Diagnostic pitfalls for <i><scp>GJB</scp>2</i>‐related hearing loss: A novel deletion detected by Array‐<scp>CGH</scp> analysis in a Japanese patient with congenital profound hearing loss

Abe, Satoko; Nishio, Shin‐ya; Yokota, Yoh; Moteki, Hideaki; Kumakawa, Kozo; Usami, Shin‐ichi

doi:10.1002/ccr3.1800

Cited by 6 publications

(6 citation statements)

References 20 publications

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“…In all the families, the mutation segregated with the phenotype, and all affected individuals reported a homozygous variant (TT genotype), except in one family where one affected individual was heterozygous (CT) and the other without any variant (CC), suggesting that there are other genes still to be discovered to explain the HI in this family. Similar to a family from Japan [37], the heterozygous GJB2-p.Arg143Trp variant in the above family did not segregate with the HI phenotype ( Figure 2B). Variants in the GJB6 gene are no longer considered as causes of hearing impairment.…”

Section: Discussionmentioning

confidence: 74%

“…In developing countries, the clinical use of NGS is still a major challenge because of the associated high cost of the equipment and the computational challenges posed by the approach [36]. However, there were some attempts to develop relatively simple, low cost, and population-specific screening approaches for some of the major hearing impairment gene mutations [37][38][39].…”

Section: Discussionmentioning

confidence: 99%

“…GJB2-p.Arg143Trp variant is known to be associated with profound HI [13,14,37]. The audiometric characterization of the GJB2-p.Arg143Trp homozygous individuals showed that they had profound HI.…”

Section: Discussionmentioning

confidence: 99%

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Enhancing Genetic Medicine: Rapid and Cost-Effective Molecular Diagnosis for a GJB2 Founder Mutation for Hearing Impairment in Ghana

Adadey

Wonkam

Aboagye

et al. 2020

Genes

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In Ghana, gap-junction protein β 2 (GJB2) variants account for about 25.9% of familial hearing impairment (HI) cases. The GJB2-p.Arg143Trp (NM_004004.6:c.427C>T/OMIM: 121011.0009/rs80338948) variant remains the most frequent variant associated with congenital HI in Ghana, but has not yet been investigated in clinical practice. We therefore sought to design a rapid and cost-effective test to detect this variant. We sampled 20 hearing-impaired and 10 normal hearing family members from 8 families segregating autosomal recessive non syndromic HI. In addition, a total of 111 unrelated isolated individuals with HI were selected, as well as 50 normal hearing control participants. A restriction fragment length polymorphism (RFLP) test was designed, using the restriction enzyme NciI optimized and validated with Sanger sequencing, for rapid genotyping of the common GJB2-p.Arg143Trp variant. All hearing-impaired participants from 7/8 families were homozygous positive for the GJB2-p.Arg143Trp mutation using the NciI-RFLP test, which was confirmed with Sanger sequencing. The investigation of 111 individuals with isolated non-syndromic HI that were previously Sanger sequenced found that the sensitivity of the GJB2-p.Arg143Trp NciI-RFLP testing was 100%. All the 50 control subjects with normal hearing were found to be negative for the variant. Although the test is extremely valuable, it is not 100% specific because it cannot differentiate between other mutations at the recognition site of the restriction enzyme. The GJB2-p.Arg143Trp NciI-RFLP-based diagnostic test had a high sensitivity for genotyping the most common GJB2 pathogenic and founder variant (p.Arg143Trp) within the Ghanaian populations. We recommend the adoption and implementation of this test for hearing impairment genetic clinical investigations to complement the newborn hearing screening program in Ghana. The present study is a practical case scenario of enhancing genetic medicine in Africa.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

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Enhancing Genetic Medicine: Rapid and Cost-Effective Molecular Diagnosis for a GJB2 Founder Mutation for Hearing Impairment in Ghana

Adadey

Wonkam

Aboagye

et al. 2020

Genes

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“…As there is not yet a disposable inner ear cell line, we decided to use the primary human nasal epithelial cells (HNECs) and small airway epithelial cells (SAECs), which effectively express GJB2 (http://dnase.genome.duke.edu/geneDetail.php?ensemblID=gjb2 (accessed on 25 April 2022)) (Figure 1A) [15]. In addition, large DFNB1 deletions have been associated with DFNB1 patients: del-920 kb [16], del-101 kb del(GJB2-D13S175) [17], del(GJB6-D13S1830) [18][19][20], del(GJB6- In addition, large DFNB1 deletions have been associated with DFNB1 patients: del-920 kb [16], del-101 kb del(GJB2-D13S175) [17], del(GJB6-D13S1830) [18][19][20], del(GJB6-D13S1854) [21], del-131kb [22], del-179 kb [23], del-8 kb [24], and a deletion of 3 kb in one patient [25].…”

Section: Introductionmentioning

confidence: 99%

3D Chromatin Organization Involving MEIS1 Factor in the cis-Regulatory Landscape of GJB2

Nabec

Blotas

Briset

et al. 2022

IJMS

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The human genome is covered by 8% of candidate cis-regulatory elements. The identification of distal acting regulatory elements and an understanding of their action are crucial to determining their key role in gene expression. Disruptions of such regulatory elements and/or chromatin conformation are likely to play a critical role in human genetic diseases. Non-syndromic hearing loss (i.e., DFNB1) is mostly due to GJB2 (Gap Junction Beta 2) variations and DFNB1 large deletions. Although several GJB2 cis-regulatory elements (CREs) have been described, GJB2 gene regulation remains not well understood. We investigated the endogenous effect of these CREs with CRISPR (clustered regularly interspaced short palindromic repeats) disruptions and observed GJB2 expression. To decipher the GJB2 regulatory landscape, we used the 4C-seq technique and defined new chromatin contacts inside the DFNB1 locus, which permit DNA loops and long-range regulation. Moreover, through ChIP-PCR, we determined the involvement of the MEIS1 transcription factor in GJB2 expression. Taken together, the results of our study enable us to describe the 3D DFNB1 regulatory landscape.

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“…Moreover, seven large DFNB1 deletions have been described in DFNB1 patients: del-920 kb [12], del-101 kb del(GJB2-D13S175) [13], del(GJB6-D13S1830) [14], del(GJB6-D13S1854) [15], del-131kb [16], del-179kb [17], and del-8kb [18]. This year, Brozkova et al described a DFNB1 deletion of 3 kb in one patient [11].…”

Section: Introductionmentioning

confidence: 99%

Whole-Genome Sequencing Improves the Diagnosis of DFNB1 Monoallelic Patients

Nabec

Collobert

Maréchal

et al. 2021

Genes

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Hearing loss is the most common sensory defect, due in most cases to a genetic origin. Variants in the GJB2 gene are responsible for up to 30% of non-syndromic hearing loss. Today, several deafness genotypes remain incomplete, confronting us with a diagnostic deadlock. In this study, whole-genome sequencing (WGS) was performed on 10 DFNB1 patients with incomplete genotypes. New variations on GJB2 were identified for four patients. Functional assays were realized to explore the function of one of them in the GJB2 promoter and confirm its impact on GJB2 expression. Thus, in this study WGS resolved patient genotypes, thus unlocking diagnosis. WGS afforded progress and bridged some gaps in our research.

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Diagnostic pitfalls for GJB2‐related hearing loss: A novel deletion detected by Array‐CGH analysis in a Japanese patient with congenital profound hearing loss

Cited by 6 publications

References 20 publications

Enhancing Genetic Medicine: Rapid and Cost-Effective Molecular Diagnosis for a GJB2 Founder Mutation for Hearing Impairment in Ghana

Enhancing Genetic Medicine: Rapid and Cost-Effective Molecular Diagnosis for a GJB2 Founder Mutation for Hearing Impairment in Ghana

3D Chromatin Organization Involving MEIS1 Factor in the cis-Regulatory Landscape of GJB2

Whole-Genome Sequencing Improves the Diagnosis of DFNB1 Monoallelic Patients

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