Suzanne de Bruijn

27 General introduction Causes of hearing loss HL is an etiologically heterogeneous trait as it involves both environmental and genetic causes. Environmental causes include complications at birth, infections, ototoxic drugs, head trauma and excessive noise exposure. In developed countries, genetic defects are estimated to underlie 50% and 60% of HL cases with a congenital onset or an onset at the age of 4 years, respectively. 36 For adult-onset HL these percentages are unknown, although it is generally accepted that the contribution of strong genetic factors decreases with age and that there is an increased exposure to damaging environmental factors during life. Consequently, adult-onset HL is generally considered a multifactorial condition, in contrast to congenital HL which is often either monogenic or caused by a non-genetic factor. 36,39 Inherited HL can display an autosomal dominant (type DFNA), autosomal recessive (DFNB), mitochondrial or X-linked (DFNX) inheritance pattern. DFNB concerns 80% of the cases with prelingual (non-syndromic) HL, DFNA 19% and mitochondrial or X-linked inherited HL concern less than 1% of the cases. 38 Besides non-syndromic forms of HL, also many syndromic forms (>300 (OMIM 41 )) have been described, in which HL is associated with distinctive additional clinical features (such as RD in Usher syndrome). 26 The majority of cases however, are non-syndromic (~70% of cases with inherited prelingual HL). 38 Similar to RD, monogenic, non-syndromic and sensorineural HL displays a high genetic heterogeneity. The condition has been associated with pathogenic variants in >150 genes. 42 Despite this large number of genes, up to 50% of all presumed genetic cases with early-onset HL can be attributed to pathogenic variants in the GJB2 gene. 43 In the Netherlands, this is true for ~10% of such cases. 43 Variants in this gene are associated with profound non-syndromic, recessively-inherited HL, but the associated phenotype is highly variable. 4,44 GJB2 encodes the gap junction beta-2 protein, also known as connexin 26 (Cx26), that functions in gap junctions connecting the supporting cells in the organ of Corti, the mesenchymal cells in the stria vascularis and fibrocytes, located in the spiral ligament that underlies the stria vascularis. 45,46 The gap junctions between these cell types are involved in the potassium-recycling pathway of the cochlea and GJB2 is therefore essential for maintenance of the ion homeostasis. 26 Besides ion homeostasis, HL-associated proteins are involved in several other biological processes. Similarly as performed for RD, a GO-enrichment analysis was performed to visualize the most important biological processes that are enriched with HL-associated proteins ( Figure 4 ). Themost significantly enriched processes for HL-associated proteins are those that entail the sensory perception of mechanical stimuli and sound. Interesting to note is that the second-most enriched process concerns “the sensory perception of