A Missense Mutation in<i> POU4F3</i> Causes Midfrequency Hearing Loss in a Chinese ADNSHL Family

Gao, Xue; Xu, Jin; Wang, Weiqian; Yuan, Yongyi; Bai, Dan; Huang, Shasha; Wang, Guojian; Su, Yu; Li, Jia; Kang, Dongyang; Mei-Guang, Zhang; Lin, Xiaobo; Dai, Pu

doi:10.1155/2018/5370802

Cited by 10 publications

(15 citation statements)

References 25 publications

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“…In deafness pedigrees, variants affecting protein function in 12 genes were verified with the positive diagnostic rate 56.67% (17/30) ( Table 3). Detailed information on these deafness pedigrees is provided in our previous studies [22][23][24][25][26][27][28][29].…”

Section: Positive Diagnostic Rate For Snvsmentioning

confidence: 99%

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Yuan

et al. 2019

Eur J Hum Genet

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Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.

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Section: Positive Diagnostic Rate For Snvsmentioning

confidence: 99%

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Yuan

et al. 2019

Eur J Hum Genet

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“…Kitano et al reported that POU4F3 -associated hearing loss usually presents with middle- or high-frequency hearing loss [ 14 ]. In 2018, we reported a family with middle-frequency hearing loss associated with POU4F3 c.602T>C (p.Leu201Pro) [ 12 ]. In this study, the proband in family C presented with typical middle-frequency hearing loss, and the older patients showed downsloping audiograms and mainly middle- and high-frequency hearing loss.…”

Section: Discussionmentioning

confidence: 99%

“…The methods for DNA library preparation, amplification, capture, detection, sequencing, and bioinformatics analyses were described previously [12]. Nonsynonymous variants were further evaluated for candidate pathogenic variants.…”

Section: Methodsmentioning

confidence: 99%

“…The tandem gait test was performed to evaluate the balance. The diagnosis of sensorineural hearing loss was made according to the WHO criteria based on audiometric examination performed as described previously (the methods description partly reproduces our wording) [ 12 ]. Tandem gait and Romberg tests were performed to evaluate balance.…”

Section: Methodsmentioning

confidence: 99%

“…In 1998, POU4F3 was first described as a disease-causing gene within the DFNA15 locus in an Israeli Jewish family [ 11 ]. To date, 32 variants (including those in this study) and whole-gene deletion of POU4F3 have been reported to cause ADNSHL with variable ages of onset and degrees of severity in various ethnic groups, including Chinese, Japanese, Dutch, Korean, and Brazilian populations [ 12 – 24 ]. In 2017, Kitano et al reported that POU4F3 variants represent the third largest cause of ADNSHL (2.5%, 15/602) in Japan and the most prevalent configuration as midfrequency hearing loss type followed by high-frequency hearing loss [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Cui

Gao²,

Huang

et al. 2020

Neural Plasticity

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Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.

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Highly variable hearing loss due to POU4F3 (c.37del) is revealed by longitudinal, frequency specific analyses

et al. 2023

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Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES). POU4F3 is noted for large intrafamilial variation including the age of onset of HL, audiogram configuration and presence of vestibular impairment. Sequential audiograms and longitudinal analyses reveal highly variable audiogram features among POU4F3 (c.37del) carriers, limiting the utility of ARTAs for clinical prognosis and management of HL. Furthermore, a comparison of ARTAs against three previously published families (1 Israeli Jewish, 2 Dutch) reveals significant interfamilial differences, with earlier onset and slower deterioration. This is the first published report of a North American family with ADSNHL due to POU4F3, the first report of the pathogenic c.37del variant, and the first study to conduct longitudinal analysis, extending the phenotypic spectrum of DFNA15.

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A Missense Mutation in POU4F3 Causes Midfrequency Hearing Loss in a Chinese ADNSHL Family

Cited by 10 publications

References 25 publications

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Highly variable hearing loss due to POU4F3 (c.37del) is revealed by longitudinal, frequency specific analyses

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