Evidence map›Paper›PMID 42214845›Full record

ArticleEBioMedicine2026

Optimising POU3F4 variant interpretation through gene-specific evidence in X-linked hearing loss.

Jia Geng, Yixin Zhao, Yu Huang, Wenyu Xiong, Mingjun Zhong, Chao Wang, Xiaolu Wang, Qian Zhang, Ting Tang, Meilin Chen and 6 more

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PubMed Full text at PMC Publisher
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Article in EBioMedicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

16 authors.

Jia GengDepartment of Otolaryngology-Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, China; Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China.
Yixin ZhaoDepartment of Otolaryngology, Head and Neck Surgery, People's Hospital, Peking University, Beijing, China.
Yu HuangInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China.
Wenyu XiongInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China.
Mingjun ZhongInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China.
Chao WangInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China.
Xiaolu WangInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China.
Qian ZhangInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China.
Ting TangInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China.
Meilin ChenInstitute 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.
Liyuan FangGenomics Center, Core Facility of West China Hospital, Sichuan University, Chengdu, China.
Ye YangInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China.
Fengxiao BuInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China. Electronic address: bufengxiao@wchscu.cn.
Jing ChengInstitute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, China. Electronic address: chengjing@wchscu.cn.
Yu LuDepartment 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.
Huijun YuanDepartment 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.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundStandardised 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.

methodsWe 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.

findingsGenomic 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.

interpretationPOU3F4 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.

fundingThis 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).

Indexed as

Genetic Diseases, X-LinkedGenetic VariationHearing LossPOU Domain FactorsAllelesBayes TheoremFemaleGenetic Association StudiesGenetic Predisposition to DiseaseHumansMaleMutationPhenotypePolymorphism, Single NucleotidePOU3F4 protein, humanPOU Domain FactorsACMG/AMP criteriaCopy-number variationGene-specific variant interpretationPOU3F4Stop-loss variantsX-linked hearing loss

Identifiers

PMID42214845
PMCPMC13242011

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.