Hearing Loss and Enlarged Vestibular Aqueduct (EVA) in a Patient Negative for Canonical EVA Genes: Potential Role of SCD5
7 affiliations
- 1Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria
- 2Department of Otorhinolaryngology, Head and Neck Surgery, Paracelsus Medical University, 5020 Salzburg, Austria
- 3Institute of Biophysics, National Research Council, 16149 Genoa, Italy
- 4Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
- 5Bioacoustics Research Laboratory, Department of Neurosciences, University of Padova, 35129 Padova, Italy
- 6Department of Otorhinolaryngology, University Hospital Regensburg, 93053 Regensburg, Germany
- 7Research and Innovation Center Regenerative Medicine & Novel Therapies (FIZ RM&NT), Paracelsus Medical University, 5020 Salzburg, Austria
Abstract
Biallelic pathogenic variants in SLC26A4 cause hearing loss with an Enlarged Vestibular Aqueduct (EVA), but approximately 50% of EVA patients in Caucasian cohorts remain genetically unresolved, suggesting the presence of overlooked variants at canonical EVA loci or the involvement of non-canonical genes. Here, we investigated a 42-year-old Caucasian male presenting with bilateral mixed hearing loss and EVA who tested negative for established EVA genes but harbored two heterozygous variants of uncertain significance: Repressor Element 1-Silencing Transcription Factor (REST) c.3272_3274delAAG (p.E1091del) and Stearoyl-CoA Desaturase 5 (SCD5) c.452T>G (p.F151C). Segregation analysis revealed that the variants were inherited from normal-hearing parents, prompting whole-genome sequencing, which ruled out causative deep intronic or promoter variants at the EVA loci SLC26A4, FOXI1, and KCNJ10, as well as in the coding regions of the genes encoding SLC26A4-interacting proteins EPHA2, IQGAP1, and AP-2. Functional testing showed that while the REST variant did not affect cell viability or transcriptional regulation, the SCD5 variant significantly reduced cell viability and induced robust intracellular accumulation of reactive oxygen species (ROS), triggering compensatory activation of the Nrf2/SOD antioxidant axis, thereby supporting pathogenicity. This study expands the phenotypic spectrum of SCD5 by suggesting a novel association between this gene and EVA for the first time and highlights the potential role of oxidative stress in inner ear malformations.
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BibTeX
@article{liuni2026hearing,
title = {{Hearing Loss and Enlarged Vestibular Aqueduct (EVA) in a Patient Negative for Canonical EVA Genes: Potential Role of SCD5}},
author = {Raffaella Liuni and Lennart Weitgasser and Paola Gavazzo and Angela Marino and Laura Astolfi and Sebastian Roesch and Silvia Dossena},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16111563},
url = {https://www.mdpi.com/2218-273X/16/11/1563},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hearing Loss and Enlarged Vestibular Aqueduct (EVA) in a Patient Negative for Canonical EVA Genes: Potential Role of SCD5
AU - Raffaella Liuni
AU - Lennart Weitgasser
AU - Paola Gavazzo
AU - Angela Marino
AU - Laura Astolfi
AU - Sebastian Roesch
AU - Silvia Dossena
PY - 2026
DA - 2026/10/26
JO - Biomolecules
DO - 10.3390/biom16111563
UR - https://www.mdpi.com/2218-273X/16/11/1563
AB - Biallelic pathogenic variants in SLC26A4 cause hearing loss with an Enlarged Vestibular Aqueduct (EVA), but approximately 50% of EVA patients in Caucasian cohorts remain genetically unresolved, suggesting the presence of overlooked variants at canonical EVA loci or the involvement of non-canonical genes. Here, we investigated a 42-year-old Caucasian male presenting with bilateral mixed hearing loss and EVA who tested negative for established EVA genes but harbored two heterozygous variants of uncertain significance: Repressor Element 1-Silencing Transcription Factor (REST) c.3272_3274delAAG (p.E1091del) and Stearoyl-CoA Desaturase 5 (SCD5) c.452T>G (p.F151C). Segregation analysis revealed that the variants were inherited from normal-hearing parents, prompting whole-genome sequencing, which ruled out causative deep intronic or promoter variants at the EVA loci SLC26A4, FOXI1, and KCNJ10, as well as in the coding regions of the genes encoding SLC26A4-interacting proteins EPHA2, IQGAP1, and AP-2. Functional testing showed that while the REST variant did not affect cell viability or transcriptional regulation, the SCD5 variant significantly reduced cell viability and induced robust intracellular accumulation of reactive oxygen species (ROS), triggering compensatory activation of the Nrf2/SOD antioxidant axis, thereby supporting pathogenicity. This study expands the phenotypic spectrum of SCD5 by suggesting a novel association between this gene and EVA for the first time and highlights the potential role of oxidative stress in inner ear malformations.
SN - 2218-273X
ER -