Hearing Phenotypes of Patients with Hearing Loss Homozygous for the <i>GJB2</i> c.235delc Mutation

Guo, Chang; Huang, Shasha; Yuan, Yongyi; Zhou, Ying; Wang, Ning; Kang, Dongyang; Yang, Su-Yan; Zhang, Xin; Gao, Xue; Dai, Pu

doi:10.1155/2020/8841522

Cited by 10 publications

(7 citation statements)

References 56 publications

(66 reference statements)

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“…Among these, GJB2 :c.109G>A and c.235delC are the 2 predominant variants in the East Asian population 7 . GJB2 :c.109G>A is associated with mild‐to‐moderate SNHL with incomplete penetrance, whereas c.235delC is associated with severe‐to‐profound SNHL 28,29 . Noticeably, USNHL occurred in 4% of the c.109G>A homozygotes and 5% of the GJB2 :c.[109G>A];[235del] compound heterozygotes 28 .…”

Section: Discussionmentioning

confidence: 99%

Genetic Underpinnings and Audiological Characteristics in Children With Unilateral Sensorineural Hearing Loss

Lee

Lin

Chiang

et al. 2023

Otolaryngol.--head neck surg.

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ObjectiveUnilateral sensorineural hearing loss (USNHL) is a condition commonly encountered in otolaryngology clinics. However, its molecular pathogenesis remains unclear. This study aimed to investigate the genetic underpinnings of childhood USNHL and analyze the associated audiological features.Study DesignRetrospective analysis of a prospectively recruited cohort.SettingTertiary referral center.MethodsWe enrolled 38 children with USNHL between January 1, 2018, and December 31, 2021, and performed physical, audiological, imaging, and congenital cytomegalovirus (cCMV) examinations as well as genetic testing using next‐generation sequencing (NGS) targeting 30 deafness genes. The audiological results were compared across different etiologies.ResultsCausative genetic variants were identified in 8 (21.1%) patients, including 5 with GJB2 variants, 2 with PAX3 variants, and 1 with the EDNRB variant. GJB2 variants were found to be associated with mild‐to‐moderate USNHL in various audiogram configurations, whereas PAX3 and EDNRB variants were associated with profound USNHL in flat audiogram configurations. In addition, whole‐genome sequencing and extended NGS targeting 213 deafness genes were performed in 2 multiplex families compatible with autosomal recessive inheritance; yet no definite causative variants were identified. Cochlear nerve deficiency and cCMV infection were observed in 9 and 2, respectively, patients without definite genetic diagnoses.ConclusionGenetic underpinnings can contribute to approximately 20% of childhood USNHL, and different genotypes are associated with various audiological features. These findings highlight the utility of genetic examinations in guiding the diagnosis, counseling, and treatment of USNHL in children.

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Section: Discussionmentioning

confidence: 99%

Genetic Underpinnings and Audiological Characteristics in Children With Unilateral Sensorineural Hearing Loss

Lee

Lin

Chiang

et al. 2023

Otolaryngol.--head neck surg.

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“…In addition, biallelic GJB2 , SLC26A4 , and CLDN9 (Ramzan et al 2021) recessive variants may cause asymmetric non-syndrome hearing loss. Specifically, the GJB2 c.235delC homozygous variant has been reported to account for a significant proportion of asymmetric hearing loss (Guo et al 2020). Nonetheless, no genetic etiology exhibiting consistently high penetration into the phenotype of asymmetric hearing loss has yet been reported, especially for nonsyndromic hearing loss.…”

Section: Discussionmentioning

confidence: 99%

Novel Molecular Genetic Etiology of Asymmetric Hearing Loss: Autosomal-Dominant LMX1A Variants

et al. 2022

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Introduction: Sensorineural hearing loss is the most common sensory disorder in humans. Genetic analyses have greatly increased our understanding of the pathogenic mechanisms in play. Thus, characterization of audiologic phenotypes by the genetic etiology may aid elucidation of the etiologies of certain types of inherited hearing loss. Further, delineation of specific audiologic phenotypes based on the genetic etiology aids our understanding of some types of inherited hearing loss in terms of the prediction of clinical course, revelation of genotype-phenotype correlations, and application of appropriate audiologic rehabilitation. Here, we describe the interesting audiologic characteristics of LMX1A-associated deafness, which revealed significant asymmetry between two ears.Methods: Among 728 probands of which genomic DNA went through exome sequencing regardless of any specific audiologic phenotypes, probands for which exome sequencing was performed and a causative LMX1A variant was found were all included. Five LMX1A-associated DFNA7 families (approximately 0.7%), the pedigrees of whom indicated autosomal-dominant hearing loss, were identified, and segregation was studied using Sanger sequencing. The affected individuals underwent comprehensive evaluations, including medical history reviews, physical examinations, imaging, and auditory phenotyping. We functionally characterized the novel LMX1A variants via computational structural modeling and luciferase reporter assays.Results: Among 728 probands of which genomic DNA went through exome sequencing, we identified four novel LMX1A heterozygous variants related to DFNA7 (c.622C>T:p.Arg208*, c.719A>G:p.Gln240Arg, c.721G>A:p.Val241Met, and c.887dup:p.Gln297Thrfs*41) and one harboring a de novo heterozygous missense LMX1A variant (c.595A>G;p. Arg199Gly) previously reported. It is important to note that asymmetric hearing loss was identified in all probands and most affected individuals, although the extent of asymmetry varied. Structural modeling revealed that the two missense variants, p.Gln240Arg and p.Val241Met, affected conserved residues of the homeodomain, thus attenuating LMX1A-DNA interaction. In addition, Arg208*-induced premature termination of translation destroyed the structure of the LMX1A protein, including the DNA-binding homeodomain, and p.Gln297Thrfs*41 led to the loss of the C-terminal helix involved in LIM2 domain interaction. Compared with the wild-type protein, all mutant LMX1A proteins had significantly reduced transactivation efficiency, indicating that the ability to elicit transcription of the downstream target genes of LMX1A was severely compromised. Thus, in line with the American College of Medical Genetics and Genomics guideline specified to genetic hearing loss, the four novel LMX1A variants were identified as "pathogenic" (p.Arg208* and p.Gln297Thrfs*41), "likely pathogenic" (p.Val241Met), and as a "variant of uncertain significance'' (p.Gln240Arg). Conclusion:For the first time, we suggest that LMX1A is one of the candidate genes which, i...

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“…Among these, GJB2:c.109G>A and c.235delC are the two predominant variants in the East Asian population 7 . GJB2:c.109G>A is associated with mild to moderate SNHL with incomplete penetrance, whereas c.235delC is associated with severe-to-profound SNHL 26,27 .…”

Section: Discussionmentioning

confidence: 99%

Genetic Underpinnings and Audiological Characteristics in Children with Unilateral Sensorineural Hearing Loss

Lee

Lin

Chiang

et al. 2022

Preprint

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Objective: Unilateral sensorineural hearing loss is a condition commonly encountered in otolaryngology clinics. However, its molecular pathogenesis remains unclear. This study aimed to investigate the genetic underpinnings of childhood unilateral sensorineural hearing loss and analyze the associated audiological features. Study Design: Retrospective analysis of a prospectively recruited cohort Setting: Tertiary referral center Methods: We enrolled 38 children with unilateral sensorineural hearing loss and performed physical, audiological, imaging, and congenital cytomegalovirus examinations as well as genetic testing using next-generation sequencing targeting 30 deafness genes. The audiological results were compared across different etiologies. Results: Causative genetic variants were identified in eight (21.1%) patients, including five with GJB2 variants, two with PAX3 variants, and one with EDNRB variant. GJB2 variants were associated with mild-to-moderate unilateral sensorineural hearing loss in various audiogram configurations, whereas PAX3 and EDNRB variants were associated with profound unilateral sensorineural hearing loss in flat audiogram configurations. In addition, whole genome sequencing and extended next-generation sequencing targeting 213 deafness genes were performed in two multiplex families compatible with autosomal recessive inheritance; yet no definite causative variants were identified. Cochlear nerve deficiency and congenital cytomegalovirus infection were observed in nine and two patients without definite genetic diagnoses. Conclusion: Genetic underpinnings can contribute to approximately 20% of childhood unilateral sensorineural hearing loss, and different genotypes are associated with various audiological features. These findings highlight the utility of genetic examinations in guiding the diagnosis, counseling, and treatment of unilateral sensorineural hearing loss in children.

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Hearing Phenotypes of Patients with Hearing Loss Homozygous for the GJB2 c.235delc Mutation

Cited by 10 publications

References 56 publications

Genetic Underpinnings and Audiological Characteristics in Children With Unilateral Sensorineural Hearing Loss

Genetic Underpinnings and Audiological Characteristics in Children With Unilateral Sensorineural Hearing Loss

Novel Molecular Genetic Etiology of Asymmetric Hearing Loss: Autosomal-Dominant LMX1A Variants

Genetic Underpinnings and Audiological Characteristics in Children with Unilateral Sensorineural Hearing Loss

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