Mutation Screening And Prenatal Diagnosis Of Hidrotic Ectodermal Dysplasia 2 In A Chinese Family

Background Hidrotic ectodermal dysplasia 2(HED2,OMIM#129500),also known as Clouston syndrome,is a rare skin disorder inherited in an autosomal-dominant inheritance with complete penetrance and variable expressivity.It occurs approximately in 1 in every 100,000 live births and characterized by nail dystrophy,partial or total alopecia,palmoplantar hyperkeratosis.The syndrome was first described by Nicolle and Hallipre in 1895 and became well known after the report of a French-Canadian family by Clouston in 1929.Later genomewide linkage analysis localized the pathogenic gene to chromosome 13q11±12.1.Linkage was confirmed by several independent mapping studies.Mutation in gap junction beta 6(GJB6)encoding connexin 30 protein was shown to be the pathogenesis of HED2 in 2000.To date,four mutations in GJB6 gene have been found in HED2 patients:G11R,A88V,V37E and D50N.All of them lead to nonsynonymous amino acid substitutions.Besides that,mutations in GJA1(V41L),GJB2(R127H),as well as the combination of a mutation N14S in GJB6 and a mutation F191L in GJB2 have been found to be related to HED2.Differential diagnosis in HED2,Pachyonychia Congenita,Congenital atrichia and Palmoplantar keratosis is essential due to their similar clinical manifestations.Objective To detect the gene mutation and clarify the diagnosis in a Chinese family suspected HED2 and to make prenatal diagnosis on the fetus.To enrich the clinical phenotype and gene pool of this rare disease and to provide clues for the study of its subsequent pathogenesis.Methods A family consisting of a total of 14 individuals including 3 HED patients was collected.Clinical information was analyzed.Blood samples of 2 patients and 4 unaffected individuals were collected.The proband’s genes related to HED2,PC,CA and PPK including GJB6,GJB2,GJA1,et al.were screened by next generation sequencing.Mutation confirmation of the proband’s father,mother,sister,wife,son and the fetus were conducted by sanger sequencing.Results A single nucleotide change c.31G>A in the N-terminal region of GJB6 gene’s exon was detected of PCR products derived from genomic DNA of the proband and his father.This substitution leads to the predicted amino acid change gly 11-to-arg(G11R).No variants were detected in other related genes including GJB2,GJA1,KRT6A,KRT6B,KRT16,KRT17 and so on.The mutation was not found in the normal individuals of this family and the fetus.Conclusions The missense mutations c.31G>A in GJB6 gene,which has been reported to cause HED2,may be the principal cause leading to HED2 in this family.Prenatal diagnosis of the fetus indicates that the fetus doesn’t inherit the pathogenic mutation.Gene test before pregnancy and prenatal diagnosis can provide help for affected family to make informed medical and personal decisions and block the transmission of pathogenic genes.