Hereditary deafness: lessons for developmental studies and genetic diagnosis

Hereditary deafness is highly heterogeneous genetically, with over 100 loci so far identified. Routine diagnostic mutation screening can be done only when a candidate gene has been identified, and preferably a candidate mutation. For syndromic forms of hearing loss it is often possible to predict the gene involved. Non-syndromic loss is much more intractable to diagnostic mutation screening because of the extensive locus heterogeneity. However, mutations in the connexin 26 (GJB2) gene and the mitochondrial m. 1555A > G mutation are sufficiently frequent in some populations to justify mutation testing. Identifying the genes mutated in syndromic hearing loss can help delineate developmental pathways.

The example of Waardenburg syndrome is used to illustrate how unravelling developmental pathways can be more complicated than defining metabolic pathways through biochemical defects. Developmental genes tend to be organised into networks rather than linear pathways, and transcription factors act in a combinatorial manner. This makes developmental pathways harder to unravel genetically than metabolic pathways.