Autosomal Dominant Nonsyndromic Deafness Research Articles

Mutation-agnostic RNA interference with engineered replacement rescues Tmc1-related hearing loss.

Hearing loss is the most common sensory deficit, of which genetic etiologies are a frequent cause. Dominant and recessive mutations in TMC1, a gene encoding the pore-forming subunit of the hair cell mechanotransduction channel, cause DFNA36 and DFNB7/11, respectively, accounting for ∼2% of genetic hearing loss. Previous work has established the efficacy of mutation-targeted RNAi in treatment of murine models of autosomal dominant non-syndromic deafness. However, application of such approaches is limited by the infeasibility of development and validation of novel constructs for each variant. We developed an allele-non-specific approach consisting of mutation-agnostic RNAi suppression of both mutant and WT alleles, co-delivered with a knockdown-resistant engineered WT allele with or without the use of woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) to augment transgene expression. This therapeutic construct was delivered into the mature murine model of DFNA36 with an AAV vector and achieved robust hair cell and auditory brainstem response preservation. However, WPRE-enhanced Tmc1 expression resulted in inferior outcomes, suggesting a role for gene dosage optimization in future TMC1 gene therapy development.

Aldh inhibitor restores auditory function in a mouse model of human deafness.

Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.

Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss.

Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.

Whole exome sequencing identifies SCD5 as a novel causative gene for autosomal dominant nonsyndromic deafness.

We report a genetic assessment of autosomal dominant, nonsyndromic, progressive sensorineural hearing loss in a Chinese family, combining whole-exome sequencing and genome-wide linkage analysis. A novel missense mutation, c.626G>C, in the SCD5 gene was identified in this family. The heterozygous missense mutation could segregate hearing loss cases among family members, and was predicted to be deleterious by Polyphen-2, LRT and Mutation Taster. SCD5 is an endoplasmic reticulum enzyme, catalyzing the formation of monounsaturated fatty acids (MUFAs) from saturated fatty acids (SFAs). It plays a crucial role in regulating lipid metabolism. The SCD5 protein is expressed in inner and outer hair cells of the organ of Corti, the stria vascularis, cells of the lateral cochlear wall behind the spiral prominence, and more strongly in spiral ganglion cells of guinea pig and human fetal cochleas. SCD5 protein was also expressed in the brain, consistent with the hearing loss feature: the patients had a poor speech discrimination score at young age and mild hearing loss as evaluated by pure tone audiometry. In summary, we identified SCD5 as a novel gene responsible for autosomal dominant nonsyndromic deafness.

A novel pore-region mutation, c.887G\u2009>\u2009A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2

BackgroundHereditary non-syndromic hearing loss is the most common inherited sensory defect in humans. The KCNQ4 channel belongs to a family of potassium ion channels that play crucial roles in physiology and disease. Mutations in KCNQ4 underlie deafness non-syndromic autosomal dominant 2, a subtype of autosomal dominant, progressive, high-frequency hearing loss.MethodsA six-generation Chinese family from Hebei Province with autosomal dominantly inherited, sensorineural, postlingual, progressive hearing loss was enrolled in this study. Mutation screening of 129 genes associated with hearing loss was performed in five family members by next-generation sequencing (NGS). We also carried out variant analysis on DNA from 531 Chinese individuals with normal hearing as controls.ResultsThis family exhibits postlingual, progressive, symmetrical, bilateral, non-syndromic sensorineural hearing loss. NGS, bioinformatic analysis, and Sanger sequencing confirmed the co-segregation of a novel mutation [c.887G > A (p.G296D)] in KCNQ4 with the disease phenotype in this family. This mutation leads to a glycine-to-aspartic acid substitution at position 296 in the pore region of the KCNQ4 channel. This mutation affects a highly conserved glutamic acid. NGS is a highly efficient tool for identifying gene mutations causing heritable disease.ConclusionsProgressive hearing loss is common in individuals with KCNQ4 mutations. NGS together with Sanger sequencing confirmed that the five affected members of this Chinese family inherited a missense mutation, c.887G > A (p.G296D), in exon 6 of KCNQ4. Our results increase the number of identified KCNQ4 mutations.

WFS1 and GJB2 mutations in patients with bilateral low-frequency sensorineural hearing loss.

Evaluating the prevalence of specific gene mutations associated with a certain audiometric configuration facilitates clinical assessment of patients with sensorineural hearing loss (SNHL). WFS1 is responsible for autosomal dominant nonsyndromic deafness 6/14/38 and is the most frequent genetic cause of low-frequency SNHL (LFSNHL); however, the exact prevalence of WFS1 mutations in LFSNHL is unknown. Therefore, we evaluated genetic mutations and clinical features in patients with nonsyndromic bilateral LFSNHL, focusing on the WFS1. Retrospective case series from 2002 to 2013 at the National Hospital Organization Tokyo Medical Center and collaborating hospitals. WFS1, GJB2, and mitochondrial DNA mutation screening was carried out for 74 of 1,007 Japanese probands with bilateral LFSNHL. WFS1 and GJB2 mutations were identified in eight of 74 cases (10.8%). Four cases had heterozygous WFS1 mutations; one case had a heterozygous WFS1 mutation and a heterozygous GJB2 mutation; and three cases had biallelic GJB2 mutations. Three cases with WFS1 mutations were sporadic; two of them were confirmed to be caused by a de novo mutation based on the genetic analysis of their parents. In the case with mutations in both WFS1 and GJB2, a de novo mutation of WFS1 was confirmed in the proband's mother by genetic screening of the mother's parents. Genetic screening focusing on LFSNHL has not been conducted. The present study first revealed the prevalence of specific gene mutations. WFS1 autosomal dominant mutations were identified even in sporadic cases. Our results also suggested a mutational hotspot in WFS1. 4. Laryngoscope, 127:E324-E329, 2017.

Different Phenotypes of the Two Chinese Probands with the Same c.889G>A (p.C162Y) Mutation in COCH Gene Verify Different Mechanisms Underlying Autosomal Dominant Nonsyndromic Deafness 9.

ObjectivesBy analyzing the different phenotypes of two Chinese DFNA9 families with the same mutation located in the intervening region between the LCCL and vWFA domains of cochlin and testing the functional changes in the mutant cochlin, we investigated the different pathogeneses for mutations in LCCL and vWFA domains.MethodsTargeted next-generation sequencing for deafness-related genes was used to identify the mutation in the proband in family #208. The probands of family #208 and family #32 with the same p.C162Y mutation were followed for more than 3 years to evaluate the progression of hearing loss and vestibular dysfunction using pure-tone audiometry, caloric testing, electrocochleogram, vestibular-evoked myogenic potential, and video head-impulse test. The disruption of normal cleavage to produce secreted LCCL domain fragments and the tendency to form aggregations of mutant cochlins were tested by in vitro cell experiments.ResultsThe two families showed different clinical symptoms. Family #32 was identified as having early-onset, progressive sensorineural hearing loss, similar to the symptoms in DFNA9 patients with cochlin mutations in the vWFA domain. The proband of family #208 endured late-onset recurrent paroxysmal vertigo attacks and progressively deteriorating hearing, similar to symptoms in those with cochlin mutations in the LCCL domain. We therefore suggest that the disrupted cleavage of the LCCL domain fragment is likely to cause vestibular dysfunction, and aggregation of mutant cochlin caused by mutations in the vWFA domain is responsible for early-onset hearing loss. The p.C162Y mutation causes either disruption of LCCL domain fragment cleavage or aggregation of mutant cochlin, resulting in the different phenotypes in the two families.ConclusionThis study demonstrates that DFNA9 families with the same genotype may have significantly different phenotypes. The mutation site in cochlin is related to the pathological mechanism underlying the different phenotypes.

Autosomal dominant hearing loss resulting from mutation in the GJB2 gene:nonsyndromic presentation in a Chinese family

Objective:To investigate the genotype, phenotype and genetic features. The mutations in GJB2, GJB3, GJB6, SLC26A4 genes, 12SrRNA and tRNASer(UCN) were tested in a Chinese family with autosomal dominant nonsyndromic hearing loss. Method:Blood samples and clinical data of the proband and her partial family members were collected. DNA was extracted from the blood samples. The GJB2, GJB3, GJB6, SLC26A4 genes, 12SrRNA and tRNASer(UCN) mutations were analyzed by polymerase chain reaction(PCR) and direct sequencing. Result:Heterozygous mutation of GJB2 R75Q was identified in the proband and her mother. No mutation of other testing genes was detected. Conclusion:The R75Q mutation of the GJB2 gene cause autosomal dominant nonsyndromic deafness in the proband and her mother. Children can inherit the R75Q mutation from their parents, so the results of gene testing will be helpful for further guidance of procreation.

A novel frameshift variant of COCH supports the hypothesis that haploinsufficiency is not a cause of autosomal dominant nonsyndromic deafness 9

COCH (coagulation factor C homology) encodes cochlin, and certain mutations of COCH cause autosomal dominant nonsyndromic deafness 9 (DFNA9). Hearing loss due to COCH mutation begins in adulthood, and 17 missense mutations and two in-frame mutations have been reported. Studies with animal and cellular models have suggested that the underlying biological mechanism of DFNA9 is the dominant-negative effect of mutated COCH and not haploinsufficiency. However, no human cases of DFNA9 that support this hypothesis have been reported. The proband of the present case was an 18-year-old male with congenital or infantile hearing loss. Targeted next-generation sequencing analysis detected a heterozygous novel frameshift mutation of COCH (c.146dupT, p.C50LfsX8) in the proband, whose hearing loss began earlier than what is typical for DFNA9. His mother also carried the mutation but had normal hearing. Consequently, the mutation was not considered to be the cause of the proband's hearing loss. This family is the first case of a truncating COCH variant and supports the hypothesis that COCH haploinsufficiency is not the cause of hearing loss in humans.

Whole Exome Sequencing Identified MCM2 as a Novel Causative Gene for Autosomal Dominant Nonsyndromic Deafness in a Chinese Family.

We report the genetic analysis of autosomal dominant, nonsyndromic, progressive sensorineural hearing loss in a Chinese family. Using whole exome sequencing, we identified a missense variant (c.130C>T, p.R44C) in the MCM2 gene, which has a pro-apoptosis effect and is involved in the initiation of eukaryotic genome replication. This missense variant is very likely to be the disease causing variant. It segregated with hearing loss in this pedigree, and was not found in the dbSNP database or databases of genomes and SNP in the Chinese population, in 76 patients with sporadic hearing loss, or in 145 normal individuals. We performed western blot and immunofluorescence to test the MCM2 protein expression in the cochlea of rats and guinea pigs, demonstrating that MCM2 was widely expressed in the cochlea and was also surprisingly expressed in the cytoplasm of terminally differentiated hair cells. We then transiently expressed the variant MCM2 cDNA in HEK293 cells, and found that these cells displayed a slight increase in apoptosis without any changes in proliferation or cell cycle, supporting the view that this variant is pathogenic. In summary, we have identified MCM2 as a novel gene responsible for nonsyndromic hearing loss of autosomal dominant inheritance in a Chinese family.

A Novel Mutation in the TECTA Gene in a Chinese Family with Autosomal Dominant Nonsyndromic Hearing Loss

TECTA-related deafness can be inherited as autosomal-dominant nonsyndromic deafness (designated DFNA) or as the autosomal-recessive version. The α-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Using targeted DNA capture and massively parallel sequencing (MPS), we screened 42 genes known to be responsible for human deafness in a Chinese family (Family 3187) in which common deafness mutations had been ruled out as the cause, and identified a novel mutation, c.257–262CCTTTC>GCT (p. Ser86Cys; p. Pro88del) in exon 3 of the TECTA gene in the proband and his extended family. All affected individuals in this family had moderate down-sloping hearing loss across all frequencies. To our knowledge, this is the second TECTA mutation identified in Chinese population. This study demonstrates that targeted genomic capture, MPS, and barcode technology might broaden the availability of genetic testing for individuals with undiagnosed DFNA.

Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss

KCNQ4, a voltage-gated potassium channel, plays an important role in maintaining cochlear ion homoeostasis and regulating hair cell membrane potential, both essential for normal auditory function. Mutations in the KCNQ4 gene lead to DFNA2, a subtype of autosomal dominant non-syndromic deafness that is characterized by progressive sensorineural hearing loss across all frequencies. Despite recent advances in the identification of pathogenic KCNQ4 mutations, the molecular aetiology of DFNA2 remains unknown. We report here that decreased cell surface expression and impaired conductance of the KCNQ4 channel are two mechanisms underlying hearing loss in DFNA2. In HEK293T cells, a dramatic decrease in cell surface expression was detected by immunofluorescent microscopy and confirmed by Western blot for the pathogenic KCNQ4 mutants L274H, W276S, L281S, G285C, G285S, G296S and G321S, while their overall cellular levels remained normal. In addition, none of these mutations affected tetrameric assembly of KCNQ4 channels. Consistent with these results, all mutants showed strong dominant-negative effects on the wild-type (WT) channel function. Most importantly, overexpression of HSP90β, a key component of the molecular chaperone network that controls the KCNQ4 biogenesis, significantly increased cell surface expression of the KCNQ4 mutants L281S, G296S and G321S. KCNQ4 surface expression was restored or considerably improved in HEK293T cells mimicking the heterozygous condition of these mutations in DFNA2 patients. Finally, our electrophysiological studies demonstrated that these mutations directly compromise the conductance of the KCNQ4 channel, since no significant change in KCNQ4 current was observed after KCNQ4 surface expression was restored or improved.

Distinct Roles of Molecular Chaperones HSP90α and HSP90β in the Biogenesis of KCNQ4 Channels

Loss-of-function mutations in the KCNQ4 channel cause DFNA2, a subtype of autosomal dominant non-syndromic deafness that is characterized by progressive sensorineural hearing loss. Previous studies have demonstrated that the majority of the pathogenic KCNQ4 mutations lead to trafficking deficiency and loss of KCNQ4 currents. Over the last two decades, various strategies have been developed to rescue trafficking deficiency of pathogenic mutants; the most exciting advances have been made by manipulating activities of molecular chaperones involved in the biogenesis and quality control of the target protein. However, such strategies have not been established for KCNQ4 mutants and little is known about the molecular chaperones governing the KCNQ4 biogenesis. To identify KCNQ4-associated molecular chaperones, a proteomic approach was used in this study. As a result, two major molecular chaperones, HSP70 and HSP90, were identified and then confirmed by reciprocal co-immunoprecipitation assays, suggesting that the HSP90 chaperone pathway might be involved in the KCNQ4 biogenesis. Manipulating chaperone expression further revealed that two different isoforms of HSP90, the inducible HSP90α and the constitutive HSP90β, had opposite effects on the cellular level of the KCNQ4 channel; that HSP40, HSP70, and HOP, three key components of the HSP90 chaperone pathway, were crucial in facilitating KCNQ4 biogenesis. In contrast, CHIP, a major E3 ubiquitin ligase, had an opposite effect. Collectively, our data suggest that HSP90α and HSP90β play key roles in controlling KCNQ4 homeostasis via the HSP40-HSP70-HOP-HSP90 chaperone pathway and the ubiquitin-proteasome pathway. Most importantly, we found that over-expression of HSP90β significantly improved cell surface expression of the trafficking-deficient, pathogenic KCNQ4 mutants L274H and W276S. KCNQ4 surface expression was restored by HSP90β in cells mimicking heterozygous conditions of the DFNA2 patients, even though it was not sufficient to rescue the function of KCNQ4 channels.

Whole exome sequencing identifies a novel DFNA9 mutation, C162Y

We report the genetic analysis of a Chinese family with autosomal dominant non-syndromic progressive sensorineural hearing loss. Taking advantage of next-generation high-throughput DNA sequencing technology, we combined whole exome capture sequencing with Sanger direct sequencing. A novel missense mutation in the coagulation factor C homolog (COCH) gene was identified in a consanguineous Chinese family. This missense mutation in the seventh exon (c.889G>A; p.C162Y) of COCH is most probably a disease-causing mutation and it segregates with the disease. The mutation is not found in the single nucleotide polymorphism (SNP) database, the yhSNP database, the 1000 genomes SNP database or in matching normal controls. It is the first reported autosomal dominant nonsyndromic sensorineural deafness 9 (DFNA9) mutation outside the limulus factor C, cochlin and late gestation lung protein and von Willebrand factor 2 domain, i.e. the first reported DFNA9 mutation in the intervening domain of cochlin, encoded by the COCH gene. In the future, we will focus on functional studies of this mutation.

Functional Mutation of SMAC/DIABLO, Encoding a Mitochondrial Proapoptotic Protein, Causes Human Progressive Hearing Loss DFNA64

SMAC/DIABLO is a mitochondrial proapoptotic protein that is released from mitochondria during apoptosis and counters the inhibitory activities of inhibitor of apoptosis proteins, IAPs. By linkage analysis and candidate screening, we identified a heterozygous SMAC/DIABLO mutation, c.377C>T (p.Ser126Leu, refers to p.Ser71Leu in the mature protein) in a six-generation Chinese kindred characterized by dominant progressive nonsyndromic hearing loss, designated as DFNA64. SMAC/DIABLO is highly expressed in human embryonic ears and is enriched in the developing mouse inner-ear hair cells, suggesting it has a role in the development and homeostasis of hair cells. We used a functional study to demonstrate that the SMAC/DIABLO(S71L) mutant, while retaining the proapoptotic function, triggers significant degradation of both wild-type and mutant SMAC/DIABLO and renders host mitochondria susceptible to calcium-induced loss of the membrane potential. Our work identifies DFNA64 as the human genetic disorder associated with SMAC/DIABLO malfunction and suggests that mutant SMAC/DIABLO(S71L) might cause mitochondrial dysfunction.

Gene localization in a Chinese family with autosomal dominant non-syndromic deafness

Conclusions: There could be another candidate gene in DFNA2, which could be responsible for the hearing loss phenotype. Objective: We collected a four-generation family from the southern part of China with autosomal dominant sensorineural hearing impairment. In order to identify the responsible pathogenic mutations in this family, we set out to identify the locus and to sequentially analyze the candidate genes in the identified region. Methods: After family ascertainment and clinical analysis, exclusive analysis was performed. Then a genome-wide scan was performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM). Fine-mapping markers were genotyped to identify the locus. Finally, we performed haplotype analyses and candidate gene DNA sequencing for the family. Results: The known genetic loci and genes were not associated with our family. The genome-wide scan and haplotype analyses traced the disease to chromosome 1p34.2–p34.3 with maximum multi-point LOD score of 3.2, which overlaps with DFNA2. We failed to identify any of the known or novel variants within KCNQ4, a voltage-gated potassium channel gene, and GJB3, a gene that encodes the gap junction protein connexin 31, which were the cloned deafness genes in DFNA2.

Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with α-tectorin and is mutated in autosomal dominant hearing loss (DFNA4)

We report on a secreted protein found in mammalian cochlear outer hair cells (OHC) that is a member of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family of adhesion proteins. Ceacam16 mRNA is expressed in OHC, and its protein product localizes to the tips of the tallest stereocilia and the tectorial membrane (TM). This specific localization suggests a role in maintaining the integrity of the TM as well as in the connection between the OHC stereocilia and TM, a linkage essential for mechanical amplification. In agreement with this role, CEACAM16 colocalizes and coimmunoprecipitates with the TM protein α-tectorin. In addition, we show that mutation of CEACAM16 leads to autosomal dominant nonsyndromic deafness (ADNSHL) at the autosomal dominant hearing loss (DFNA4) locus. In aggregate, these data identify CEACAM16 as an α-tectorin-interacting protein that concentrates at the point of attachment of the TM to the stereocilia and, when mutated, results in ADNSHL at the DFNA4 locus.

MiRNA mutations are not a common cause of deafness

Mutations in miRNA genes have been implicated in hearing loss in human families and mice. It is also possible that mutations in miRNA binding sites of inner ear targets alter gene expression levels and lead to hearing loss. To investigate these possibilities we screened predicted target genes of the miR-183 miRNA cluster known to be expressed in the inner ear sensory epithelium. In one Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL), we identified a homozygous variant in a predicted miR-96/182 binding site in the 3'UTR of the RDX (DFNB24) gene. However, in vitro functional studies showed that this site is not a functional target for miR-96/182. We extended our study to include the miR-183 genes themselves and 24 additional predicted target genes of the miRNA-183 cluster. Screening these miRNAs and target sequences in numerous families segregating either autosomal dominant non-syndromic deafness (ADNSHL) or ARNSHL did not identify any potential deafness-causing mutations. These results suggest that mutations disrupting gene regulation by the miR-183 cluster are not a common cause of human hearing loss.

Predicting candidate genes for human deafness disorders: a bioinformatics approach.

BackgroundThere are more than 50 genes for autosomal dominant and autosomal recessive nonsyndromic hereditary deafness that are yet to be cloned. The human genome sequence and expression profiles of transcripts in the inner ear have aided positional cloning approaches. The knowledge of protein interactions offers additional advantages in selecting candidate genes within a mapped region.ResultsWe have employed a bioinformatic approach to assemble the genes encoded by genomic regions that harbor various deafness loci. The genes were then in silico analyzed for their candidacy by expression pattern and ability to interact with other proteins. Such analyses have narrowed a list of 2400 genes from suspected regions of the genome to a manageable number of about 140 for further analysis.ConclusionWe have established a list of strong candidate genes encoded by the regions linked to various nonsyndromic hereditary hearing loss phenotypes by using a novel bioinformatic approach. The candidates presented here provide a starting point for mutational analysis in well-characterized families along with genetic linkage to refine the loci. The advantages and shortcomings of this bioinformatic approach are discussed.

A novel G21R mutation of the GJB2 gene causes autosomal dominant non-syndromic congenital deafness in a Cuban family

Deafness is a complex disorder affecting 1/1000 infants. In developed countries, more than 50% of deafness cases are thought to have a genetic cause. At least 40 loci for dominant non-syndromic deafness and another 30 for recessive non-syndromic deafness have been described. Mutations in the GJB2 gene are the cause of an important number of cases of non-syndromic recessive deafness but are not as common in non-syndromic dominant deafness cases. We describe here a new dominant mutation (G21R) in the GJB2 gene which causes deafness and has been identified in a three generation Cuban family with dominant non-syndromic congenital sensorineural profound deafness.