Evidence for an autosomal recessive pattern of inheritance in Keratitis-ichthyosis-deafness (KID) syndrome: Exome sequencing reveals a novel homozygous GJB2 mutation

Abstract

GJB2 encodes for connexin26 (Cx26), a small transmembrane protein component of the gap junction, which is essential for cellular communication in many epithelial cells. Mutations in GJB2 cause autosomal recessive and dominant non-syndromic hearing loss. Few mutations with a dominant transmission have been also linked to syndromic forms affecting the cochlea in combination with the epidermis. The severity and type of the resulting hyperproliferative epidermal disorders are however quite heterogeneous.The purpose of this study was to identify the genetic cause of a rare ectodermal dysplasia, keratitis-ichthyosis-deafness (KID) syndrome in three siblings of Saudi Arabian origin, born to first-cousin healthy parents. The affected presented with the classic phenotypic triad of KID syndrome including diffuse hyperkeratotic erythroderma, neurosensory hearing loss and vascularizing keratitis. Several other features were susceptibility to infections, dental dysplasia, hypohydrosis, growth delay and short stature. Exome sequencing revealed a missense GJB2 mutation (NM_004004: c.244A > G; p.Ile82Val), which is pathogenic in the homozygous state. We present evidence that KID syndrome can be caused by a homozygous GJB2 mutation and demonstrate an autosomal recessive mode of inheritance for the first time at a molecular level.The spectrum of skin manifestations associated with gap junction gene mutations is still growing, particularly in the case of Cx26. Our findings add to the list of pathogenic variants associated with this condition, and contribute to an insight into the genotype-phenotype correlations of Cx26 mutations, thus elucidating the function of different regions of the protein and further add to the widely diverging associated phenotypes.