Cases Of Deafness Research Articles

T8M mutation in connexin-26 impairs the connexon topology and shifts its interaction paradigm with lipid bilayer leading to non-syndromic hearing loss

Abstract Approximately, two third cases of non-syndromic deafness are caused by mutation in GJB2; which encodes a β-class gap-junction protein, connexin-26 (Cx26). Cx26 is expressed in cochlea, inner ear and epidermis. It plays an important role in the process of sound transduction through cochlea by permitting the distribution of ions and second messengers (cAMP and inositol 1,4,5-triphosphate (IP3)) through adjacent cells. Any damage in Cx26 structure may disturb the equilibrium of auditory cells and underlying auditory neurotransmission of ions through cochlea which results in partial or complete hearing loss. Current study establishes the use of in-silico approaches to characterize a known deafness-associated frameshift mutation (T8M) in Cx26. The Ca2 + ion interactions were comparatively evaluated in Cx26WT and Cx26T8M structures. Clearly, more stable interactions of Cx26WT were observed with Ca2 + as compared to Cx26T8M, indicating significant changes in the connexon-membrane topology of Cx26T8M. We observed noteworthy differences in Cx26T8M-based tunnel formation and pore characteristics as well as structural differences which may affect release of Ca2 + ions. Thus disturbance in ionic concentration may dysfunction the cochlear hair cells leading to non-syndromic deafness.

Molecular study of patients with auditory neuropathy.

Auditory neuropathy is a type of hearing loss that constitutes a change in the conduct of the auditory stimulus by the involvement of inner hair cells or auditory nerve synapses. It is characterized by the absence or alteration of waves in the examination of brainstem auditory evoked potentials, with otoacoustic and/or cochlear microphonic issues. At present, four loci associated with non‑syndromic auditory neuropathy have been mapped: Autosomal recessive deafness‑9 [DFNB9; the otoferlin (OTOF) gene] and autosomal recessive deafness‑59 [DFNB59; the pejvakin (PJVK) gene], associated with autosomal recessive inheritance; the autosomal dominant auditory neuropathy gene [AUNA1; the diaphanous‑3 (DIAPH3) gene]; and AUNX1, linked to chromosomeX. Furthermore, mutations of connexin26[the gap junctionβ2 (GJB2) gene] have also been associated with the disease. OTOF gene mutations exert a significant role in auditory neuropathy. In excess of 80pathogenic mutations have been identified in individuals with non‑syndromic deafness in populations of different origins, with an emphasis on the p.Q829X mutation, which was found in ~3% of cases of deafness in the Spanish population. The identification of genetic alterations responsible for auditory neuropathy is one of the challenges contributing to understand the molecular bases of the different phenotypes of hearing loss. Thus, the present study aimed to investigate molecular changes in the OTOF gene in patients with auditory neuropathy, and to develop a DNA chip for the molecular diagnosis of auditory neuropathy using mass spectrometry for genotyping. Genetic alterations were investigated in 47patients with hearing loss and clinical diagnosis of auditory neuropathy, and the c.35delG mutation in the GJB2 gene was identified in three homozygous patients, and the heterozygous parents of one of these cases. Additionally, OTOF gene mutations were tracked by complete sequencing of 48exons, although these results are still preliminary. Studying the genetic basis of auditory neuropathy is of utmost importance for obtaining a differential diagnosis, developing more specific treatments and more accurate genetic counseling.

Response to 'A relational approach to Saviour Siblings?' by Selgelid.

In his concise argument, 'A relational approach to saviour siblings?', Selgelid reiterates some of the arguments raised in the author meets critics discussion of my book, Saviour Siblings In this response, I highlight an important misunderstanding in one of the arguments put forward by Selgelid, which forms the basis of a large portion of his analysis. Contrary to what Selgelid contends, I do not use the deafness case in my discussion of the non-identity problem to contend that the case of selecting for deafness is ethically different from the case of saviour siblings. As I state in my reply, I use the case of deafness not as a comparator for saviour siblings but rather to illustrate the different categories of risk that apply in selection cases Given this confusion, I restate my objection to relying on the non-identity problem in evaluating risk of harm associated with the embryo biopsy process for preimplantation genetic diagnosis. Finally, I reiterate that the individual interests of saviour siblings remain important in the decision-making matrix and emphasise that Saviour Siblings offers a more contextualised approach to the welfare of the child in selective reproduction, which includes both individual and collective interests.

A novel technique for simultaneous multi-gene mutation screening in 225 patients with nonsyndromic hearing loss

Using simultaneous multi-gene mutation screening to investigate the new method molecular epidemiological basis of 225 patients with nonsyndromic hearing loss in Tianjin, and verifying the for simultaneous multi-gene mutation screening. Two hundred and twenty-five patients with severe non-syndromic deafness from Tianjin CDPF and Association of the Deaf were included in the study. The single nucleotide polymorphisms scan, (SNPscan) technique was used for screening the 115 spots mutations in three common deafness-related genes (GJB2, SLC26A4, mtDNA 12S rRNA) of patients with nonsyndromic hearing loss in Tianjin. We verified the results by Sanger sequencing. Among the 225 patients, there were 111 cases of deafness caused by mutation (49.3%). Using this method, up to 50% of the patients in our study were identified to have hereditary HL caused by mutations in the three genes. 56 patients with the GJB2 mutations were detected (24.9%), including 30 cases of homozygous mutations (13.3%), 26 patients (11.6%) of compound heterozygous mutations, and 21 cases (9.33%) of single heterozygous mutations. 50 patients with the SLC26A4 mutations were detected (22.2%), including 22 cases of homozygous mutations(9.8%), 28 patients (12.4%) of compound heterozygous mutations, and 22 cases (9.8%) of single heterozygous mutations. mtDNA 12S rRNA A1555G mutation was detected in 5 patients (2.2%). mtDNA 12S rRNA 1494C>T mutation was not detected. We verified the results by Sanger sequencing. The accuracy of the sequencing results was 100%. The SNPscan cost eight hours and 160 yuan (each sample). Applying SNPscan technology can be accurate, rapid and cost-effective diagnostic screening in patients with hearing loss for etiology investigation. It is expected to become an effective means of large-scale genetic testing for hereditary deafness.

Electrical Brain Responses to Beat Irregularities in Two Cases of Beat Deafness.

Beat deafness, a recently documented form of congenital amusia, provides a unique window into functional specialization of neural circuitry for the processing of musical stimuli: Beat-deaf individuals exhibit deficits that are specific to the detection of a regular beat in music and the ability to move along with a beat. Studies on the neural underpinnings of beat processing in the general population suggest that the auditory system is capable of pre-attentively generating a predictive model of upcoming sounds in a rhythmic pattern, subserved largely within auditory cortex and reflected in mismatch negativity (MMN) and P3 event-related potential (ERP) components. The current study examined these neural correlates of beat perception in two beat-deaf individuals, Mathieu and Marjorie, and a group of control participants under conditions in which auditory stimuli were either attended or ignored. Compared to control participants, Mathieu demonstrated reduced behavioral sensitivity to beat omissions in metrical patterns, and Marjorie showed a bias to identify irregular patterns as regular. ERP responses to beat omissions reveal an intact pre-attentive system for processing beat irregularities in cases of beat deafness, reflected in the MMN component, and provide partial support for abnormalities in later cognitive stages of beat processing, reflected in an unreliable P3b component exhibited by Mathieu—but not Marjorie—compared to control participants. P3 abnormalities observed in the current study resemble P3 abnormalities exhibited by individuals with pitch-based amusia, and are consistent with attention or auditory-motor coupling accounts of deficits in beat perception.

Non-syndromic congenital hearing loss

Non-syndromic congenital hearing loss is a global problem. It is the most common disorder at birth, occurring in 1-2/1000 newborns. Congenital hearing loss leads to delayed language development, impaired psychosocial interactions abnormal behavior and poor educational achievement. Genetic transmission is implicated in 50% of the cases of congenital deafness. Of these, about 70 % are non-syndromic. Genetic counseling is essential to making the parents aware of the most appropriate treatment. Classification and the rationale for screening of hearing loss in the newborn will be reviewed here.

A Case of Sudden Deafness with Intralabyrinthine Hemorrhage Intralabyrinthine Hemorrhage and Sudden Deafness.

Sudden hearing deterioration may occur in our population, but it is difficult to explain the exact pathophysiology and the cause. Magnetic resonance imaging (MRI) in sudden sensorineural hearing loss (SSNHL) is usually useful to evaluate neural lesions such as acoustic schwannoma and hemorrhage in labyrinth. Recently some cases of SSNHL caused by intralabyrintine hemorrhage were reported by the advance of MRI. In the case of intralabyrintine hemorrhage, MRI showed a hyperintense signal in the labyrinth on the pre-contrast and contrast enhanced T1-weighted image and relatively weak intensity on T2-weighted image. The prognosis SSNHL by intralabyrintine hemorrhage is generally known to be poor. We report a case of sudden deafness with intralabyrintine hemorrhage who has a history of anticoagulant administration, with a review of literature.

Retrospective multicenter evaluation of the "fly-catching syndrome" in 24 dogs: EEG, BAER, MRI, CSF findings and response to antiepileptic and antidepressant treatment.

The fly-catching syndrome (FCS) is a rare canine condition of sudden, occasional, or constant episodes of biting the air. It may be accompanied by jumping, licking, and swallowing. The etiology of FCS is unknown and controversial. Various explanations for its occurrence have included epileptoid disorders such as visual cortex epileptiform disturbances and simple and complex partial seizures as well as compulsive disorders, hallucinatory behavior, and stereotypy. A retrospective multicenter analysis of 24 dogs with clinical symptoms of FCS is presented. Clinical signs at the time of presentation, the mean age at onset of the disease, the response to treatment, and the clinical outcome were recorded and analyzed in all patients. All dogs underwent clinical, neurological, and otoscopic examinations. Complete blood cell counts (CBCs) and serum chemistry panels were obtained from each dog. Diagnostic testing included MRI and EEG examinations in 21 cases, BAER in 19 cases, and CSF analysis in 20 cases. The EEG revealed spike activity in 8 (38%) of the 21 cases, 7 of which had activity in the occipital lobes. The brainstem auditory evoked response (BAER) revealed three cases of bilateral deafness. The MRI revealed six cases of Chiari malformation (CM), one case of syringohydromyelia (SM), and one case of a falx cerebri meningioma. The dogs were divided into groups according to their treatment protocol. Group A included dogs treated with phenobarbital (PB), and group B consisted of dogs treated with fluoxetine (FLX). Thirty-six percent of the dogs in group A responded to PB, while 100% of the dogs in group B responded to FLX. The results suggest that FCS is more responsive to FLX than PB. However, the etiology of this behavior remains unclear in most cases.

Occupational noise-induced deafuess diaqnosis analysis in Jiangsu from 2006 to 2009

In order to provide the evidence for taking the measures to prevent noise hazards, the condition sand influence factors of occupational noise deafness diagnosis in Jiangsu province from 2006 to 2013 were analyzed. According to the 13 administrating personnel report of noise deafness diagnosed occupational disease prevention and control institutions in Jiangsu province from 2006 to 2013, the diagnosis of occupational noise deafness were retrospectively analyzed. By the end of December 31 2013, 297 cases of noise deafness were diagnosis occupational disease within this province. Occupational noise deafness has localized on the machinery industry, textile and light industry. Regional distribution mainly concentrated in Suzhou, Yangzhou, Nanjing, Nantong. 83.16% in 297 cases were mild noise deafness. The distribution of occupational noise deafness cases in Jiangsu province has specific charateristics. It is not balanced in different regions, and most of them are the mild noise deafness, male, length of service in more than 15 years, the onset age is 40~60 years old, According to characteristics of the occupational noise deafness cases in Jiangsu province, Specific occupational health service will help to reduce the occurrence of occupational noise deafness, and protect the worker's health effectively.

Keratitis-Ichthyosis-Deafness Syndrome-Associated Cx26 Mutants Produce Nonfunctional Gap Junctions but Hyperactive Hemichannels When Co-Expressed With Wild Type Cx43

Mutations in Cx26 gene are found in most cases of human genetic deafness. Some mutations produce syndromic deafness associated with skin disorders, like Keratitis Ichthyosis Deafness syndrome (KID). Because in the human skin Cx26 is co-expressed with other connexins, like Cx43 and Cx30, and since KID syndrome is inherited as autosomal dominant condition, it is possible that KID mutations change the way Cx26 interacts with other co-expressed connexins. Indeed, some Cx26 syndromic mutations showed gap junction dominant negative effect when co-expressed with wild type connexins, including Cx26 and Cx43. The nature of these interactions and the consequences on hemichannels and gap junction channels functions remain unknown. In this study we demonstrate that syndromic mutations at the N-terminus segment of Cx26, change connexin oligomerization compatibility, allowing aberrant interactions with Cx43. Strikingly, heteromeric oligomer formed by Cx43/Cx26 (syndromic mutants) show exacerbated hemichannel activity, but nonfunctional gap junction channels; this also occurs for those Cx26 KID mutants that do not show functional homomeric hemichannels. Heterologous expression of these hyperactive heteromeric hemichannels increases cell membrane permeability, favoring ATP release and Ca2+ overload. The functional paradox produced by oligomerization of Cx43 and Cx26 KID mutants could underlie the severe syndromic phenotype in human skin.

Imaging assessment of profound sensorineural deafness with inner ear anatomical abnormalities

ObjectiveTo explore the value of a combined computed tomography (CT) and magnetic resonance imaging (MRI) in evaluating profound sensorineural deafness patients before cochlear implant (CI) surgery. MethodsA retrospective analysis of 1012 cases of profound sensorineural deafness that received CI was performed. ResultsA total of 96 cases were diagnosed with inner ear abnormalities including large vestibular aqueduct syndrome (LVAS, n = 61), Michel deformity (n = 3), cochlear incomplete partition I (n = 2), cochlear incomplete partition II (n = 6), cochlear hypoplasia with vestibular malformation (n = 3), cochlear ossification (n = 3), bilateral internal auditory canal obstruction (n = 5) and internal auditory canal stenosis (n = 2). ConclusionHigh resolution CT (HRCT) can display bony structures while MRI can image the membranous labyrinth in preoperative evaluation for cochlear implantation. The combination of these two modalities provides reliable anatomical information regarding the bony and membranous labyrinths, as well as the auditory nerve.

The tonotopicity of styrene-induced hearing loss depends on the associated noise spectrum

The neuropharmacological and cochleotoxic effects of styrene can exacerbate the impact of noise on the peripheral auditory receptor. The mechanisms through which co-exposure to noise and styrene impairs hearing are complex as the slowly developing cochleotoxic process can be masked in the short-term by the rapid pharmacological effect on the central nervous system. The current investigation was therefore designed to delineate the auditory frequency range sensitive to noise, to styrene, and to noise and styrene combined. In case of different frequency ranges targeted by noise and styrene, it would be possible to point out the main factor responsible for cases of deafness by looking at the location of the audiometric deficits. Male Brown-Norway rats were exposed to 600-ppm styrene, to an octave band noise centered at 8kHz, or to both noise and styrene. The noise exposure was of two different types: impulse noise with a LEX,8h (equivalent continuous noise level averaged over 8h) of 80dB and continuous noise with a LEX,8h of 85dB SPL. Hearing was tested using a non-invasive technique based on distortion product otoacoustic emissions. Hearing data were completed with histological analysis of cochleae. The results showed that exposure to styrene alone caused outer hair cell losses in the apical cochlear region, which discriminates low frequencies. In contrast, noise-induced hearing loss was located at half an octave above the central frequency of the spectrum, around 10–12kHz. Damage due to impulse noise was significantly exacerbated by styrene, and the noise spectrum defined the location of the cochlear trauma. Combined exposure caused greater cell losses than the sum of losses measured with the impulse noise and styrene alone. The fact that the tonotopicity of the styrene-induced damage depends on the associated noise spectrum complicates the diagnosis of styrene-related hearing loss with a tone-frequency audiometric approach. In conclusion, there is not really a frequency specificity of impairments due to styrene.

A case of cortical deafness and loss of vestibular and somatosensory sensations caused by cerebrovascular lesions in bilateral primary auditory cortices, auditory radiations, and postcentral gyruses – complete loss of hearing despite normal DPOAE and ABR

Conclusion: A right-handed 38-year-old man’s complete loss of hearing could be diagnosed as cortical deafness caused by cerebral vascular lesions in bilateral auditory cortices. Objective: The aim of this case report was to study the pathophysiology of a particular patient who manifested deafness without residual hearing and lost somatosensory sensation, vestibular sensation, and articulation ability after a right internal carotid-posterior communicating artery (IC-PC) aneurysm and subarachnoidal hemorrhage. Methods: MRI, aphasia and neurological tests, subjective and objective audiometry, and vestibular function tests were performed. Results: The neurological test revealed system loss of somatosensory sensation with normal motor function and articulation ability. Brain imaging revealed extensive infarction in the bilateral primary auditory cortices, postcentral gyruses, and the bilateral partial third frontal gyruses. Pure-tone audiometry of both ears revealed off-the-scale results and speech audiometry demonstrated 0% maximum speech discrimination. However, objective audiometry showed normal distortion product otoacoustic emissions (DPOAE) and normal auditory brainstem response (ABR). The patient showed 0% perception of environmental, speech, and music sounds in both ears. He was unable to feel vestibular sensation despite normal caloric nystagmus. He showed no damage to his larynx or articulation organs.

Late Sudden Deafness in Unoperated Ear of Patients with Otospongiosis: Case Studies

Background: It is not known whether there is etiological relationship between otospongiosis and sudden deafness. The most common etiologies that explain sudden deafness are viral infections, vascular and autoimmune process. Methods: Two cases of patients with otospongiosis that have developed sudden deafness are presented. Results-Case report: We report two cases of late sudden deafness in the unoperated ear of patients with otospongiosis. Both patients underwent previous surgical treatment in the contralateral ear with a a short period of hearing improvement and poor hearing outcome some days after. In both reported cases the patients with bilateral otospongiosis had sudden deafness affecting both ears. The first episodes had the onsets postoperatively at the operated ears. The second episodes were at the contralateral ears in the late follow-up, especially considering that in both cases the patients showed satisfactory results regarding hearing improvement postoperatively although temporarily we therefore question the existence of the association between otospongiosis and sudden deafness. Case Study Guimaraes et al.; BJMMR, 9(7): 1-6, 2015; Article no.BJMMR.17420 2 Discussion: Sudden deafness in patients with otospongiosis is a rare occurrence and because of the few cases reported, it is not possible to establish any relationship. Maybe there is a possible immunological cause for the association of otosclerosis and sudden deafness. Conclusion: The association between sudden deafness and otosclerosis can be considered.

Growing Burden of Paediatric Deafness-Challenges in Diagnosis and Rehabilitation in India

Paediatric deafness is a handicap affecting approximately 4–6/1000 newborns. The primary justification for early identification of deafness in children relates to the direct impact on their speech and language development which is further related to the academic, social and emotional impairment and disability. In a developing country like ours, the detected number of pediatric deafness cases may be like a tip of an iceberg as 70% of population lives in rural India where due to lack of basic medical infrastructure facility and social factors most of the cases are unnoticed till the age of 3–4 yrs, when the age of complete speech development occurs. So the delay in detection of deafness is very common amongst general population. Various studies has been done in India in different parts in relation to the incidence, causes, risk factors, etc but being the second highest population in the world, the exact number and percentage of deaf children is difficult to calculate. Various organizations including National programme for detection of deafness are working towards the early identification and rehabilitations measures but we still need to go a long way.

Non-organic hearing loss in United Kingdom military personnel

Non-organic hearing loss (NOHL) is a condition in which there is audiometric discrepancy between the real hearing threshold and the measured threshold of the patient, in the absence of any organic disease. It can, rarely, be the manifestation of a somatoform disorder when it is known as conversion deafness. We present a case of conversion deafness diagnosed following a five-year period of apparent fluctuating unilateral hearing loss, and discuss the diagnosis, clinical and occupational considerations of managing this condition in a military environment.

Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss.

BackgroundHereditary hearing loss is genetically heterogeneous, and hundreds of mutations in than 60 genes are involved in this disease. Therefore, it is difficult to identify the causative gene mutations involved. In this study, we combined targeted genomic capture and massively parallel sequencing (MPS) to address this issue.MethodsUsing targeted genomic capture and MPS, 104 genes and three microRNA regions were selected and simultaneously sequenced in 23 unrelated probands of Chinese families with nonsyndromic hearing loss. The results were validated by Sanger sequencing for all available members of the probands’ families. To analyze the possible pathogenic functional effects of the variants, three types of prediction programs (Mutation Taster, PROVEAN and SIFT) were used. A total of 195 healthy Chinese Han individuals were compared as controls to verify the novel causative mutations.ResultsOf the 23 probands, six had mutations in DFNA genes [WFS1 (n = 2), COCH, ACTG1, TMC1, and POU4F3] known to cause autosomal dominant nonsyndromic hearing loss. These included one novel in-frame indel mutation, three novel missense mutations and two reported missense mutations. Furthermore, one proband from a family with recessive DFNB carried two monoallelic mutations in the GJB2 and USH2A genes. All of these mutations co-segregated with the hearing loss phenotype in 36 affected individuals from 7 families and were predicted to be pathogenic.ConclusionsMutations in uncommon deafness genes contribute to a portion of nonsyndromic deafness cases. In the future, critical gene mutations may be accurately and quickly identified in families with hereditary hearing loss by targeted genomic capture and MPS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0311-1) contains supplementary material, which is available to authorized users.

Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing

Mutations in the Gjb2 gene, which encodes a gap junction protein connexin26 (Cx26), are the most prevalent form of hereditary deafness in humans and represent about half of non-syndromic congenital deafness cases in many ethnic populations. Cochlear potassium (K+) recycling in mature cochlea is required for normal hearing. It is thought that gap junctions are essential for K+ recycling and that Gjb2 mutations cause Gjb2-associated deafness by disrupting K+ recycling in mature cochlea. Here we present evidence showing that Gjb2 is required for normal development of the neonatal organ of Corti prior to the onset of the hearing in mice. In the conditional Gjb2 null (cCx26 null) mice, ribbon synapses in inner hair cells remained poorly developed, the afferent type I fibers failed to finish the refinement process to form convergent innervation to individual inner hair cells. The spontaneous depolarizing activities in the supporting cells, which normally diminish in the wild type cochleae after postnatal day 8 (P8), remained strong in the cochlea after P8 in the mutant mice. Furthermore, the deafness phenotype was readily generated only if the Cx26 expression in the organ of Corti was significantly reduced before P6. Similar amount of Cx26 reduction in more mature cochleae had a much weaker effect in damaging the hearing sensitivity. Our findings indicated that Cx26 plays essential roles in the maturation process of the organ of Corti prior to the establishment of high K+ in the endolymph and the onset of hearing. These results suggest that successful treatment of Cx26 deafness requires early intervention before the cochlea fully matures.

Combined examination of sequence and copy number variations in human deafness genes improves diagnosis for cases of genetic deafness.

BackgroundCopy number variations (CNVs) are the major type of structural variation in the human genome, and are more common than DNA sequence variations in populations. CNVs are important factors for human genetic and phenotypic diversity. Many CNVs have been associated with either resistance to diseases or identified as the cause of diseases. Currently little is known about the role of CNVs in causing deafness. CNVs are currently not analyzed by conventional genetic analysis methods to study deafness. Here we detected both DNA sequence variations and CNVs affecting 80 genes known to be required for normal hearing.MethodsCoding regions of the deafness genes were captured by a hybridization-based method and processed through the standard next-generation sequencing (NGS) protocol using the Illumina platform. Samples hybridized together in the same reaction were analyzed to obtain CNVs. A read depth based method was used to measure CNVs at the resolution of a single exon. Results were validated by the quantitative PCR (qPCR) based method.ResultsAmong 79 sporadic cases clinically diagnosed with sensorineural hearing loss, we identified previously-reported disease-causing sequence mutations in 16 cases. In addition, we identified a total of 97 CNVs (72 CNV gains and 25 CNV losses) in 27 deafness genes. The CNVs included homozygous deletions which may directly give rise to deleterious effects on protein functions known to be essential for hearing, as well as heterozygous deletions and CNV gains compounded with sequence mutations in deafness genes that could potentially harm gene functions.ConclusionsWe studied how CNVs in known deafness genes may result in deafness. Data provided here served as a basis to explain how CNVs disrupt normal functions of deafness genes. These results may significantly expand our understanding about how various types of genetic mutations cause deafness in humans.

Sequencing of GJB2 in Cameroonians and Black South Africans and comparison to 1000 Genomes Project Data Support Need to Revise Strategy for Discovery of Nonsyndromic Deafness Genes in Africans.

Mutations in the GJB2 gene, encoding connexin 26, could account for 50% of congenital, nonsyndromic, recessive deafness cases in some Caucasian/Asian populations. There is a scarcity of published data in sub-Saharan Africans. We Sanger sequenced the coding region of the GJB2 gene in 205 Cameroonian and Xhosa South Africans with congenital, nonsyndromic deafness; and performed bioinformatic analysis of variations in the GJB2 gene, incorporating data from the 1000 Genomes Project. Amongst Cameroonian patients, 26.1% were familial. The majority of patients (70%) suffered from sensorineural hearing loss. Ten GJB2 genetic variants were detected by sequencing. A previously reported pathogenic mutation, g.3741_3743delTTC (p.F142del), and a putative pathogenic mutation, g.3816G>A (p.V167M), were identified in single heterozygous samples. Amongst eight the remaining variants, two novel variants, g.3318-41G>A and g.3332G>A, were reported. There were no statistically significant differences in allele frequencies between cases and controls. Principal Components Analyses differentiated between Africans, Asians, and Europeans, but only explained 40% of the variation. The present study is the first to compare African GJB2 sequences with the data from the 1000 Genomes Project and have revealed the low variation between population groups. This finding has emphasized the hypothesis that the prevalence of mutations in GJB2 in nonsyndromic deafness amongst European and Asian populations is due to founder effects arising after these individuals migrated out of Africa, and not to a putative "protective" variant in the genomic structure of GJB2 in Africans. Our results confirm that mutations in GJB2 are not associated with nonsyndromic deafness in Africans.