Apparent phenotypic anticipation in autosomal dominant connexin 26 deafness

Connexin 26 (GJB2) mutations are associated with various types of hearing loss, either without associated symptoms or with skin disease, constituting a form of syndromic hearing loss. These mutations can lead to deafness in either a recessive or a dominant autosomal form of inheritance.

Ascertainment of a Jewish Ashkenazi family with nonsyndromic hearing loss led to the construction of a pedigree for a four-generation family, with hearing loss detected in three successive generations. The entire coding region of the GJB2 gene was amplified and sequenced by Sanger sequencing.

Audiological analysis revealed that the age of onset and severity of hearing loss were earlier and more severe, respectively, in each successive generation of an Ashkenazi Jewish family. A mutation, c.224G>A, leading to missense p.Arg75Gln was detected only in the affected members of the family.

The entire coding region of GJB2 should be checked in hearing-impaired patients by Sanger sequencing, rather than examination only of the two most prevalent mutations, regardless of mode of inheritance or ethnicity. Furthermore, predictions regarding phenotype based on genotype can be difficult to make due to clinical variability in multigenerational families, as demonstrated in the family presented in this study.