Academic Journal
Optimising POU3F4 variant interpretation through gene-specific evidence in X-linked hearing loss.
| Τίτλος: | Optimising POU3F4 variant interpretation through gene-specific evidence in X-linked hearing loss. |
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| Συγγραφείς: | Geng J; Department of Otolaryngology-Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, China; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China., Zhao Y; Department of Otolaryngology, Head and Neck Surgery, People's Hospital, Peking University, Beijing, China., Huang Y; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China., Xiong W; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China., Zhong M; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China., Wang C; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China., Wang X; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China., Zhang Q; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China., Tang T; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China., Chen M; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China; Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Hunan, China., Fang L; Genomics Center, Core Facility of West China Hospital, Sichuan University, Chengdu, China., Yang Y; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China., Bu F; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China. Electronic address: bufengxiao@wchscu.cn., Cheng J; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China. Electronic address: chengjing@wchscu.cn., Lu Y; Department of Otolaryngology-Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, China; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China. Electronic address: luyu@wchscu.cn., Yuan H; Department of Otolaryngology-Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, China; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China. Electronic address: yuanhj301@wchscu.cn. |
| Πηγή: | EBioMedicine [EBioMedicine] 2026 Jun; Vol. 128, pp. 106318. Date of Electronic Publication: 2026 May 29. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101647039 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-3964 (Electronic) Linking ISSN: 23523964 NLM ISO Abbreviation: EBioMedicine Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Amsterdam] : Elsevier B.V., [2014]- |
| Ιατρικοί όροι (MeSH): | POU Domain Factors*/genetics , POU Domain Factors*/chemistry , Hearing Loss*/genetics , Hearing Loss*/diagnosis , Genetic Diseases, X-Linked*/genetics , Genetic Diseases, X-Linked*/diagnosis , Genetic Variation*, Humans ; Genetic Association Studies ; Bayes Theorem ; Mutation ; Polymorphism, Single Nucleotide ; Female ; Male ; Phenotype ; Genetic Predisposition to Disease ; Alleles |
| Περίληψη: | Background: Standardised variant interpretation frameworks inadequately accommodate the distinct mutational and phenotypic architectures inherent to specific genes or diseases. POU3F4 exemplifies this limitation in X-linked hearing loss, where stringent genotype-phenotype correlations and localised mutational hotspots dominate the pathogenic landscape. We sought to establish a calibrated, gene-specific evidentiary model to resolve interpretive inconsistencies for POU3F4. Methods: We sequenced 20,666 unrelated individuals with hearing loss and 7,258 controls using targeted panel and genome sequencing to capture single-nucleotide, indel, and structural variants in POU3F4. By integrating clinical phenotyping, paralog-based residue constraint modelling, and Bayesian likelihood-ratio analysis, we redefined evidence criteria for this gene. Representative stop-loss alleles underwent functional characterisation to elucidate their molecular consequences. Findings: Genomic analysis identified 123 distinct POU3F4 variants, 87 of which were classified as pathogenic (P) or likely pathogenic (LP). Structural variants accounted for 29 of these P/LP variants, with breakpoints enriched in repeat-dense sequence across the locus. Incomplete partition type III cochlear malformation showed near-diagnostic coupling to POU3F4, with 96.4% of affected cases carrying P/LP variants, supporting escalation of PP4 to strong evidence. P/LP missense variants were significantly concentrated at paralog-conserved residues, and Bayesian modelling of this constraint produced a positive likelihood ratio of 33.0 (95% confidence interval 10.68-102.28), consistent with moderate-strength hotspot evidence of PM1. Applying the calibrated rules reclassified 17 single nucleotide variants or small indels and resolved 16 of 34 variants of uncertain significance. Functional assays demonstrated that stop-loss variants generate hydrophobic C-terminal extensions that destabilise POU3F4, driving nuclear depletion and loss of transcriptional activity. Enforced nuclear targeting restored localisation but not transcription, implicating protein instability rather than impaired nuclear import as the dominant mechanism. Interpretation: POU3F4 pathogenicity is defined by a highly specific cochlear signature and profound topological constraint. Quantitative calibration of these features substantially refines diagnostic resolution in POU3F4-mediated hearing loss. The convergence of genomic modelling and functional validation establishes a calibrated evidentiary framework for consistent variant classification. Funding: This work was supported by National Natural Science Foundation of China (82530036, 82471889, 82171836), National Key Research and Development Program of China (2024YFC3405704), West China Hospital, Sichuan University 1.3.5 Project for Disciplines of Excellence grant ZYJC20002, Sichuan Provincial Natural Science Foundation (2024NSFSC0648). (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of interests All the authors declare no competing interests. |
| Contributed Indexing: | Keywords: ACMG/AMP criteria; Copy-number variation; Gene-specific variant interpretation; POU3F4; Stop-loss variants; X-linked hearing loss |
| Substance Nomenclature: | 0 (POU3F4 protein, human) 0 (POU Domain Factors) |
| Entry Date(s): | Date Created: 20260529 Date Completed: 20260613 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| PubMed Central ID: | PMC13242011 |
| DOI: | 10.1016/j.ebiom.2026.106318 |
| PMID: | 42214845 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 2352-3964 |
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| DOI: | 10.1016/j.ebiom.2026.106318 |