Qin Liu1, Jing Cheng2, Yu Lu2, Jia Zhou1, Li Wang1, Changliang Yang1, Guang Yang1, Hui Yang1, Jingyuan Cao1, Zhao Zhang1, Yi Sun3. 1. Department of Otorhinolaryngology, General Hospital of Central Theater Command, Chinese People's Liberation Army, Wuhan, 430000, China. 2. Medical Genetics Center, The First Affiliated Hospital, Army Medical University, Chongqing, 400038, China. 3. Department of Otorhinolaryngology, General Hospital of Central Theater Command, Chinese People's Liberation Army, Wuhan, 430000, China; Southern Medical University, Guangzhou, 510000, China. Electronic address: sunyi_wuhan@126.com.
Abstract
OBJECTIVE: Waardenburg Syndrome (WS) is a neurocristopathy with an autosomal dominant mode of inheritance and highly genetic heterogeneity. To date, mutations of PAX3, SOX10, MITF, EDNRB, EDN3 and SNAI2 have been implicated in the pathogenesis of WS. In this study, we aimed to identify pathogenic genes among WS families and to analyze the pathogenic relationship between genotypes and phenotypes. METHODS: In this study, all six families studied were from Hubei province, China.WS patients underwent screening for all deafness genes including PAX3, SOX10, MITF, EDNRB, EDN3 and SNAI2 using Massively Parallel Sequencing (MPS) and validation of mutations using Sanger sequencing. RESULTS: Clinical evaluation revealed prominent phenotypic variability in Hubei WS patients. Two WS1 families and four WS2 families were diagnosed in six families. Sensorineural hearing loss was the most common, followed by iris pigmentary abnormality. Molecular genetic analysis of the WS genes for six families revealed five novel heterozygous mutations. Two mutations occurred in the PAX3 gene: one nonsense mutation c.667C > T(p.Arg223Ter) and one missense mutation c.220C > T(p.Arg74Cys).One missense mutation c.331T > C (p.Phe111Leu) and one nonsense mutation c.346C > T(p.Gln116Ter) were detected in the SOX10 gene. Two mutations were detected in the MITF gene: one splice site mutation c.859-1G > A and one nonsense mutation c.859G > T(p.Glu287Ter). Among them, the mutations (SOX10 c.331T > C and MITF c.859G > T) were de novo mutations. CONCLUSION: In this study, six mutations were found to be associated with the phenotype of patients. Our data helped illuminate the phenotypic and genotypic spectrum of WS in Hubei province and could have implications for the genetic counseling of WS in Hubei province.
OBJECTIVE:Waardenburg Syndrome (WS) is a neurocristopathy with an autosomal dominant mode of inheritance and highly genetic heterogeneity. To date, mutations of PAX3, SOX10, MITF, EDNRB, EDN3 and SNAI2 have been implicated in the pathogenesis of WS. In this study, we aimed to identify pathogenic genes among WS families and to analyze the pathogenic relationship between genotypes and phenotypes. METHODS: In this study, all six families studied were from Hubei province, China.WSpatients underwent screening for all deafness genes including PAX3, SOX10, MITF, EDNRB, EDN3 and SNAI2 using Massively Parallel Sequencing (MPS) and validation of mutations using Sanger sequencing. RESULTS: Clinical evaluation revealed prominent phenotypic variability in Hubei WSpatients. Two WS1 families and four WS2 families were diagnosed in six families. Sensorineural hearing loss was the most common, followed by iris pigmentary abnormality. Molecular genetic analysis of the WS genes for six families revealed five novel heterozygous mutations. Two mutations occurred in the PAX3 gene: one nonsense mutation c.667C > T(p.Arg223Ter) and one missense mutation c.220C > T(p.Arg74Cys).One missense mutation c.331T > C (p.Phe111Leu) and one nonsense mutation c.346C > T(p.Gln116Ter) were detected in the SOX10 gene. Two mutations were detected in the MITF gene: one splice site mutation c.859-1G > A and one nonsense mutation c.859G > T(p.Glu287Ter). Among them, the mutations (SOX10 c.331T > C and MITF c.859G > T) were de novo mutations. CONCLUSION: In this study, six mutations were found to be associated with the phenotype of patients. Our data helped illuminate the phenotypic and genotypic spectrum of WS in Hubei province and could have implications for the genetic counseling of WS in Hubei province.