Three novel GJB2 GJB2 (connexin 26) variants associated with autosomal dominant syndromic and nonsyndromic hearing loss

摘要

Connexin 26 (Cx26), encoded by the GJB2 gene, is a key protein involved in the formation of gap junctions in epithelial organs including the inner ear and palmoplantar epidermis. Pathogenic variants in GJB2 are responsible for approximately 50% of inherited sensorineural deafness. The majority of these variants are associated with autosomal recessive inheritance; however, rare reports of dominantly co‐segregating variants have been published. Since we began offering GJB2 testing in 2003, only about 2% of detected GJB2 variants from our laboratory have been classified as dominant. Here we report three novel dominant GJB2 variants (p.Thr55Ala, p.Gln57_Pro58delinsHisSer, and p.Trp44Gly); two associated with syndromic sensorineural hearing loss and one with nonsyndromic hearing loss. In the kindred with the p.Thr55Ala variant, the proband and his father present with only leukonychia as a cutaneous finding of their syndromic hearing loss. This phenotype has been previously documented in conjunction with palmoplantar hyperkeratosis, but isolated leukonychia is a novel finding likely associated with the unique threonine to alanine change at codon 55 (other variants at this codon have been reported in cases of nonsyndromic hearing loss). This report contributes to the short list of GJB2 variants associated with autosomal dominant hearing loss, highlights the variability of skin and nail findings associated with such cases, and illustrates the occurrence of both syndromic and nonsyndromic presentations with changes in the same gene.