Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant

• Published in: Human genetics Vol. 141; no. 3-4; pp. 465 - 484
• Main Authors: Smits, Jeroen J., de Bruijn, Suzanne E., Lanting, Cornelis P., Oostrik, Jaap, O’Gorman, Luke, Mantere, Tuomo, Cremers, Frans P. M., Roosing, Susanne, Yntema, Helger G., de Vrieze, Erik, Derks, Ronny, Hoischen, Alexander, Pegge, Sjoert A. H., Neveling, Kornelia, Pennings, Ronald J. E., Kremer, Hannie
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2022; Springer; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Deafness; DNA sequencing; Epigenetic inheritance; Epigenetics; Ethylenediaminetetraacetic acid; Gene Function; Gene mapping; Gene mutations; Genetic aspects; Genomes; Genomics; Genotypes; Haplotypes; Health aspects; Hearing loss; Hearing Loss - genetics; Hearing Loss, Sensorineural - genetics; Heritability; Human Genetics; Humans; Investigations; Membrane Transport Proteins - genetics; Metabolic Diseases; Molecular Medicine; Mutation; Nucleotide sequencing; Original Investigation; Phenotype; Phenotypes; RNA; Sulfate Transporters - genetics; The Molecular Genetics of Hearing and Deafness; Vestibular Aqueduct - abnormalities; Vestibular system; Whole genome sequencing
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-021-02336-6

Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype–phenotype correlation, a significant part of cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4 . To explore the missing heritability, we first determined the presence of the previously described EVA-associated haplotype (Caucasian EVA (CEVA)), characterized by 12 single nucleotide variants located upstream of SLC26A4 . We found this haplotype and a delimited V1-CEVA haplotype to be significantly enriched in our M1 patient cohort (10/16 cases). The CEVA haplotype was also present in two M0 cases (2/12). Short- and long-read whole genome sequencing and optical genome mapping could not prioritize any of the variants present within the CEVA haplotype as the likely pathogenic defect. Short-read whole-genome sequencing of the six M1 cases without this haplotype and the two M0/CEVA cases only revealed previously overlooked or misinterpreted splice-altering SLC26A4 variants in two cases, who are now genetically explained. No deep-intronic or structural variants were identified in any of the M1 subjects. With this study, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases. For pinpointing the pathogenic effect of the CEVA haplotype, additional analyses are required addressing defect(s) at the RNA, protein, or epigenetic level.