Analyses of del(GJB6‐D13S1830) and del(GJB6‐D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families

Pandya, Arti; O’Brien, Alexander; Kovasala, Michael; Bademci, Güney; Tekin, Mustafa; Arnos, Kathleen S.

doi:10.1002/mgg3.1171

Cited by 11 publications

(13 citation statements)

References 80 publications

(98 reference statements)

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“…Six GJB6 large genomic deletions have been found and previously reported, they are: >920kb deletion [114], 179 kb deletion [115], 131 kb deletion [116], del(GJB2-D13S175), del(GJB6-D13S1830) and del(GJB6-D13S1854) [117]. In addition to the six, there was a report of a seventh GJB6 deletion, del(GJB6-D13S1834), in February 2020 [118]. We identified the large genomic deletions, GJB6-D13S1830, and GJB6-D18S1854 as the frequently reported GJB6 variants.…”

Section: Discussionmentioning

confidence: 91%

Connexin Genes Variants Associated with Non-Syndromic Hearing Impairment: A Systematic Review of the Global Burden

Adadey

Wonkam‐Tingang

Aboagye

et al. 2020

Life

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Mutations in connexins are the most common causes of hearing impairment (HI) in many populations. Our aim was to review the global burden of pathogenic and likely pathogenic (PLP) variants in connexin genes associated with HI. We conducted a systematic review of the literature based on targeted inclusion/exclusion criteria of publications from 1997 to 2020. The databases used were PubMed, Scopus, Africa-Wide Information, and Web of Science. The protocol was registered on PROSPERO, the International Prospective Register of Systematic Reviews, with the registration number “CRD42020169697”. The data extracted were analyzed using Microsoft Excel and SPSS version 25 (IBM, Armonk, New York, United States). A total of 571 independent studies were retrieved and considered for data extraction with the majority of studies (47.8% (n = 289)) done in Asia. Targeted sequencing was found to be the most common technique used in investigating connexin gene mutations. We identified seven connexin genes that were associated with HI, and GJB2 (520/571 publications) was the most studied among the seven. Excluding PLP in GJB2, GJB6, and GJA1 the other connexin gene variants (thus GJB3, GJB4, GJC3, and GJC1 variants) had conflicting association with HI. Biallelic GJB2 PLP variants were the most common and widespread variants associated with non-syndromic hearing impairment (NSHI) in different global populations but absent in most African populations. The most common GJB2 alleles found to be predominant in specific populations include; p.Gly12ValfsTer2 in Europeans, North Africans, Brazilians, and Americans; p.V37I and p.L79Cfs in Asians; p.W24X in Indians; p.L56Rfs in Americans; and the founder mutation p.R143W in Africans from Ghana, or with putative Ghanaian ancestry. The present review suggests that only GJB2 and GJB3 are recognized and validated HI genes. The findings call for an extensive investigation of the other connexin genes in many populations to elucidate their contributions to HI, in order to improve gene-disease pair curations, globally.

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Section: Discussionmentioning

confidence: 91%

Connexin Genes Variants Associated with Non-Syndromic Hearing Impairment: A Systematic Review of the Global Burden

Adadey

Wonkam‐Tingang

Aboagye

et al. 2020

Life

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“…Seven large genomic deletions of GJB6 have been previously reported, including >920 kb deletion (Feldmann et al, 2009 ), 179 kb deletion (Tayoun et al, 2016 ), 131 kb deletion (Wilch et al, 2010 ), del( GJB6 -D13S175), del( GJB6 -D13S1830), del( GJB6 -D13S1854; Bliznetz et al, 2017 ) and del( GJB6 -D13S1834; Pandya et al, 2020 ). Homozygous deletion of GJB6 results in severe to profound hearing loss in humans, similar to the mouse model (Teubner et al, 2003 ; Mei et al, 2017 ; Pandya et al, 2020 ). In many cases, the large deletions of GJB6 disrupt a 50 cis-acting element upstream of both genes, which abolishes the expression of GJB2 , and hence is responsible for the phenotype (Rodriguez-Paris and Schrijver, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

“…In many cases, the large deletions of GJB6 disrupt a 50 cis-acting element upstream of both genes, which abolishes the expression of GJB2 , and hence is responsible for the phenotype (Rodriguez-Paris and Schrijver, 2009 ). A recent study reported the del ( GJB6 -D13S1830) deletion in 16.35% of all GJB2 heterozygotes, which causes more profound hearing loss than those with bi-allelic change in GJB2 (Pandya et al, 2003 , 2020 ; Snoeckx et al, 2005 ). The more severe audiological findings in digenic probands cannot be explained by the sole theory of a putative cis-regulatory element in the deleted region (Pandya et al, 2020 ), suggesting that both GJB6 and GJB2 products may contribute to the hearing loss.…”

Section: Discussionmentioning

confidence: 99%

“…Seven large genomic deletions of GJB6 have been previously reported, including >920 kb deletion (Feldmann et al, 2009), 179 kb deletion (Tayoun et al, 2016), 131 kb deletion (Wilch et al, 2010), del(GJB6-D13S175), del(GJB6-D13S1830), del(GJB6-D13S1854; Bliznetz et al, 2017) and del(GJB6-D13S1834; Pandya et al, 2020). Homozygous deletion of GJB6 results in severe to profound hearing loss in humans, similar to the mouse model (Teubner et al, 2003;Mei et al, 2017;Pandya et al, 2020). In many cases, the large deletions of GJB6 disrupt a 50 cis-acting element upstream of both genes, which abolishes the expression of GJB2, and hence is responsible for the phenotype (Rodriguez-Paris and Schrijver, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Connexin30-Deficiency Causes Mild Hearing Loss With the Reduction of Endocochlear Potential and ATP Release

Chen

et al. 2022

Front. Cell. Neurosci.

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GJB2 and GJB6 are adjacent genes encoding connexin 26 (Cx26) and connexin 30 (Cx30), respectively, with overlapping expressions in the inner ear. Both genes are associated with the commonest monogenic hearing disorder, recessive isolated deafness DFNB1. Cx26 plays an important role in auditory development, while the role of Cx30 in hearing remains controversial. Previous studies found that Cx30 knockout mice had severe hearing loss along with a 90% reduction in Cx26, while another Cx30 knockout mouse model showed normal hearing with nearly half of Cx26 preserved. In this study, we used CRISPR/Cas9 technology to establish a new Cx30 knockout mouse model (Cx30−/−), which preserves approximately 70% of Cx26. We found that the 1, 3, and 6-month-old Cx30−/− mice showed mild hearing loss at full frequency. Immunofluorescence and HE staining suggested no significant differences in microstructure of the cochlea between Cx30−/− mice and wild-type mice. However, transmission electron microscopy showed slight cavity-like damage in the stria vascularis of Cx30−/− mice. And Cx30 deficiency reduced the production of endocochlear potential (EP) and the release of ATP, which may have induced hearing loss. Taken together, this study showed that lack of Cx30 can lead to hearing loss with an approximately 30% reduction of Cx26 in the present Cx30 knockout model. Hence, Cx30 may play an important rather than redundant role in hearing development.

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“…Moreover, all affected matrilineal relatives in these families exhibited variable severity, age at onset and audiometric configuration of hearing loss, which suggested that the mitochondrial 12S rRNA mutations were not sufficient to produce enough clinical phenotypes, hence, other modified factors including AmAn, nuclear genes, mitochondrial haplogroups or epigenetic modification may contribute to the deafness expression. Furthermore, mutations in GJB2 [42], GJB3 [43], GJB6 [44] and TRMU [45] were implicated to be associated with hearing impairment. However, the absent of any functional variants in these genes suggested that nuclear modified genes may not play active roles in the clinical expression of deafness-associated 12S rRNA mutations.…”

Section: Discussionmentioning

confidence: 99%

Screening for deafness-associated mitochondrial 12S rRNA mutations by using a multiplex allele-specific PCR method

et al. 2020

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Mitochondrial 12S rRNA A1555G and C1494T mutations are the major contributors to hearing loss. As patients with these mutations are sensitive to aminoglycosides, mutational screening for 12S rRNA is therefore recommended before the use of aminoglycosides. Most recently, we developed a novel multiplex allele-specific PCR (MAS-PCR) that can be used for detecting A1555G and C1494T mutations. In the present study, we employed this MAS-PCR to screen the 12S rRNA mutations in 500 deaf patients and 300 controls from 5 community hospitals. After PCR and electrophoresis, two patients with A1555G and one patient with C1494T were identified, this was consistent with Sanger sequence results. We further traced the origin of three Chinese pedigrees. Clinical evaluation revealed variable phenotypes of hearing loss including severity, age at onset and audiometric configuration in these patients. Sequence analysis of the mitochondrial genomes from matrilineal relatives suggested the presence of three evolutionarily conserved mutations: tRNACys T5802C, tRNALys A8343G and tRNAThr G15930A, which may result the failure in tRNAs metabolism and lead to mitochondrial dysfunction that was responsible for deafness. However, the lack of any functional variants in GJB2, GJB3, GJB6 and TRMU suggested that nuclear genes may not play active roles in deafness expression. Hence, aminoglycosides and mitochondrial genetic background may contribute to the clinical expression of A1555G/C1494T-induced deafness. Our data indicated that the MAS-PCR was a fast, convenience method for screening the 12S rRNA mutations, which was useful for early detection and prevention of mitochondrial deafness.

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Analyses of del(GJB6‐D13S1830) and del(GJB6‐D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families

Cited by 11 publications

References 80 publications

Connexin Genes Variants Associated with Non-Syndromic Hearing Impairment: A Systematic Review of the Global Burden

Connexin Genes Variants Associated with Non-Syndromic Hearing Impairment: A Systematic Review of the Global Burden

Connexin30-Deficiency Causes Mild Hearing Loss With the Reduction of Endocochlear Potential and ATP Release

Screening for deafness-associated mitochondrial 12S rRNA mutations by using a multiplex allele-specific PCR method

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