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
|Author:||Smits, Jeroen J.1,2,3; de Bruijn, Suzanne E.2,3; Lanting, Cornelis P.1;|
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
|Online Access:||PDF Full Text (PDF, 1.6 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022032425028
|Publish Date:|| 2022-03-24
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.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1184 Genetics, developmental biology, physiology
3121 General medicine, internal medicine and other clinical medicine
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).
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