Clinical Characteristics And Molecular Etiology Of Common Syndromic Deafness With Ocular Abnormalities

Background and ObjectivesAccording to the World Health Organization,about 5% of the world population suffer from hearing impairment,of which approximately 60% related to genetic factors.About 30% of hereditary deafness are syndromic.There are more than 400 types of syndromic deafness reported so far,of which about 90 types are accompanied by eye abnormalities.Waardenburg syndrome(WS)and Usher syndrome are the most common syndromes of deafness with eye abnormalities.WS has a highly variable phenotypic expression and genetic heterogeneity.At present,nearly 400 mutations in 6genes have been found related to it,and it is divided into four subtypes according to genotype and phenotype.Usher syndrome has been divided into three subtypes,and there are about 14 genes or loci associated with it.Among them,the CDH23 gene is more special.Most studies believe that nonsense mutations,splicing mutations and frameshift mutations of the CDH23 gene will cause 1D Usher syndrome,and missense mutations will cause non-syndromic deafness.In this study,the clinical characteristics and molecular etiology of WS and Usher syndrome cases were investigated to clarify the correlation between phenotype and genotype and provide a basis for accurate diagnosis,monitoring,treatment,genetic counseling,and birth defect intervention for related diseases.MethodsCooperate with the Affiliated Hospitals of Zhengzhou University and other units to collect and sort out the suspected hereditary deafness cases.The cases of deafness accompanied by eye abnormalities are screened out,and their clinical features are comprehensively characterized and analyzed for clinical diagnosis.The final diagnosis was made based on clinical symptoms and pathogenic mutations detected by highthroughput sequencing technology combined with bioinformatics.According to the ACMG guidelines,the pathogenicity of the variant is carried out,and if necessary,its function was verified by biological experiments.Results(1)From September 2018 to February 2021,a total of 936 cases of suspected hereditary deafness were collected.(2)Sixteen cases of syndrome deafness with eye abnormalities were screened out,of which 14 cases were diagnosed as WS(from 7 families)and 2 cases with Usher syndrome(from 1 family).(3)The molecular pathogenesis of seven WS families was clarified.A total of seven heterozygous variants including c.1459C>T,c.123 del,and c.959-409＿1173+3402del of PAX3 gene(NM＿181459.4),c.198＿262del and c.529＿556del of SOX10 gene(NM＿006941.4),and c.731G>A and c.970 dup of MITF gene(NM＿000248.3)were found for the first time.(4)We had established an induced pluripotent stem cell carrying PAX3:c.123 del heterozygous mutations,which will provide a tool for future WS research.(5)For Usher syndrome cases,we confirmed that CDH23(NM＿022124.5):c.6049G>A can affect splicing,and discovered a new compound heterozygous pattern of USH1 D caused by CDH23 gene mutations.Conclusions Waardenburg syndrome and Usher syndrome account for about 1.71% of the hereditary deafness population in Henan.We confirmed the highly variable phenotypic expressivity and genetic heterogeneity of WS patients in the Chinese population,and expanded its spectrum of genetic mutations.We found and confirmed that the compound heterozygosity composed of splicing mutations and missense mutations of the CDH23 gene can cause USH1 D syndrome deafness,which is a new compound heterozygous pattern.Our study enriches the compound heterozygous pattern of CDH23 and provides a basis for the diagnosis of related diseases and interventions for birth defects.