Suzanne de Bruijn

233 Exploring the missing heritability in subjects with hearing loss and EVA INTRODUCTION SLC26A4 encodes the transmembrane anion transporter pendrin and ismost abundantly expressed in the inner ear, thyroid gland, kidney, and airways epithelia. 1-5 The 780 amino acid protein is part of the solute carrier family 26 and plays a pivotal role in chloride, bicarbonate and iodine transport. In the inner ear, pendrin functions as a Cl - /HCO 3 - exchanger. The protein is expressed in the epithelial cells of the cochlea (outer sulcus and spindle cells), the vestibular labyrinth (transitional cells), and the endolymphatic duct and sac (mitochondrial-rich cells). 6,7 Expression of pendrin is essential for the development of the (murine) auditory and vestibular system and for maintaining ion homeostasis in the endolymphatic fluid and the endocochlear potential. 2,7-9 Defects in SLC26A4 are among the most frequent causes (up to 10%) of early-onset autosomal recessive hearing loss (arHL); non-syndromic DFNB4 (MIM: 600791) and Pendred syndrome (MIM: 274600). 10 Individuals carrying biallelic pathogenic SLC26A4 variants are affected by variable, often progressive and predominantly sensorineural HL with a congenital or childhood-onset. 11,12 In Pendred syndrome, the HL phenotype is accompanied by an iodine organification defect that can lead to thyroid goiter. 13 In individuals affected by either syndromic or non-syndromic SLC26A4- associated HL, a unilateral or bilateral enlarged vestibular aqueduct (EVA) is observed, which is the most common imaging abnormality in individuals with HL. 14,15 In some cases, EVA can be part of Mondini dysplasia: an inner ear malformation that includes both EVA and cochlear incomplete partition type II. Although Mondini dysplasia can be observed in both Pendred syndrome and DFNB4 cases, cases with the syndromic type of HL are more likely to present Mondini dysplasia than those with non-syndromic HL. 16,17 Pathogenic variants in SLC26A4 have a loss-of-function effect, leading tomalfunctioning of the pendrin ion transporter. Besides the antenatal formation of an EVA, this ultimately leads to acidification of the endolymphatic fluids in the inner ear during embryonic development. 7,18 Although the exact molecular pathogenic mechanism remains to be elucidated, the lack of pendrin function ultimately leads to degeneration of the sensory cells in the inner ear. 7 Despite the strong association between defects of SLC26A4 and HL combined with an EVA, genetic screening of subjects with this combination of defects often does not reveal biallelic pathogenic variants in SLC26A4 (coined M2). Cohort studies report that 14-31% of the subjects with an EVA and HL carry a monoallelic pathogenic variant in SLC26A4 (M1), whereas in 10-65% of the subjects, no potentially pathogenic variant in the coding or splice site regions of the gene can be identified (M0). 16,19,20 Segregation