5The deafness-gene landscape

TMore than a hundred genes

Non-syndromic deafness is extraordinarily heterogeneous: over a hundred genes and loci have been implicated, encoding a wide spectrum of cochlear proteins — structural elements of the hair bundle (the myosins, actin-associated proteins), cell-junction and adhesion molecules (cadherin-23, the connexins), extracellular linkers, and ion transporters and channels (pendrin, the potassium channels). Most are individually rare; only GJB2 is common.[2011]

CThe question that organises them

For the implant clinician, the useful way to cut through this complexity is to ask of each gene a single question: where in the ear is it expressed? A cochlear implant bypasses the hair cells and delivers its signal to the spiral-ganglion neurons. So the genes divide naturally into two groups — those acting in the membranous labyrinth (the cochlear sensory apparatus) and those acting in the spiral ganglion(the neural target) — and that division predicts the implant's result.[2012]

CMembranous-labyrinth genes

The large majority of well-characterised deafness genes act in the membranous labyrinth — the hair cells, supporting cells, stria vascularis and tectorial membrane. GJB2 (connexin-26), SLC26A4 (pendrin), OTOF (otoferlin), TECTA, MYO7Aand the mitochondrial genes all sit here. Their mutations cripple the cochlea but leave the spiral ganglion intact, so when the implant takes over the spiral ganglion's stimulation, it finds a healthy target — and outcomes are good.[2014]

CSpiral-ganglion genes

A smaller, clinically crucial group of genes is expressed in or essential to the spiral-ganglion neurons themselves — TMPRSS3, the deafness-dystonia gene TIMM8A (DDON / Mohr-Tranebjærg), and others. When these fail, the lesion is in the very cells the implant must drive. The device cannot bypass a diseased target, and outcomes become variable or poor. This is the group that makes genotype prognostically powerful — and ethically charged.[2012]

CReading the map clinically

Used at the point of care, the map converts a genetic result into a prognostic statement. A pathogenic variant in a membranous-labyrinth gene supports an optimistic conversation and early implantation; a variant in a spiral-ganglion gene tempers expectations and may intensify rehabilitation planning. The map is the bridge between the testing technology of the last module and the outcome predictions of the next — and its formal statement is the spiral-ganglion hypothesis (Module 8).

Before that, the practical question: how is all this genetic information actually obtained, and how should it sit in the work-up? First, the testing technology (Module 6).