scholarly journals Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy

Genes ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 355 ◽  
Author(s):  
Fernanda Porto ◽  
Evan Jones ◽  
Justin Branch ◽  
Zachry Soens ◽  
Igor Maia ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Molecular Screening ◽  
Leber Congenital Amaurosis

Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy

2019 ◽  
Vol 104 (7) ◽  
pp. 932-937 ◽  
Author(s):  
Ke Xu ◽  
Yue Xie ◽  
Tengyang Sun ◽  
Xiaohui Zhang ◽  
Chunjie Chen ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Case Series ◽  
Clinical Findings ◽  
Chinese Patients ◽  
Pcr Analysis ◽  
Common Mutation ◽  
Essential Information ◽  
Leber Congenital Amaurosis ◽  
Targeted Next Generation Sequencing

BackgroundLeber congenital amaurosis (LCA) and early onset severe retinal dystrophy (EOSRD) are clinically and genetically heterogeneous inherited retinal disorders that cause severe visual impairment in children. The objective of this study was to describe the mutation profile and phenotypic characteristics in Chinese patients with LCA or EOSRD.MethodsRetrospective consecutive case series (2010–2017) study was performed in 148 probands (91 with LCA and 57 with EOSRD). All patients underwent ophthalmic evaluation. Mutations were revealed using targeted next-generation sequencing, followed by Sanger DNA-sequencing and real-time quantitative PCR analysis.ResultsWe identified two diseasing-causing mutations in 88 unrelated patients, heterozygous autosomal dominant mutations in 11 probands and X-linked hemizygous mutations in 11 patients, for an overall mutation detection rate of 74.3% (110/148). We detected 158 different disease-causing mutations involving 14 LCA genes, 16 retinitis pigmentosa or cone-rod dystrophy genes and 3 syndromic retinal dystrophy genes. Of these 158 mutations, 98 were novel. The most common mutation was p.Q141X of AIPL1, with a gene-specific allele frequency of 60%. The first five most frequently mutated genes were AIPL1 (11.0%), RPGRIP1 (8.8%) and CEP290, GUCY2D and RPE65 (each 7.7%) in the patients with LCA and RPGR (12.3%), CRB1 (10.5%), RPE65 (10.5%), RDH12 (7.0%) and RP2 (5.3%) in the patients with EOSRD.ConclusionsOur results revealed that the mutation spectrum of patients with LCA differs from that of the patients with EOSRD and established the configuration of the mutation frequencies for each LCA gene in Chinese patients, thereby providing essential information for future genetic counselling and gene therapy.

An Assessment of the Apex Microarray Technology in Genotyping Patients with Leber Congenital Amaurosis and Early-Onset Severe Retinal Dystrophy

2007 ◽  
Vol 48 (12) ◽  
pp. 5684 ◽  
Author(s):  
Robert H. Henderson ◽  
Naushin Waseem ◽  
Rowan Searle ◽  
Jacqueline van der Spuy ◽  
Isabelle Russell-Eggitt ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Microarray Technology ◽  
Leber Congenital Amaurosis

scholarly journals A high prevalence of biallelic RPE65 mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy

2019 ◽  
Vol 40 (2) ◽  
pp. 110-117
Author(s):  
W. Bailey Glen ◽  
M. Millicent W. Peterseim ◽  
Ramses Badilla ◽  
Iya Znoyko ◽  
Andre Bourg ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Costa Rican ◽  
Leber Congenital Amaurosis ◽  
High Prevalence

scholarly journals Pathogenicity Reclassification of RPE65 Missense Variants Related to Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy

Genes ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 24 ◽  
Author(s):  
Fabiana Motta ◽  
Renan Martin ◽  
Fernanda Porto ◽  
Elizabeth Wohler ◽  
Rosane Resende ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Early Onset ◽  
Retinal Dystrophy ◽  
Low Frequency ◽  
Sequencing Data ◽  
Leber Congenital Amaurosis ◽  
Missense Variants ◽  
Inherited Retinal Dystrophies ◽  
Inherited Retinal Dystrophy ◽  
Uncertain Significance

A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two RPE65 missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these RPE65 variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic RPE65 variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines.

scholarly journals Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

2021 ◽  
pp. bjophthalmol-2020-318483
Author(s):  
Malena Daich Varela ◽  
Thales Antonio Cabral de Guimaraes ◽  
Michalis Georgiou ◽  
Michel Michaelides
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Early Onset ◽  
Viral Vectors ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Dystrophy ◽  
European Medicines Agency ◽  
Current Management ◽  
Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. RPE65-related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11-cis-retinal and cell therapy’s aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation.

Longitudinal clinical course of three Japanese patients with Leber congenital amaurosis/early-onset retinal dystrophy with RDH12 mutation

2014 ◽  
Vol 128 (3) ◽  
pp. 219-228 ◽  
Author(s):  
Kazuki Kuniyoshi ◽  
Hiroyuki Sakuramoto ◽  
Kazutoshi Yoshitake ◽  
Kosuke Abe ◽  
Kazuho Ikeo ◽  
...  
Keyword(s):  
Early Onset ◽  
Clinical Course ◽  
Retinal Dystrophy ◽  
Japanese Patients ◽  
Leber Congenital Amaurosis
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