Analysis of genotype and phenotype of hereditary retinal diseases which are easily misdiagnosed as amblyopia / 中华实验眼科杂志

Objective@#To analysis the genotype and phenotype of hereditary retinal diseases (HRD) which are easily misdiagnosed as amblyopia.@*Methods@#A case-control study was designed.The patients with HRD who were misdiagnosed as amblyopia in Ningxia Eye Hospital from January to December, 2017 were recruited in this study.The clinical medical history and ophthalmic examinations of patients and their family members were recorded, and family maps were drawed.Peripheral venous blood (5 ml) from each patient and their family members was collected, and genomic DNA was extract.The target sequence capture sequencing technology was used to detect the genetic testing in serum of the patient, and the pathogenic mutation site was determined by Sanger sequencing and co-segregation verification.Genetic testing results with related ophthalmic examination were considered together to analyze the relationship between genotype and phenotype.This study followed the Declaration of Helsinki.Written informed consent was obtained from each subject or the guardian prior to entering study cohort.This study protocol was approved by Ethic Committee of People's Hospital of Ningxia Hui Autonomous Region Hospital (No.2016018).@*Results@#Twenty-two patients with HRD were enrolled in the study, including 10 Stargardt disease (STGD), 8 cases of cone dystrophy (COD) or cone and rod dystrophy (CRD), and 5 cases of familial exudative vitreoretinopathy(FEVER). Nine patients were detected to have pathogenic mutations, and the positive rate was 40.9%, of which 4 patients with STGD carried mutation gene, including ABCA4 and PROM1 genes; mutations in RPGR, PROM1 and GUCY2D genes were detected in 3 patients with COD or CRD; TSPAN12 gene mutation were detected in 2 patients with FEVER.Eleven mutation sites were detected, 4 of which were newly discovered mutation sites.All of the patients in 9 HRD families developed symptoms during adolescence.At the early stage of the disease, there was severe damage to the eyesight, but the fundus was normal or only slightly abnormal.As the disease progressed, the fundus changes were characteristic, and there were clinical phenotypic overlap between some diseases.All family genotypes and clinical phenotypes were co-separated.@*Conclusions@#The main pathogenic gene of STGD is ABCA4 gene, and PROM1 gene can also cause partial STGD; COD and CRD have similar clinical manifestations, and the pathogenic genes also cross each other, and the genetic pattern is diverse; FEVER caused by mutation of TSPAN12 gene is autosomal dominant, and the mutation type has missense mutation and frameshift mutation.HRDs lack typical early clinical signs, and genetic diagnosis can provide pre-symptomatic diagnosis.

Progress in research on LCA2 gene therapy / 国际眼科杂志(Guoji Yanke Zazhi)

@#Leber's congenital amaurosis(LCA)is a genetic eye disease that can cause blindness. Infants with LCA may have a severe low vision or loss of vision at the early stage. The LCA2 type of this disease is related to RPE65 mutation. According to previous studies, there is no effective treatment for genetic retinal diseases including LCA2. In recent years, with the advances in gene therapy technology, great progress in the treatment of genetic retinal diseases has been made, among which the most successful one is the gene therapy of LCA2. This paper briefly introduces the development of the gene therapy of LCA2, and reviews the correlation between age and injection type, dosage, injection method, measuring method as well as therapeutic effect and the stability of therapeutic effect in previous clinic trials, which provides reference and clinical treatment experience for the clinical application of the gene therapy of LCA2 in China.

Rapid identification of pathogenic mutations in sporadic hereditary retinal dystrophies using targeted next-generation sequencing / 中华实验眼科杂志

Background Hereditary retinal diseases (HRDs) are a group of retinal degenerative diseases with significant genetic and clinical heterogeneities.Traditional techniques are challenging for detection of pathogenic mutations.Objective This study was to identify the diseasing-causal genes in 20 Chinese families with a variety of HRDs.Methods Family histories and ophthalmic examinations were obtained from all participants in 20 sporadic families.Targeted sequence capture array technique with next-generation sequencing (NGS) was performed to detect pathogenic mutations in 232 identified genes associated with HRDs.Variants detected by NGS were filtered by bioinformatic analysis HRDs.Genotype-phenotype correlation was also assessed.Results We identified 11 patients with pathogenic mutations,including 8 compound heterozygous mutations and 3 homozygous mutations,which were not yet reported.These findings showed genetic diagnoses in 11 of 20 patients,with the positive rate of 55％.Among them,6 patients were autosomal recessive inheritance and 5 were unspecific.Identification of different mutations and divergent phenotypes revealed 5 patients were affected with cone-rod dystrophy,3 patients with Leber congenital amaurosis,1 patient with congenital stationary night blindness,1 patient with Best vitelliform macular dystrophy and 1 patient with Stargardt disease.Conclusions Targeted NGS is an effective approach for the genetic diagnoses of HRDs.These findings provide insights into understanding the genotype-phenotype correlations in HRDs.

Correct interpretation and evaluation of the results of clinical trials of gene therapy for Leber congenital amaurosis / 中华实验眼科杂志

The treatment of hereditary retinal disease is still one of the contemporary scientific problems.Leber congenital amaurosis (LCA) is one type of congenital retinal diseases.Desirable results have been achieved in ongoing clinical trials of gene therapy for LCA,and the efficacy and safety in the intraocular injection of a gene inserted in an adeno-associated virus (AAV) have been verified abroad.These results bring hope and opportunity to LCA patients.China has more hereditary retinal disease patients,but gene therapy for hereditary retinal disease and LCA is lacking.Rightly interpreting and objectively evaluating the clinical trials of gene therapy of LCA will provide us with many important references and useful clues to further help us organize and implement clinical trials of gene therapy for hereditary retinal disease in the future.