Identification of CDH23 mutations in Korean families with hearing loss by whole-exome sequencing

Woo, Hae-Mi; Park, Hong-Joon; Park, Mi-Hyun; Kim, Boyoung; Shin, Joong-Wook; Yoo, Won Gi; Koo, Soo Kyung

doi:10.1186/1471-2350-15-46

Cited by 20 publications

(26 citation statements)

References 17 publications

(23 reference statements)

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“…In a Japanese study, CDH23 mutations were reported to be frequent after GJB 2 and SLC26A4 in children and adults with hearing impairment [6]. Recently, CDH23 mutations have been reported in the Korean deaf population [7, 8], and genetic loads of CDH23 and its implications in the Korean pediatric population have also recently been reported [9]. Accordingly, p.P240L in CDH23 proved to exert a strong founder effect in the Korean pediatric population with severe-to-profound nonsyndromic SNHL.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…A homozygous c.5985C > A (p.Y1995X) variant, a heterozygous p.E1006K, and p.D1663V were detected in the Chinese population [47,48]. The mutation frequency spectrum of CDH23 among the recessive inherited cases is 5.7% in the Japanese population and 15% in the Korean population [16,19,49]. Other gene variants were also analyzed using such programs such as V66 M variant of human BDNF in psychiatric disorders and computational modeling of complete HOXB13 protein for predicting the functional effect of SNPs and the associated role in hereditary prostate cancer [50,51].…”

Section: Discussionmentioning

confidence: 99%

“…It accounted for up to 32% of Usher syndrome type 1 cases [13]. More than 24 associated mutations have been reported as missense mutations that clearly appeared as an important cause of hearing loss in Asian populations [16][17][18][19]. Recent research studies suggest that in silico mutation prediction might be used as a first-line molecular diagnosis tool serving both genetic counseling and mutation verification and variant classification [45,46].…”

Section: Discussionmentioning

confidence: 99%

“…More than 350 associated mutations have been reported as either homozygous nonsense, frame-shift, splice-site, or missense mutations [14,15]. Defective CDH23 was also detected in autosomal recessive non-syndromic hearing loss (OMIM #601386) (DFNB12) where more than 24 associated mutations have been reported as missense mutations [16][17][18][19]. In the cell membrane, CDH23 interacts with procadherin 15 (PCDH15) to create stereocilia organization and hair bundle formation which reflects its importance in normal inner-ear mechanotransduction [20].…”

Section: Introductionmentioning

confidence: 99%

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In silico analysis of a novel causative mutation in Cadherin23 gene identified in an Omani family with hearing loss

Al-Kindi

Al-Khabouri

Al-Lamki

et al. 2020

Journal of Genetic Engineering and Biotechnology

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Background: Hereditary hearing loss is a heterogeneous group of complex disorders with an overall incidence of one in every 500 newborns presented as syndromic and non-syndromic forms. Cadherin-related 23 (CDH23) is one of the listed deafness causative genes. It is found to be expressed in the stereocilia of hair cells and in the retina photoreceptor cells. Defective CDH23 have been associated mostly with prelingual severe-to-profound sensorineural hearing loss (SNHL) in either syndromic (USH1D) or non-syndromic SNHL (DFNB12) deafness. The purpose of this study was to identify causative mutations in an Omani family diagnosed with severe-profound sensorineural hearing loss by whole exome sequencing technique and analyzing the detected variant in silico for pathogenicity using several in silico mutation prediction software. Results: A novel homozygous missense variant, c.A7436C (p. D2479A), in exon 53 of CDH23 was detected in the family while the control samples were all negative for the detected variant. In silico mutation prediction analysis showed the novel substituted D2479A to be deleterious and protein destabilizing mutation at a conserved site on CDH23 protein. Conclusion:In silico mutation prediction analysis might be used as a useful molecular diagnostic tool benefiting both genetic counseling and mutation verification. The aspartic acid 2479 alanine missense substitution might be the main disease-causing mutation that damages CDH23 function and could be used as a genetic hearing loss marker for this particular Omani family.

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“…Similar to ARHGEF40 and BRD9, the function of CDH23 has not been established hitherto [47] in spite of being implicated in Usher syndrome type ID and non-syndromic hearing loss [50]. CDH23 belongs to the cadherin family, a family that mediates calcium-dependent cell adhesion [51]. Here, CDH23 was associated with biologic processes, such as the positive regulation of cytosolic calcium, regulation of cytosolic ion concentration, and cellular calcium ion homeostasis.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

Campos¹,

Fragoso²,

Luís³

et al. 2020

Genes

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Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.

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Identification of CDH23 mutations in Korean families with hearing loss by whole-exome sequencing

Cited by 20 publications

References 17 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

In silico analysis of a novel causative mutation in Cadherin23 gene identified in an Omani family with hearing loss

High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

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