Spectrum and frequencies of non <scp><i>GJB2</i></scp> gene mutations in Czech patients with early non‐syndromic hearing loss detected by gene panel NGS and whole‐exome sequencing

Brožková, Dana Šafka; Marková, Simona Poisson; Meszarosova, Anna Uhrova; Jencik, Jan; Čejnová, Vlasta; Čada, Zdeněk; Lastuvkova, Jana; Rašková, Dagmar; Seeman, Pavel

doi:10.1111/cge.13839

Cited by 22 publications

(14 citation statements)

References 19 publications

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“…Hearing restoration using gene therapy offers great hope for causative therapy of genetic forms of severe hearing impairment. Here, we asked whether AAV-mediated gene therapy could be applicable in a knock-out mouse model of non-syndromic hearing impairment DFNB93 ( Picher et al, 2017 ), characterized by moderate to severe hearing loss in patients ( Tabatabaiefar et al, 2011 ; Schrauwen et al, 2012 ; Bademci et al, 2016 ; Marková et al, 2016 ; Picher et al, 2017 ; Koohiyan et al, 2019 ; Park et al, 2020 ; Safka Brozkova et al, 2020 ). Plasmids encoding for bicistronic expression of Cabp2 and eGFP via the P2A peptide driven by the hCMV/hBA promoter and followed by the WPRE and bGH posttranscriptional elements were packaged into AAV2/1, and PHP.eB capsids ( Figure 1A and Supplementary Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…So far, to our knowledge, no gene-therapy study has targeted the Cabp2 gene, which encodes calcium binding protein 2, a potent modulator of voltage-gated Ca V 1.3 channels in inner hair cells (IHCs). Pathologic mutations in CABP2 have been identified in Iranian, Turkish, Italian, Czech, and Pakistani families ( Tabatabaiefar et al, 2011 ; Schrauwen et al, 2012 ; Bademci et al, 2016 ; Marková et al, 2016 ; Picher et al, 2017 ; Koohiyan et al, 2019 ; Park et al, 2020 ; Safka Brozkova et al, 2020 ) that lead to autosomal recessive moderate to severe non-syndromic hearing impairment DFNB93. Audiological assessment in those patients revealed an auditory synaptopathy phenotype with often intact otoacoustic emissions signifying outer hair cell (OHC) function being present at least in some patients ( Picher et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model

Oestreicher

Picher

Rankovic

et al. 2021

Front. Mol. Neurosci.

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Clinical management of auditory synaptopathies like other genetic hearing disorders is currently limited to the use of hearing aids or cochlear implants. However, future gene therapy promises restoration of hearing in selected forms of monogenic hearing impairment, in which cochlear morphology is preserved over a time window that enables intervention. This includes non-syndromic autosomal recessive hearing impairment DFNB93, caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels CaV1.3. Based on disease modeling in Cabp2–/– mice, DFNB93 hearing impairment has been ascribed to enhanced steady-state inactivation of IHC CaV1.3 channels, effectively limiting their availability to trigger synaptic transmission. This, however, does not seem to interfere with cochlear development and does not cause early degeneration of hair cells or their synapses. Here, we studied the potential of a gene therapeutic approach for the treatment of DFNB93. We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2–/– mice and assessed the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC CaV1.3 function resulting in improved hearing of Cabp2–/– mice. These preclinical results prove the feasibility of DFNB93 gene therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model

Oestreicher

Picher

Rankovic

et al. 2021

Front. Mol. Neurosci.

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“…TMC1 variants are a relatively common genetic cause of non-syndromic hearing loss, and accounts for 3.4% (19/557) of Pakistani ARNSHL patients (Kitajiri et al 2007a, b), 2.4% (3/125) of Chinese ARNSHL patients (Yang et al 2013), 0.69% (3/433) of Chinese hearing loss patients (Yuan et al 2020), 3.1% (4/131) of Western European GJB2-negative ARNSHL patients (Sommen et al 2016), 0.5% (1/200) of Dutch hearing loss patients (Seco et al 2017), 0.8% (4/491) of Palestinian hearing loss patients (Abu Rayyan et al 2020), 0.5% (1/197) of Czech hearing loss patients (Safka Brozkova et al 2020), 4.3% (4/93) to 8.1% (7/86) of Turkish ARNSHL (Kalay et al 2005;Sirmaci et al 2009), 5.9% (5/85) of Tunisian ARNSHL (Tlili et al 2008) and 0.9% (10/1119) of American (Sloan-Heggen et al 2016) hearing loss patients. Most cases of TMC1-associated hearing loss are identified as autosomal recessive inherited hearing loss, and only limited cases are identified as autosomal dominant.…”

Section: Introductionmentioning

confidence: 99%

Prevalence and clinical features of autosomal dominant and recessive TMC1-associated hearing loss

Nishio

Usami

2021

Hum Genet

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TMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (DFNA36) and autosomal recessive non-syndromic hearing loss (DFNB7/11). To date, 125 pathogenic variants in TMC1 have been reported. Most of the TMC1 variants are responsible for autosomal recessive hearing loss, with only 8 variants reported as causative for DFNA36. Here, we reported the prevalence of TMC1-associated hearing loss in a large non-syndromic hearing loss cohort of about 12,000 subjects. As a result, we identified 26 probands with TMC1-associated hearing loss, with the estimated prevalence of TMC1-associated hearing loss in the Japanese hearing loss cohort being 0.17% among all patients. Among the 26 probands with TMC1-associated hearing loss, 15 cases were identified from autosomal dominant hearing loss families. Based on the audiometric data from the probands, family members and previously reported cases, we evaluated hearing deterioration for DFNA36 patients. In addition, we performed haplotype analysis for 11 unrelated autosomal dominant hearing loss families carrying the same variant TMC1: NM_138691:c.1627G > A:p.Asp543Asn. The results clearly indicated that the same haplotype was present despite the families being unrelated, supporting the contention that this variant occurred by founder mutation.

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“…To estimate the stability of outcomes, we conducted sensitivity analyses by assessing the effects of removing low-quality publications (Francey et al, 2012 ; Chang and Choi, 2014 ; Gu et al, 2015 ; Vona et al, 2015 ; Bademci et al, 2016 ; Mehta et al, 2016 ; Sommen et al, 2016 ; Baux et al, 2017 ; Zazo Seco et al, 2017 ; Cabanillas et al, 2018 ; Guan et al, 2018 ; Marková et al, 2018 ; Sheppard et al, 2018 ; Back et al, 2019 ; Budde et al, 2020 ; Downie et al, 2020 ; Kim et al, 2020 ; Safka Brozkova et al, 2020 ). The summary prevalence of DFNB16 in non-GJB2 HL patients was 3.98% (95% CI: 0.0260–0.0606, I 2 = 70%, p < 0.01), which stabilized the findings in the range of that of crude analysis.…”

Section: Resultsmentioning

confidence: 99%

Prevalence and Characteristics of STRC Gene Mutations (DFNB16): A Systematic Review and Meta-Analysis

et al. 2021

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Background: Mutations in the STRC (MIM 606440) gene, inducing DFNB16, are considered a major cause of mild–moderate autosomal recessive non-syndromic hearing loss (ARNSHL). We conducted a systematic review and meta-analysis to determine the global prevalence and characteristics of STRC variations, important information required for genetic counseling.Methods: PubMed, Google Scholar, Medline, Embase, and Web of Science were searched for relevant articles published before January 2021.Results: The pooled prevalence of DFNB16 in GJB2-negative patients with hearing loss was 4.08% (95% CI: 0.0289–0.0573), and the proportion of STRC variants in the mild–moderate hearing loss group was 14.36%. Monoallelic mutations of STRC were 4.84% (95% CI: 0.0343–0.0680) in patients with deafness (non-GJB2) and 1.36% (95% CI: 0.0025–0.0696) in people with normal hearing. The DFNB16 prevalence in genetically confirmed patients (non-GJB2) was 11.10% (95% CI: 0.0716–0.1682). Overall pooled prevalence of deafness–infertility syndrome (DIS) was 36.75% (95% CI: 0.2122–0.5563) in DFNB16. The prevalence of biallelic deletions in STRC gene mutations was 70.85% (95% CI: 0.5824–0.8213).Conclusion: Variants in the STRC gene significantly contribute to mild–moderate hearing impairment. Moreover, biallelic deletions are a main feature of STRC mutations. Copy number variations associated with infertility should be seriously considered when investigating DFNB16.

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Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non‐syndromic hearing loss detected by gene panel NGS and whole‐exome sequencing

Cited by 22 publications

References 19 publications

Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model

Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model

Prevalence and clinical features of autosomal dominant and recessive TMC1-associated hearing loss

Prevalence and Characteristics of STRC Gene Mutations (DFNB16): A Systematic Review and Meta-Analysis

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