EMQN Best Practice guidelines for diagnostic testing of mutations causing non-syndromic hearing impairment at the DFNB1 locus
Abstract
Hearing impairment is the most common sensory disorder, affecting one in every 500-1000 newborns (http://hearing.screening.nhs.uk/nationalprog). It is estimated that about half of these have a genetic cause, whereas the other half are caused by environmental factors, such as rubella or CMV infection during pregnancy, factors associated with prematurity or ototoxic medication.
In most genetic cases, the inheritance pattern is autosomal recessive (80%), but also autosomal dominant (17%), X-linked (2-3%) and mitochondrial (60 identified causative genes (http://hereditaryhearingloss.org/). Remarkably, defects in one locus (DFNB1) account for up to 50% of cases in many populations, which makes this the most common cause of non-syndromic, prelingual hearing impairment and deafness.
The locus was described for the first time in 19941 and the first mutations in 1997.2, 3 The DFNB1 locus (OMIM* 220290) contains two genes associated with hearing loss, GJB2 (OMIM*121011) and GJB6 (OMIM*604418), encoding connexin 26 (CX26) and connexin 30 (CX30), respectively. The reference sequences are given in Table 1.
Connexins aggregate to form connexons, consisting of six connexin proteins in heteromeric or homomeric complexes located at gap junctions, and which are involved in the transport of ions and other low-molecular weight components between cells.