Analysis Of Audiological And Genetic Characteristics Of Deafness In A Family With Waardenburg Syndrome

Objective:Waardenburg syndrome(WS)is a congenital autosomal-dominant syndrome deafness.The condition is characterized by sensorineural hearing loss and pigment disturbances of the hair,skin and iris.WS can be divided into 4 types According to its clinical classification.It is the most common type of syndromic hearing impairment with highly genetic heterogeneity and proved to be related by 6 genes as follows:PAX3,MITF,SNAI2,EDN3,EDNRB and SOX10.The present study aimed to identify the genetic causes of Waardenburg syndrome type Ⅱ in a family,to analyze the audiological and genetic characteristics of the WS family,and to provide a few of proposals about genetic and matrimonial for this family.Methods:In this study,the propositus is a 15-year-old boy from Jianshui county in Yunnan province.We found that the phenotype of the propositus associate to WS2.We traced the WS family with 16 members through a family information survey,which has 2 WS2 deafness patients.Subsequently we collected basic information about all family members.Furthermore we obtain more detailed clinical data from 2 WS patients,including history from presentation,history of using ototoxic drug,history of progressive deafness,phenotype related WS and history of cochlear implant surgery.The preoperative hearing speech level was assessed by clinical audiological tests including pure tone audiometr(PTA),acoustic impedance and auditory brainstem response(ABR).CT scan for temporal bone and cranial MRI were also performed.WPS2019 was used to map the family.Peripheral blood samples were collected in 3 family members with the their consents.DNA samples were extracted from peripheral blood samples by QIAGEN DNA Blood Mini Kit.Candidate genes(PAX3,MITF,SNAI2,EDN3,EDNRB and SOX 10)were sequenced by the Trusight One sequencing panelon the illumina NextSeq500 platform.The sequencing data were analyzed by the ANNOVAR software,and the variants were screened and annotated following the ACMG guidelines by several databases including the dbSNP,HGMD,1000Genomes Project,ClinVar and ESP6500 databases.After Trusight One sequencing,the result was verified by the Sanger DNA sequencing technology.Results:(1)The propositus(III-4)and his mother(II-4)was diagnosed with WS2.They showed profound bilateral sensorineural hearing loss,right iris pigment loss and W index<1.95.Temporal CT scan and cranial MRI in propositus showed bilateral semicircular canal malformations(2)A nonsense heterozygous mutation was found in the coding region of exon 2 in the SOX 10 gene of proband and his mother.The nonsense heterozygous mutation could cause the replacement of the 85 thlysine codon by stop codon(255G>A,)and further more possibly cause terminating the protein translation in advance.However,propositus’s father had no mutation of genes above mentioned.Conclusions:(1)A nonsense heterozygous mutation in SOX10(c.255G>A)gene have been identified in this WS2 family,which have no record through searching some important information such as the dbSNP,HGMD,1000 Genomes Project,ClinVar and ESP6500 databases.(2)Corollary can be drawn based on the rule of autosomal dominant inheritance and Mendel heredity law,we speculate that the mutant gene of SOX10(c.255G>A)assume autosomal dominant inheritance in this family,and the propositus is likely to pass on the pathogenic gene to the next generation.(3)The application of gene sequencing technology in the molecular genetic diagnosis of WS patients has far-reaching significance in Yunnan province.