University of Oulu

Smits, J.J., de Bruijn, S.E., Lanting, C.P. et al. Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant. Hum Genet (2021). https://doi.org/10.1007/s00439-021-02336-6

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

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Author: Smits, Jeroen J.1,2,3; de Bruijn, Suzanne E.2,3; Lanting, Cornelis P.1;
Organizations: 1Hearing and Genes, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands
2Department of Human Genetics, Radboud University Medical Center, Internal Postal Code 855, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
3Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
4Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, Oulu, Finland
5Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
6Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
7Radboud Expertise Center for Immunodeficiency and Autoinflammation and Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
8Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022032425028
Language: English
Published: Springer Nature, 2021
Publish Date: 2022-03-24
Description:

Abstract

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.

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Series: Human genetics
ISSN: 0340-6717
ISSN-E: 1432-1203
ISSN-L: 0340-6717
Volume: In press
DOI: 10.1007/s00439-021-02336-6
OADOI: https://oadoi.org/10.1007/s00439-021-02336-6
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: 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).
Copyright information: © The Author(s) 2021, corrected publication 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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