Dataset Information

A novel nonsense mutation in MYO15A is associated with non-syndromic hearing loss: a case report.

ABSTRACT:

Background

Hearing loss is genetically heterogeneous and is one of the most common human defects. Here we screened the underlying mutations that caused autosomal recessive non-syndromic hearing loss in a Chinese family.

Case presentation

The proband with profound hearing loss had received audiometric assessments. We performed target region capture and next generation sequencing of 127 known deafness-related genes because the individual tested negative for hotspot variants in the GJB2, GJB3, SLC26A4, and MTRNR1 genes. We identified a novel c.6892C > T (p.R2298*) nonsense mutation and a c.10251_10253delCTT (p.F3420del) deletion in MYO15A. Sanger sequencing confirmed that both mutations were co-segregated with hearing loss in this family and were absent in 200 ethnically matched controls. Bioinformatics analysis and protein modeling indicated the deleterious effects of both mutations. The p.R2298* mutation leads to a truncated protein and a loss of the functional domains.

Conclusions

Our results demonstrated that the hearing loss in this case was caused by novel, compound heterozygous mutations in MYO15A. The p.R2298* mutation in MYO15A was reported for the first time, which has implications for genetic counseling and provides insight into the functional roles of MYO15A mutations.

SUBMITTER: Ma D

PROVIDER: S-EPMC6090657 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

A novel nonsense mutation in MYO15A is associated with non-syndromic hearing loss: a case report.

Ma Di D Shen Shanshan S Gao Hui H Guo Hui H Lin Yumei Y Hu Yuhua Y Zhang Ruanzhang R Wang Shayan S

BMC medical genetics 20180801 1

<h4>Background</h4>Hearing loss is genetically heterogeneous and is one of the most common human defects. Here we screened the underlying mutations that caused autosomal recessive non-syndromic hearing loss in a Chinese family.<h4>Case presentation</h4>The proband with profound hearing loss had received audiometric assessments. We performed target region capture and next generation sequencing of 127 known deafness-related genes because the individual tested negative for hotspot variants in the G ...[more]

PMID: 30068307

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Project description:BackgroundMYO15A 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.MethodsFifteen 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.ResultsWe 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.ConclusionOur 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.

Project description:Mutations in the MYO15A gene are a widely recognized cause of autosomal recessive non-syndromic sensorineural hearing loss (NSHL) globally. Here, we examined the role and the genotype-phenotype correlation of MYO15A variants in a cohort of Chinese NSHL cases. Eighty-one cases with evidenced MYO15A variants from the 2263 Chinese NSHL cases, who underwent next-generation sequencing (NGS), were enrolled in the study. We investigated the association of MYO15A variants with the severity, progression and age of onset of hearing loss, as well as compared it to the previous reports in different nationalities. The cases were divided into groups according to the number of truncating variants: 2 truncating, 1 truncating and 1 non-truncating, 2 non-truncating variants, and compared the severity of HL among the groups. MYO15A accounted for 3.58% (81/2263) of all NSHL cases. We analyzed 81 MYO15A-related NSHL cases, 73 of whom were with congenital bilateral, symmetric or severe-to-profound hearing loss (HL), however, 2 of them had a postlingual, asymmetric, mild or moderate HL. There were 102 variants identified in all MYO15A structural domains, 76.47% (78/102) of whom were novel. The most common types of detected variants were missense (44/102, 43.14%), followed by frameshift (27/102, 26.47%), nonsense (14/102, 13.72%), splice site (10/102, 9.80%), in frame (4/102, 3.92%), non-coding (2/102, 1.96%) and synonymous (1/102, 0.98%). The most recurrent variant c.10245_10247delCTC was detected in 12 cases. We observed that the MYO15A variants, located in its N-terminal, motor and FERM domains, led to partial deafness with better residual hearing at low frequencies. There were 34 cases with biallelic truncating variants, 37 cases with monoallelic truncating variants, and 13 cases with biallelic non-truncating variants. The biallelic non-truncating variants group had the least number of cases (12/81), and most of them (10/12) were with profound NSHL. MYO15A is a major gene responsible for NSHL in China. Cases with MYO15A variants mostly showed early-onset, symmetric, severe-to-profound hearing loss. This study is by far the largest focused on the evaluation of the genotype-phenotype correlations among the variants in the MYO15A gene and its implication in the outcome of NSHL. The biallelic non-truncating MYO15A variants commonly caused profound HL, and the cases with one or two truncating MYO15A variants tended to increase the risk of HL. Nevertheless, further investigations are needed to clarify the causes for the variable severities and progression rates of hearing loss and the detected MYO15A variants in these cases.

Dataset Information

A novel nonsense mutation in MYO15A is associated with non-syndromic hearing loss: a case report.

Background

Case presentation

Conclusions

Publications

A novel nonsense mutation in MYO15A is associated with non-syndromic hearing loss: a case report.

Similar Datasets

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