Investigation of GSDME results in the identification of the first pathogenic synonymous variants and genotype-phenotype correlations

Joseph J Chin; W Daniel Walls; Kai Wang; Amanda M Odell; Diana L Kolbe; Kevin T A Booth; Hela Azaiez; Richard J H Smith

doi:10.1007/s00439-025-02782-6

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Investigation of GSDME results in the identification of the first pathogenic synonymous variants and genotype-phenotype correlations

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Investigation of GSDME results in the identification of the first pathogenic synonymous variants and genotype-phenotype correlations

Joseph J Chin, W Daniel Walls, Kai Wang, Amanda M Odell, Diana L Kolbe, Kevin T A Booth, Hela Azaiez and Richard J H Smith

Human genetics, Vol.144(11-12), pp.1127-1138

12/2025

DOI: 10.1007/s00439-025-02782-6

PMCID: PMC12689683

PMID: 41020988

Appears in UI Libraries Support Open Access

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Abstract

Despite advances in the genetic diagnosis of hearing loss, there remains room for improvement. One way to improve the genetic diagnostic rate is the proper assessment of synonymous variants that are often bioinformatically filtered out. We used GSDME as a model to demonstrate the importance of assessing synonymous variants. Variants in the gene GSDME (also known as DFNA5) are associated with autosomal dominant nonsyndromic hearing loss. The hearing loss is typically progressive and downsloping. All reported causative variants of GSDME-related hearing loss involve the skipping of exon 8, which results in the expression of a constitutively active, but truncated protein that induces apoptosis of cochlear hair cells. A retrospective search of previously tested patients identified 3 novel pathogenic synonymous GSDME variants. The functional impact of these variants was confirmed in vitro via a minigene splicing assay. We also observed variant-dependent differences in the levels of aberrant splicing, leading us to hypothesize that partial loss of splicing will result in a less severe hearing loss phenotype as compared to complete loss of splicing. Audiometric analysis found an association between complete loss of splicing and greater initial and/or more quickly progressing hearing loss as compared to partial loss of splicing. Over the course of the study, we also found limited correlation between in silico prediction and in vitro observed effects of a variant on splicing, indicating the need to cautiously apply in silico prediction tools in the context of genetic diagnosis.

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Title: Subtitle: Investigation of GSDME results in the identification of the first pathogenic synonymous variants and genotype-phenotype correlations
Creators: Joseph J Chin - University of Iowa
W Daniel Walls - University of Iowa
Kai Wang - University of Iowa
Amanda M Odell - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, 200 Hawkins Drive-21151 PFP, Iowa City, IA, 52242, USA
Diana L Kolbe - University of Iowa
Kevin T A Booth - Indiana University
Hela Azaiez - Indiana University
Richard J H Smith - University of Iowa
Resource Type: Journal article
Publication Details: Human genetics, Vol.144(11-12), pp.1127-1138
DOI: 10.1007/s00439-025-02782-6
PMID: 41020988
PMCID: PMC12689683
NLM abbreviation: Hum Genet
ISSN: 1432-1203
eISSN: 1432-1203
Publisher: Springer Nature
Grant note: GM139776 / National Institutes of Health-National Institute of General Medical Sciences DC002842 / National Institutes of Health-National Institute on Deafness and Other Communication Disorders
Language: English
Electronic publication date: 09/29/2025
Date published: 12/2025
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; Biostatistics; Otolaryngology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984966801002771

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