Identification of a Novel Founder EYA4 Structural Variant in North America

Jacquelyn K DeVries; Miles J Klimara; Amanda M Odell; Diana L Kolbe; Nicole Meyer; Paige L Harlan; Hela Azaiez; Richard J. H Smith

doi:10.1155/humu/4463081

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Identification of a Novel Founder EYA4 Structural Variant in North America

Journal article

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Identification of a Novel Founder EYA4 Structural Variant in North America

Jacquelyn K DeVries, Miles J Klimara, Amanda M Odell, Diana L Kolbe, Nicole Meyer, Paige L Harlan, Hela Azaiez and Richard J. H Smith

Human mutation, Vol.2026, 4463081

07/02/2026

DOI: 10.1155/humu/4463081

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Abstract

Objective(s) Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a genetically heterogeneous disorder. Copy‐number and structural variants (SVs) in EYA4 are a rare cause of hearing loss at the DFNA10 locus. We aimed to determine the genetic etiology of hearing loss in a series of families with ADNSHL. Methods We performed a retrospective review of patients referred for targeted genomic enrichment and massively parallel sequencing using the OtoSCOPE panel, which covers known genes associated with nonsyndromic hearing loss (NSHL). Genetic findings and available phenotypic data were reviewed by a multidisciplinary team to assess variant pathogenicity. Haplotypes were reconstructed using variants in EYA4 and flanking regions. Results A novel pathogenic SV in EYA4 involving a 5.8 kb deletion of the Terminal Exons 19 and 20, with insertion of a short, inverted downstream sequence, was identified in five North American probands with a family history consistent with ADNSHL. Segregation analysis demonstrated cosegregation with hearing loss in two affected relatives. This SV is the most frequently detected pathogenic variant in EYA4 in our cohort, accounting for five of 25 (20%) DFNA10 diagnoses to date. Haplotype reconstruction demonstrated an extended shared 857 kB haplotype surrounding the region. Conclusion This study expands the mutational spectrum of EYA4‐associated hearing loss. The complexity of this novel SV, its identical breakpoint structure, and shared haplotype support a founder origin of this allele rather than a recurrent event. These findings highlight the importance of systematic and comprehensive CNV/SV analysis in routine genetic testing for hearing loss and show that clinically relevant complex SVs may be overlooked without careful evaluation.

Etiology

Genomics

Mutation

Audiometry

Exons

Families & family life

Genealogy

Genetic analysis

Genetic testing

Genotype & phenotype

Haplotypes

Hearing loss

Hearing protection

Pathogenicity

Polymorphism

UIOWA OA Agreement

Details

Title: Subtitle: Identification of a Novel Founder EYA4 Structural Variant in North America
Creators: Jacquelyn K DeVries - University of Iowa
Miles J Klimara - University of Iowa
Amanda M Odell - University of Iowa
Diana L Kolbe - University of Iowa
Nicole Meyer - University of Iowa
Paige L Harlan - University of Iowa
Hela Azaiez - University of Iowa
Richard J. H Smith - University of Iowa
Resource Type: Journal article
Publication Details: Human mutation, Vol.2026, 4463081
DOI: 10.1155/humu/4463081
ISSN: 1059-7794
eISSN: 1098-1004
Publisher: Wiley
Grant note: National Institute on Deafness and Other Communication Disorders: DC017955, DC012049, DC002842, 5T32DC000040
This project was supported in part by NIH-NIDCD Grants DC002842, DC012049, and DC017955 (RJHS) and NIH-NIDCD Grant 5T32DC000040 (M.J.K. and J.K.D.).
Language: English
Date published: 07/02/2026
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9985179853002771

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