High prevalence of CDH23 mutations in patients with congenital high-frequency sporadic or recessively inherited hearing loss

Mizutari, Kunio; Mutai, Hideki; Namba, Kazunori; Miyanaga, Yuko; Nakano, Atsuko; Arimoto, Yukiko; Masuda, Sawako; Morimoto, Noriko; Sakamoto, Hirokazu; Kaga, Kimitaka; Matsunaga, Tatsuo

doi:10.1186/s13023-015-0276-z

Cited by 39 publications

(35 citation statements)

References 29 publications

(53 reference statements)

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“…A contribution of the p.P240L allele to our adult-onset postlingual SNHL was confirmed by a higher frequency of this allele (2/64) in our adult SNHL cohort than in normal controls (1/2040) ( p <0.0001 by Fischer’s exact test). The p.P240L homozygotes were previously reported to cause prelingual severe-to-profound SNHL in a majority of cases [6, 9, 31]. According to our study, as well as previous Japanese studies, audiological phenotypes of CDH23 compound heterozygotes that carry one p.P240L allele seem to be highly variable [6, 31].…”

Section: Discussionsupporting

confidence: 80%

“…The p.P240L homozygotes were previously reported to cause prelingual severe-to-profound SNHL in a majority of cases [6, 9, 31]. According to our study, as well as previous Japanese studies, audiological phenotypes of CDH23 compound heterozygotes that carry one p.P240L allele seem to be highly variable [6, 31]. Indeed, SH151-324 carrying p.P240L/p.R1588W manifested progressive SNHL, which started from mid to high frequencies at the age of 20.…”

Section: Discussionsupporting

confidence: 78%

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Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

Kim

Lee

et al. 2016

PLoS ONE

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CDH23 mutations have mostly been associated with prelingual severe-to-profound sensorineural hearing loss (SNHL) in either syndromic or nonsyndromic SNHL (DFNB12). Herein, we demonstrate the contribution of CDH23 mutations to postlingual nonsyndromic SNHL (NS-SNHL). We screened 32 Korean adult probands with postlingual NS-SNHL sporadically or in autosomal recessive fashion using targeted panel or whole exome sequencing. We identified four (12.5%, 4/32) potential postlingual DFNB12 families that segregated the recessive CDH23 variants, qualifying for our criteria along with rapidly progressive SNHL. Three of the four families carried one definite pathogenic CDH23 variant previously known as the prelingual DFNB12 variant in a trans configuration with rare CDH23 variants. To determine the contribution of rare CDH23 variants to the postlingual NS-SNHL, we checked the minor allele frequency (MAF) of CDH23 variants detected from our postlingual NS-SNHL cohort and prelingual NS-SNHL cohort, among the 2040 normal control chromosomes. The allele frequency of these CDH23 variants in our postlingual cohort was 12.5%, which was significantly higher than that of the 2040 control chromosomes (5.53%), confirming the contribution of these rare CDH23 variants to postlingual NS-SNHL. Furthermore, MAF of rare CDH23 variants from the postlingual NS-SNHL group was significantly higher than that from the prelingual NS-SNHL group. This study demonstrates an important contribution of CDH23 mutations to poslingual NS-SNHL and shows that the phenotypic spectrum of DFNB12 can be broadened even into the presbycusis, depending on the pathogenic potential of variants. We also propose that pathogenic potential of CDH23 variants and the clinical fate of DFNB12 may be predicted by MAF.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 78%

Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

Kim

Lee

et al. 2016

PLoS ONE

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“…16,17,41 We did not observe this kind of genotypephenotype correlation in the current cohort; however, we noted that the rates of missense mutations of MYO7A and PCDH15 found in the USH2 patients were much higher than those detected in the USH1 patients. Two patients (019791 and 019691) were found harboring the mutations of more than one genes-one RP-causing gene and one USH1 gene or one inherited hearing loss gene.…”

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confidence: 52%

Comprehensive Molecular Screening in Chinese Usher Syndrome Patients

Sun

Ren

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese patients with USH and to describe the clinical features of the patients with mutations. METHODS.A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations. RESULTS.We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles. CONCLUSIONS.Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future.

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“…The threshold MAF for autosomal-dominant variants was set to 0.001, according to the criterion of "automatically benign" variants for autosomal-dominant variants adopted by the CLINGEN hearing loss expert panel [60]. The threshold MAF for autosomalrecessive variants was set to 0.003 in population databases and 0.005 in Japanese population databases, to avoid excluding an established pathogenic variant in CDH23 (NM_022124: c.719C>T) [61,62], which is present at an exceptionally high MAF in Japanese population databases (0.00248139 in HGVD [59] and 0.00327511 in our in-house data [55]).…”

Section: Genetic Analysismentioning

confidence: 99%

Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans

et al. 2020

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Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss. Furthermore, we detected another de novo missense variant of SLC12A2 in a sporadic case. SLC12A2 encodes Na + , K + , 2Cl − cotransporter (NKCC) 1 and plays critical roles in the homeostasis of K + -enriched endolymph. Slc12a2-deficient mice have congenital, profound deafness; however, no human variant of SLC12A2 has been reported as associated with hearing loss. All identified SLC12A2 variants mapped to exon 21 or its 3'-splice site. In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain. In vitro functional analysis demonstrated that Cl − influx was significantly decreased in all SLC12A2 variants studied. Immunohistochemistry revealed that SLC12A2

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High prevalence of CDH23 mutations in patients with congenital high-frequency sporadic or recessively inherited hearing loss

Cited by 39 publications

References 29 publications

Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

Comprehensive Molecular Screening in Chinese Usher Syndrome Patients

Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans

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