as well as being congenital. Disease symmetry and reasonable window for intervention highlight CRB1 retinal dystrophies as a promising target for trials of novel therapeutics.
Topics: Humans; Genotype; Retrospective Studies; Mutation; Retinal Dystrophies; Retinitis Pigmentosa; Phenotype; Eye Proteins; Membrane Proteins; Nerve Tissue Proteins
PubMed: 36099972
DOI: 10.1016/j.ajo.2022.09.002 -
Asia-Pacific Journal of Ophthalmology... 2020: Retinal dystrophies (RDs) comprise relatively rare but devastating causes of progressive vision loss. They represent a spectrum of diseases with marked genetic and... (Review)
Review
: Retinal dystrophies (RDs) comprise relatively rare but devastating causes of progressive vision loss. They represent a spectrum of diseases with marked genetic and clinical heterogeneity. Mutations in the same gene may lead to different diagnoses, for example, retinitis pigmentosa or cone dystrophy. Conversely, mutations in different genes may lead to the same phenotype. The age at symptom onset, and the rate and characteristics of peripheral and central vision decline, may vary widely per disease group and even within families. For most RD cases, no effective treatment is currently available. However, preclinical studies and phase I/II/III gene therapy trials are ongoing for several RD subtypes, and recently the first retinal gene therapy has been approved by the US Food and Drug Administration for RPE65-associated RDs: voretigene neparvovec-rzyl (Luxturna). With the rapid advances in gene therapy studies, insight into the phenotypic spectrum and long-term disease course is crucial information for several RD types. The vast clinical heterogeneity presents another important challenge in the evaluation of potential efficacy in future treatment trials, and in establishing treatment candidacy criteria. This perspective describes these challenges, providing detailed clinical descriptions of several forms of RD that are caused by genes of interest for ongoing and future gene or cell-based therapy trials. Several ongoing and future treatment options will be described.
Topics: DNA; DNA Mutational Analysis; Genetic Therapy; Genetic Vectors; Humans; Mutation; Retinal Dystrophies; Treatment Outcome
PubMed: 32511120
DOI: 10.1097/APO.0000000000000290 -
The British Journal of Ophthalmology Sep 2017Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by... (Review)
Review
Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70-80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention.
Topics: Animals; Drug Therapy; Eye Diseases, Hereditary; Eye Proteins; Genetic Therapy; Genotype; Humans; Leber Congenital Amaurosis; Molecular Biology; Mutation; Retinal Dystrophies
PubMed: 28689169
DOI: 10.1136/bjophthalmol-2016-309975