Dataset Information

Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment.

ABSTRACT: BACKGROUND:Hearing loss is a genetically and phenotypically heterogeneous disorder. OBJECTIVES:The purpose of this study was to determine the genetic cause underlying the postlingual progressive hearing loss in two Iranian families. METHODS:We used OtoSCOPE, a next-generation sequencing platform targeting >150 genes causally linked to deafness, to screen two deaf probands. Data analysis was completed using a custom bioinformatics pipeline, and variants were functionally assessed using minigene splicing assays. RESULTS:We identified two homozygous splice-altering variants (c.37G>T?and c.662-1G>C) in the CEACAM16 gene, segregating with the deafness in each family. The minigene splicing results revealed the c.37G>T results in complete skipping of exon 2 and loss of the AUG start site. The c.662-1G>C activates a cryptic splice site inside exon 5 resulting in a shift in the mRNA reading frame. CONCLUSIONS:These results suggest that loss-of-function mutations in CEACAM16 result in postlingual progressive hearing impairment and further support the role of CEACAM16 in auditory function.

SUBMITTER: Booth KT

PROVIDER: S-EPMC6060001 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Old gene, new phenotype: splice-altering variants in <i>CEACAM16</i> cause recessive non-syndromic hearing impairment.

Booth Kevin T KT Kahrizi Kimia K Najmabadi Hossein H Azaiez Hela H Smith Richard Jh RJ

Journal of medical genetics 20180427 8

<h4>Background</h4>Hearing loss is a genetically and phenotypically heterogeneous disorder.<h4>Objectives</h4>The purpose of this study was to determine the genetic cause underlying the postlingual progressive hearing loss in two Iranian families.<h4>Methods</h4>We used OtoSCOPE, a next-generation sequencing platform targeting >150 genes causally linked to deafness, to screen two deaf probands. Data analysis was completed using a custom bioinformatics pipeline, and variants were functionally ass ...[more]

PMID: 29703829

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Project description:BACKGROUND:MYO15A variants are responsible for human non-syndromic autosomal recessive deafness (DFNB3). The majority of MYO15A variants are associated with a congenital severe-to-profound hearing loss phenotype, except for MYO15A variants in exon 2, which cause a milder auditory phenotype, suggesting a genotype-phenotype correlation of MYO15A. However, MYO15A variants not in exon 2 related to a milder phenotype have also been reported, indicating that the genotype-phenotype correlation of MYO15A is complicated. This study aimed to provide more cases of MYO15A variation with diverse phenotypes to analyse this complex correlation. METHODS:Fifteen Chinese autosomal recessive non-syndromic hearing loss (ARNSHL) individuals with MYO15A variants (8 males and 7 females) from 14 unrelated families, identified by targeted gene capture of 127 known candidate deafness genes, were recruited. Additionally, we conducted a review of the literature to further analyses all reported MYO15A genotype-phenotype relationships worldwide. RESULTS:We identified 16 novel variants and 12 reported pathogenic MYO15A variants in 15 patients, two of which presented with a milder phenotype. Interestingly, one of these cases carried two reported pathogenic variants in exon 2, while the other carried two novel variants not in exon 2. Based on our literature review, MYO15A genotype-phenotype correlation analysis showed that almost all domains were reported to be correlated with a milder phenotype. However, variants in the N-terminal domain were more likely to cause a milder phenotype. Using next-generation sequencing (NGS), we also found that the number of known MYO15A variants with milder phenotypes in Southeast Asia has increased in recent years. CONCLUSION:Our work extended the MYO15A variant spectrum, enriched our knowledge of auditory phenotypes, and tried to explore the genotype-phenotype correlation in different populations in order to investigate the cause of the complex MYO15A genotype-phenotype correlation.

Dataset Information

Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment.

Publications

Old gene, new phenotype: splice-altering variants in <i>CEACAM16</i> cause recessive non-syndromic hearing impairment.

Similar Datasets

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