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

Jeroen J Smits, Suzanne E de Bruijn, DOOFNL Consortium, Cornelis P Lanting, Jaap Oostrik, Luke O'Gorman, Tuomo Mantere, Frans P M Cremers, Susanne Roosing, Helger G Yntema, Erik de Vrieze, Ronny Derks, Alexander Hoischen, Sjoert A H Pegge, Kornelia Neveling, Ronald J E Pennings, Hannie Kremer, M.P. van der Schroeff

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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.

Original languageEnglish
Pages (from-to)465-484
Number of pages20
JournalHuman Genetics
Issue number3-4
Publication statusPublished - Apr 2022

Bibliographical note

Funding Information:
The authors thank Lieke Lamers, Jolinda Put and Evelien Verwoerd for their assistance in genetic analyses and Ronald van Beek, Ellen Kater-Baats, Marcel Nelen and Michiel Oorsprong for technical support. We would like to thank Mieke Wesdorp for including subjects in the study and Galuh D.N. Astuti and Christian Gilissen for their contribution to statistical and bioinformatic analyses. We thank the Radboudumc Genomics Technology Center, Radboud University Medical Center Nijmegen, for their technical assistance. The DOOFNL consortium is a Dutch nationwide collaboration on hereditary hearing loss and consists of M.F. van Dooren, S.G. Kant, H.H.W. de Gier, E.H. Hoefsloot, M.P. van der Schroeff (ErasmusMC, Rotterdam, the Netherlands), L.J.C. Rotteveel, F.G. Ropers (LUMC, Leiden, the Netherlands), J.C.C. Widdershoven, J.R. Hof, E.K. Vanhoutte (MUMC+, Maastricht, the Netherlands), I. Feenstra, H. Kremer, C.P. Lanting, R.J.E. Pennings, H.G. Yntema (Radboudumc, Nijmegen, the Netherlands), R.H. Free and J.S. Klein Wassink-Ruiter (UMCG, Groningen, the Netherlands), R.J. Stokroos, A.L. Smit, M.J. van den Boogaard (UMC, Utrecht, the Netherlands) and F.A. Ebbens, S.M. Maas, A. Plomp, T.P.M. Goderie, P. Merkus and J. van de Kamp (Amsterdam UMC, Amsterdam, the Netherlands).

Funding Information:
This study was financially supported by a DCMN Radboudumc grant (to H.K. and F.P.M.C.) and by a grant of the Heinsius-Houbolt foundation (to R.J.E.P. and H.K). TM was supported by the Sigrid Jusélius Foundation. This research was part of the Netherlands X-omics Initiative and partially funded by NWO (The Netherlands Organization for Scientific Research; project 184.034.019).

Publisher Copyright:
© 2021, The Author(s).


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