Suzanne de Bruijn

248 Chapter 5 Chao et al., the present study showed that subjects with biallelic pathogenic variants in the coding regions and splice sites of SLC26A4 have a degree of HL that is similar to that of subjects with a monoallelic SLC26A4 variant and the CEVA haplotype. Due to the small sample size, we could not test the hypothesis that the CEVA haplotype acts as a modifier in M0 subjects as reported previously. 23 ns ns ns Figure 3. Results of audiometric evaluation in affected individuals. PTA 0.5-4 kHz for ears with an EVA. Each dot represents the hearing level of an ear with an enlarged vestibular aqueduct, allocated to genotype class (M2, M1/CEVA, M1, M0/CEVA and M0). The M1/CEVA group also includes subjects with an M1/V1-CEVA genotype. For an objective comparison, the same methods as used by Chao et al. (2019) were applied. DISCUSSION In this study we investigated 28 genetically unexplained Dutch index cases with HL and a unilateral or bilateral EVA. To elucidate the missing heritability in monoallelic SLC26A4 cases, who represent 14-31% of subjects with HL and EVA 16,20 , extensive genomic analyses as well as phenotyping were performed. Important findings in this study were (1) the enrichment of a shared (V1-)CEVA haplotype in M1 SLC26A4 cases, (2) two SLC26A4 splice variants and (3) the identification of a FOXI1 variant in three subjects suggesting a contribution of this variant to the etiology of HL and EVA. Furthermore, the genotype-phenotype analyses revealed that the severity of the HL associated with biallelic variants (M2) in SLC26A4 is comparable to the HL associated with a monoallelic variant in SLC26A4 with or without the CEVA haplotype (M1 and M1/CEVA). For six M1 individuals, it could not be conclusively determined whether the CEVA haplotype was present in trans with the (likely) pathogenic SLC26A4 variant, as no genetic material of family members could be obtained. However, we anticipated that