The Relation Between Congenital Cytomegalovirus Infection Leading To Hearing Loss And Mutation Of GJB2Gene

Objective Many studies have shown that congenital cytomegalovirus (CMV) infection was an important cause of sensorineural hearing loss (SNHL) in children worldwide. However, the pathogenesis of SNHL in children with congenital CMV infection remains not well understood. The injury to cochlear perilymphatic epithelial cells directly induced by CMV and inflammatory response may play a role. Studies have proven that the mutations of GJB2on human chromosome13q11-q12was an important risk factor of SNHL. Moreover, researches indicated that congenital CMV infection may cause chromosome aberrations including selective chromosome breakages, chromosome pulverization, premature chromatid condensation, and structural injury to the centrosome in chromosome1. However, whether CMV infection can induce mutations of GJB2in chromosome13remains unclear. We examined the mutation frequency of GJB2in neonates with and without congenital CMV infection as well as in their corresponding parents in present study, to determine whether congenital CMV infection leads to hearing loss through inducing mutation of GJB2gene.Methods Infants within14days of life, hospitalized in department of neonatology affiliated our hospital from August,2008to August,2011were enrolled in this study. All neonates were routine tested for congenital CMV infection by Enzyme linked immunosorbent assay (ELISA).The urine samples from neonates positive for CMV-IgM or CMV-IgG were further tested by fluorescent quantitative polymerase chain reaction (FQ-PCR) for CMV infection. The final diagnosis of congenital CMV infection was based on FQ-PCR assay. Neonates with hypoxic-ischemic encephalopathy, severe intraventricular hemorrhage (grade3to4), purulent meningitis, bilirubin encephalopathy, external auditory canal malformation, and family history of deafness, were excluded from this study. Blood specimens were obtained from neonates in both CMV-infected and CMV-uninfected groups. For neonates with GJB2mutation, the blood samples from their parents were further detected for GJB2mutation. In order to clarify the incidence of deafness, all the infants were tested by using Auditory brainstem response (ABR) testing equipment at the ages from1to1.5years.Results In the early stage,9,741neonates were enrolled in this study, who were routine tested by ELISA assays, of them3,195cases with positive of CMV-IgM or IgG were further detected by FQ-PCR assays. The positive rates of FQ-PCR assay were77.27%(17/22) in neonates with positive of CMV-IgM, but only3.47%(135/3893) among children with positive of CMV-IgG (χ2=319.324, P=0.000). ABR testing were completed in63of152cases neonates with congenital CMV infection and in96neonates without congenital CMV infection at ages from1to1.5years, In63neonates with infection, the CMV-DNA level (copy/ml urine) in infants with hearing loss group was higher than that in normal hearing group [5.37±1.18(n=8) vs.3.32±0.79(n=55),t=7.46, P=0.000]. The similar positive rates of mutation in GJB2gene were found in neonates with and without congenital CMV infection [34.9%(22/63) vs.32.3%(31/96), χ2=0.118, P=0.734]. In order to explore the relationship among congenital CMV infection, GJB2mutation, and hearing loss, we analyzed the mutation spectrum in group1(neonates with congenital CMV infection and hearing loss [n=8]), group2(neonates with congenital CMV infection and normal hearing [n=55]), and group3(neonates with normal hearing but without congenital CMV infection [n=96]). The overall frequency of GJB2mutations was50%(4/8) in group1, which was not significantly different from those in group2[32.7%(18/55), P=0.434] and group3(32.3%, P=0.438) respectively. Since no significant difference was found among above3groups of infants, it is of interest to know what exactly caused the mutation of GJB2in neonates with and without congenital CMV infection. In order to determine whether the mutation of GJB2in neonates was inherited from their parents, GJB2gene in53pairs of parents whose offspring had GJB2mutation (22with and31without congenital CMV infection) were also sequenced and found all mutation spectrum of GJB2in neonates were found in both or one of their parents.Conclusion Congenital CMV infections may cause deafness in neonates, but such process is irrelevant with GJB2gene mutation.