Clinical And Genetic Studies Of ABCA4 Gene-related Retinal Degeneration Diseases

Purpose:To analyze the clinical features of ABCA4-associated retinal disease and identify pathogenic mutations,aiming to summarize the characteristics of genotypes and study the correlation of genotypes and phenotypes.Methods:Patients diagnosed with retinal dystrophy in the clinic during 2010 to 2016 were collected.Clinical features and genetic analysis were studied.?Clinical study:Medical history and family history were recorded,ophthalmic examinations including BCVA,slit-lamp biomicroscopy,indirect ophthalmoscopy,fundus photograph,visual field(VF),electroretinogram(ERG)?optical coherence tomography(OCT)and fundus autofluorescence(FAF)were taken if possible.?Genetic study:Venous blood(5 ml)from the patients and relatives were collected and extracted into genomic DNA.Panel based next-generation sequencing(NGS)was performed to identify the pathogenic mutations.All ABCA4-mutated patients were selected for further study of their genotypes.Results:64 patients from 57 pedigrees were collected,of which 35 were male and 29 were female.The age at examination ranged from 6 to 67 years,with a median age of 21 years.Among them 49 patients were STGD,6 patients were CRD and 9 patients were diagnosed with RP.?Clinical features:Patients with STGD presents various degrees of macular atrophy and yellow flecks or pigments in peripheral retina were also observed in some patients.Full-field ERG manifestes different levels of decrease and more severe for cone response.Patients with CRD have mild to moderate fundus change and relatively severe ERG damage.Patients of RP suffered poor vision especially at night since childhood and presents a genetal atrothy of retina and bone spicule pigments.Flat response or more severe decrease for rod response can be observed.?Molecular genetic results:ABCA4 variants were identified in all 57 probands:The most frequent ABCA4 mutation in this cohort was c.2424C>G:p.Y808X.Altogether,80 different disease-causing ABCA4 variants were identified by us including 46 missense(57.5%),12 nonsense(15%),15 small deletion or insertion(18.8%)and 7 splice defect(8.8%).29 mutations(35%)of them are novel.Conclusion:ABCA4 gene mutations can lead to STGD,CRD and RP.Patients differ vastly on one-set age,severity and progression of disease.STGD and CRD share some overlap which will increase the difficulty for diagnosis.The mutational spectrum of ABCA4 gene in China is quite different from other ethnics.The relation between genotype and phenotype should be further studied.Next-generation sequencing(NGS)can save time and at the same time,offer adequate genetic information.