Identification Of The Causative Genes For A Family With Usher Syndrome And The Meta Analysis Of Epidemiological Studies In Usher Syndrome

Objective1.To analyze epidemiological data obtained from present studies related to Usher Syndrome by the Meta analysis.To assess the detection rate of causative mutations in each Usher gene,and to investigate the hotspot mutations of USH2 A gene in different regions.2.To identify the causative mutation using target region sequencing technology.Methods1.Epidemiological studies of Usher syndrome were collected from the following databases: CNKI,Wan Fang,VIP,Chinese biomedical literature databases,Pub Med,Cochrane Library,Embase,Web of science and other medical database.Time range from the establishment of the database to December 2020.The retrieved literature was screened according to the developed inclusion and exclusion criteria,and data extraction and quality evaluation were performed for the included literature.The effect size rate and 95% CI,χ2,Z and P were used to measure the results.Sensitivity analysis and subgroup analysis were performed when necessary.Publication bias assessment was performed using the Egger method.2.Collected clinical information from patient with Usher syndrome and her families.Peripheral venous blood DNA was extracted from each individual.The target region sequencing technology was used to screen causative gene mutations in this patient.Then the further study were performed using Sanger Sequencing on the other family members in terms of verify the mutation sites.Results1.A total of 19 articles were included in this study.We performed a metaanalysis of data from High-Throughput Sequencing studies in 1172 patients with Usher syndrome.The detection rate of causative mutations in each Usher gene:MYO7A: 19.9%(233/1172),USH1C: 2.0%(24/1172),CDH23: 5.5%(64/1172),PCDH15: 3.1%(36/1172),SANS: 0.9%(11/1172),CIB2: 0.1%(1/1172),USH2A: 50.2%(588/1172),GPR98: 4.9%(58/1172),DFNB31:0.1%(1/1172),CLRN1: 2.0%(23/1172),PDZD7: 0.1%(1/1172),ARSG:0.2%(2/1172),CEP250: 0.2%(2/1172).In these 11 studies,no mutation was found in USH1 E,USH1H,USH1 K,HARS.The proportion of each Usher syndrome subtype: USH Ⅰ: 31.6%(369/1172),USH Ⅱ: 55.2%(647/1172),USH Ⅲ: 2.0%(23/1172),atypical USH: 0.4%(5/1172).In 10.9%(128/1172)no causative mutation was found in Usher genes.1.2%(14/1172)of the patients detected other genes unrelated to Usher syndrome.In 10.9%(128/1172)no causative mutation was found in Usher genes.In 9.7%(114/1172)did not found any causative mutations.A total of 1137 USH2 A variants were found in 19 studies,and 10 of the most frequent variants were screened out.To investigate the association between 10 variants and USH2 A,each variant showed a significant association with USH2 A.In European populations,6 variants(c.2299 del G,c.11864G>A,c.7595-2144A>G,c.10712C>T,c.2610C>A,c.2276G>T)showed a significant association with USH2 A,c.802 G > A was not significantly associated with USH2 A.In Asian populations,4 variants(c.8559-2A>G,c.2802T>G,c.100＿101ins T,c.802G>A)showed a significant association with USH2 A,c.7595-2144 A > G was not significantly associated with USH2 A.In African and North American populations,c.2299 del G with high mutation frequency.However,in each of these 2 regions there is only one small sample of literature involved this variant,we need more trials with adequate samples from these 2 regions for further study.2.The patient presented with moderate to severe bilateral sensorineural hearing impairment and began to suffer from night blindness and hypopsia at the age of 10.Fundus examination suggested bilateral posterior pole of retina turbidity,the retina is cinerous,characteristic bone spicule pigment and macular hole of right eye.There were no clinical manifestations of abnormal vestibular function.Parents of the proband had a normal clinical phenotype.According to the USH diagnostic and classification criteria,the patient’s initial diagnosis was USH2,and the genetic pattern was consistent with autosomal recessive inheritance.Target sequence capture was used to identify variants,The proband was a compound heterozygotes of USH2 A c.9570+1G>A/ c.2187C>A(p.Cys729*),c.9570+1G>A was maternal,the variant was pathogenic which was previously reported.And c.2187C>A(p.Cys729*)was paternal,the variant was novel.Conclusion1.USH Ⅱ is the most frequent form,USH Ⅰ is the second,and USH Ⅲ is rare.USH2 A was the most predominant pathogenic gene in USH II,and MYO7 A accounts for the highest proportion of USH Ⅰ.The gene profile of USH is very similar across regional populations,but with different mutation hotpots.2.The proband was a compound heterozygotes of USH2 A c.9570+1G>A/c.2187C>A(p.Cys729*),the diagnosis of this patient was USH II.This study not only expands the spectrum of pathogenic variants in Usher syndrome and also provides valuable genetic information for further molecular biology studies and early diagnosis,treatment,prevention of USH.