Deep Phenotyping and Molecular Elucidation of a New Syndrome: Ectodermal Dysplasia Caused by IRF6 Variants

The diagnosis of an ectodermal dysplasia (ED) is often made by dermatologists. Some of the more than 50 distinct ectodermal dysplasias, however, are still largely unknown and their pathogenesis is poorly understood. Since we recently discovered that variants of the Interferon Regulatory Factor 6 (IRF6) gene IRF6 may cause ED, we have further investigated the link between this gene and maldevelopment of tissues originating from the embryonic ectoderm. Disease characterization in two previously reported subjects and one newly identified patient (mosaic status) included systematic clinical and genetic evaluation, assessment of all available patient records and dental radiographs, hearing tests and immunostaining of skin samples. Structural models of native and mutant IRF6 were analysed to elucidate the pathogenesis. IRF6-associated ED, a combination of natal teeth (irregularly), absent sweat glands, hidradenitis suppurativa-like symptoms, onychodysplasia, agenesis of numerous deciduous and permanent teeth, and sensorineural hearing impairment, was linked to amino acid substitutions in a region between the DNA-binding domain and the protein-binding domain of IRF6, which has not yet been assigned a function. Genotype-phenotype correlations from a total of five patients and immunohistochemical data support the assumption that IRF6-associated ED is based on a gain-of-function mechanism. Thus, IRF6 variants are not only the cause of Van der Woude syndrome and popliteal pterygium syndrome, two diseases with cleft lip/palate as common features, but are most likely responsible also for a new, challenging syndrome without orofacial clefting. Our results facilitate accurate and early diagnosis in affected individuals and may pave the way for specific treatment.