A Novel POU Domain Class 3 Transcription Factor 4 Mutation Causes X-Linked Non-Syndromic Hearing Loss in a Chinese Family
Hearing loss (HL) is a genetically heterogeneous disorder, with over 120 genes implicated in its pathogenesis. Among these, X-linked forms account for a small but significant proportion of cases. POU domain class 3 transcription factor 4 (POU3F4), also known as BRN-4, is a critical gene associated with X-linked non-syndromic HL (DFNX2). This study reports a novel nonsense mutation in POU3F4 causing DFNX2 in a three-generation Chinese Han family, expanding the mutational spectrum of this disorder and underscoring the clinical and genetic complexity of hereditary HL.
Clinical Presentation and Family Pedigree
The proband, a 20-year-old male, presented with congenital bilateral severe-to-profound HL. Clinical evaluations revealed intact tympanic membranes, no middle ear effusion, and unresponsive auditory brainstem responses at 105 dB normalized hearing level (dBnHL) in both ears (Figure 1B, 1C). High-resolution computed tomography (CT) of the temporal bones demonstrated bilateral cochlear hypoplasia in the inferior gyrus, absence of the spiral plate, and aberrant communication between the vestibule and cochlea (Figure 1D). These findings aligned with inner ear malformations characteristic of DFNX2.
The family pedigree included 14 members across three generations, with five affected individuals (four males and one female) exhibiting HL (Figure 1A). Male members (II:2, II:7, III:4, III:5) and one female (II:1) showed variable HL onset and severity. Notably, the female proband’s mother (II:2) developed HL at one year of age, while other carrier females (II:3, II:5) had normal hearing. This pattern suggested X-linked recessive inheritance with incomplete penetrance or modifying factors in female carriers.
Genetic Analysis and Mutation Identification
Whole-exome sequencing (WES) was performed on six family members, including the proband (III:4), his parents (II:3, II:4), and extended relatives (II:1, II:2, III:1). A novel hemizygous or heterozygous mutation (POU3F4, NM_000307.3: c.C76>T, p.Gln26*) was identified. This mutation substitutes a glutamine codon (CAG) with a premature stop codon (TAG), truncating the protein at residue 26 (Figure 1E, 1F). Sanger sequencing confirmed segregation of the mutation with the disease phenotype: affected males (II:7, III:4, III:5) harbored the hemizygous variant, while female carriers (II:3, II:5) were heterozygous. Unaffected males (II:4, III:1, III:2) lacked the mutation, supporting its pathogenicity. The mutation was absent in 250 ethnically matched controls, excluding a benign polymorphism.
Functional Implications of the POU3F4 Mutation
The POU3F4 gene, located at Xq21.1, encodes a transcription factor critical for inner ear morphogenesis. The protein comprises a POU-specific domain (75 amino acids) and a POU-homeodomain (63 amino acids), both essential for DNA binding and transcriptional regulation. Truncation at residue 26 eliminates these functional domains, disrupting normal cochlear development.
In murine models, Pou3f4 deficiency causes malformations of the stapes, cochlear duct, and spiral ganglion neurons. Similarly, human POU3F4 mutations correlate with inner ear anomalies, including incomplete partition of the cochlea, stapes fixation, and perilymphatic gushers during cochlear implantation. The proband’s CT findings—cochlear hypoplasia and vestibulocochlear communication—align with these phenotypes, reinforcing the mutation’s role in aberrant inner ear development.
Phenotypic Variability and Female Carriers
Female carriers (II:3, II:5) exhibited normal hearing, consistent with X-linked recessive inheritance. However, the proband’s mother (II:2), a heterozygous carrier, had early-onset severe HL. This contrasts with prior reports of minimal or late-onset HL in female POU3F4 mutation carriers. Possible explanations include skewed X-inactivation, where the mutant allele is predominantly active in auditory structures, or environmental modifiers. The study highlights the need for long-term audiologic monitoring in female carriers, even in families with typical X-linked inheritance patterns.
Cochlear Implantation Outcomes
Cochlear implantation (CI) remains the primary intervention for severe-to-profound HL in DFNX2. The proband (III:4) underwent CI, demonstrating postoperative sound detection, while his cousin (III:5) showed favorable language development after unilateral implantation at age six. However, DFNX2 patients often present surgical challenges due to perilymphatic gushers, caused by abnormal connections between the subarachnoid space and cochlea. Preoperative CT and genetic diagnosis enable surgeons to anticipate and manage intraoperative complications, optimizing outcomes.
Diagnostic and Counseling Implications
This study underscores the utility of whole-exome sequencing (WES) in diagnosing hereditary hearing loss (HL), particularly in small pedigrees with atypical presentations. The proband’s younger family members (III:1, III:2, III:3) sought genetic counseling to assess offspring risks. WES confirmed that they do not carry the POU3F4 mutation, alleviating concerns regarding DFNX2 transmission. However, maternal variants unrelated to POU3F4 were identified, necessitating further evaluation for potential HL risk.
Prenatal testing and preimplantation genetic diagnosis (PGD) are viable options for families with confirmed POU3F4 mutations. Early genetic diagnosis also informs neonatal hearing screening protocols, enabling timely intervention.
Conclusion
The c.C76>T (p.Gln26) mutation in POU3F4 represents a novel pathogenic variant causing X-linked non-syndromic HL in this Chinese family. Functional truncation of the protein disrupts inner ear development, correlating with severe auditory and structural deficits. Variable expressivity in female carriers and the proband’s favorable CI outcomes emphasize the importance of genetic testing and tailored clinical management. This study expands the POU3F4* mutation spectrum and reinforces the role of precision medicine in hereditary HL.
DOI: 10.1097/CM9.0000000000000425
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