The Screening Of GJB2 Gene Mutation In Chinese Sporadic Sensorineural Hearing Loss Patients

Sensorineural Hearing Loss is one of the most common human congenital diseases, and also one of the most common diseases in otology clinic. It is affected by many co-factors, including gene mutation, aging, and application of ototoxic drugs, infectious diseases and noise exposure. According to literature, about 1 to 3 in 1000 newborns suffers from deafness. In congenital hearing loss, about 50% cases are caused by gene mutations and as high as 50% autosomal recessive hearing loss are related with GJB2 gene mutations. Since 1997 when the first deafness-related mutation of GJB2 was reported, over 150 mutations are detected. Among them,60% are autosomal recessive, while 20% unclassified. According to different literature, GJB2 mutations frequencies vary among different ethnic groups. For example,35delG are most frequently seen in Caucasian,167delT in Jewish, while 235delC in East Asian. In China, there are more than 8 billion sensorineural hearing loss patients, accounting for 63% of deaf population. Up to 2-10% patients in our otology clinic complain of simple bilateral sensorineural hearing loss. In recent years, multi-center studies about GJB2 mutation screening have been carried out in China, mainly in deaf-mute schools. These studies also pointed out that 235delC is the most prevalent GJB2 pathogenic mutation in China, carrier rate ranging from 13%-21%, and common polymorphisms such as 79G>A, controversial mutations such as 109G>A. However, few data focusing on sporadic sensorineural hearing loss patients in outpatient department, especially among mild to moderate hearing loss ones, of GJB2 gene mutation screening and pathological patterns are provided. Therefore, screening for GJB2 gene mutations in Chinese sporadic sensorineural hearing loss population, especially in otology clinic, extending the screening subjects from mere severe to profound hearing loss patients to mild to moderate level, is beneficial for completing clinical data for clinical and prenatal diagnosis for deafness, as well as for genetic counseling, also important for epidemiologic database of genetic hearing loss.Objective:To study the relationship between hearing loss and GJB2 gene mutation.Methods:233 sensorineural hearing loss patients,85 consanguinities and 100 controls visited during Mat 29 2008 to April 6 2010 were collected in our otology clinic. Screenings for GJB2 gene and mitochondria DNA 12SrRNA mutation were performed. Results:172 (73.8%) patients has GJB2 gene mutations,109G>A carriers 57 cases(24.5%), allele frequency 17.4%; 235delC carrier 25 cases(10.7%), allele frequency 6.9%。47 cases (20.2%) are believed to be GJB2-related,5 cases (2.1%) are mtDNA mutation related.17 GJB2 mutations, and including 4 novel mutations were detected. In pathogenic mutations, the most prevalent one is 109G>A (32cases, 68.1% of GJB2-related deafness cases), including 24 109G>A homozygote (10.3%of all patients,51.1% of all GJB2-related cases), followed by 235delC (18 cases,38.3% of GJB2-related cases), including 72 35delC homozygote (only 3.0% of all patients, 14.9% of GJB2-related cases).299-300delAT 4 cases (8.5% of GJB2-related cases), including 1 homozygote. In patient group there are 15 compound heterozygote pathogenic mutations, including 4 109G>A/235delC,1109G>A/299-300delAT,2 109G>A/427C＞T,3 235delC/299-300delAT, each 1 case of 176del16/235delC, 235delC/504insAACG,235delC/605ins46,235delC/257C＞G and 79G>A,109G>A/478G>A. In family and control groups,109G>A exist only as heterozygote (15 cases and 6 cases),no compound pathogenic mutation were found in these two groups. In patient group, we found 5 cases of mtDNA pathogenic mutations, including 3 1555A>G,1 1494C＞T,1 1519insCA. Conclusion:1.GJB2 109G>A is the most prevalent GJB2 pathogenic mutant in sporadic sensorineural hearing loss patients and is inherited in autosomal recessive manner. The following ones are 235delC and 299-300delAT.2. Hearing petterns:235delC homozygote has early onset(85.7% before 5 years of age) and with severe hearing impairment(42.9% severe to profound) and flat audiograph(57.1%), while 109G>A homozygote has late onset(ranging from 5 to 47 years of age), lower grade of hearing loss (95.8% mild to moderate) and sloping audiograph(87.5%).3.79G>A,341A>G is polymorphism. 4.257C＞G,478G>A are pathogenic; 368C＞A is unclassified; novel mutations 65A>C, 88A>G,380G>T,494G>A(1 heterozygous cases each) function unknown.