Early audiological phenotype in patients with mutations in the USH2A gene.

INTRODUCTION: Nowadays, due to universal newborn hearing screening (UNHS) the number of children with mild-to-moderate hearing loss diagnosed in the first year of life has increased significantly. Aside from that, identification of the genetic cause improves the genetic counselling of the families and allows to reveal possible comorbidities which may need a special approach. OBJECTIVE: To present the characteristics of the early audiologic phenotype in hearing impaired patients with biallelic mutations in the USH2A gene based on systematic analysis of the audiological data. PATIENTS AND METHODS: 13 patients with mutations in the USH2A gene underwent audiological examination. Most of them were found among a large group of infants with bilateral nonsyndromic sensorineural hearing loss (SNHL) examined under 12 months. RESULTS: Eight out of eleven children failed UNHS and were initially diagnosed as having bilateral nonsyndromic SNHL. Seven children underwent an audiological assessment before the age of 9 months. The earliest audiological examination was carried out at 1 and 3 months. The children with pathogenic variants in the USH2A gene in our examined group were identified in the first year of life via UNHS. The hearing threshold levels (HTL) for the USH2A group are compactly distributed between 51.25 dB and 66.25 dB, quartiles are 54 dB and 63.4 dB, with a median of 60 dB. The audiological profile of patients with biallelic USH2A mutations differs from audiograms of patients who had STRC-related hearing loss. We have not found any significant elevation in hearing thresholds in the first decade of life. We also estimated the prevalence of the USH2A and STRC mutations among GJB2-negative infants with bilateral nonsyndromic SNHL examined under 12 months, and it was 7.5% and 16.1%, respectively. CONCLUSION: According to our results, the early hearing phenotype in pediatric patients with biallelic mutations in the USH2A- gene is characterized by nonsyndromic mild-to-moderate SNHL in the first decade of life. Our results indicate that the presence of mutations in the USH2A or STRC genes can be expected in a child with congenital mild-to-moderate nonsyndromic SNHL. This information is of practical importance for parents, as they have to know the prognosis of hearing loss for their child from the very beginning. Post-screening follow-up should include adequate clinical, genetic, and social support for children and their parents.

[Hearing loss due to mutations in the genes responsible for Usher syndrome]. / Narushenie slukha pri mutatsiyakh v genakh, otvetstvennykh za sindrom Ashera.

Usher syndrome is characterized by congenital bilateral sensorineural hearing loss and progressive retinitis pigmentosa, and has an autosomal recessive type of inheritance. The purpose of this work is to summarize the modern data of a clinical picture of Usher syndrome and analyse hearing impairment properties. The frequency of the syndrome among children suffering from hearing loss and deafness is from 3 to 10%. The prevalence of the syndrome in the world is estimated as 4.4 per 100.000 population. The complexity of the diagnosis of the syndrome lies in the significant clinical and genetic heterogeneity. Hearing and vision problems begin at different ages. Primary diagnosis begins with the clinical diagnosis of bilateral hearing loss and visual impairment manifests later. In this case the initial diagnosis of nonsyndromal hearing loss will not be definitive. Molecular genetic studies contribute to the early clinical diagnosis of the syndrome. Understanding the cause of the disease allows to conduct correct medical and genetic counseling and get closer to solving treatment problems.

[Ethical analysis of work environment in audiology]. / Analiz eticheskikh aspektov trudovoi deyatel'nosti vrachei-surdologov-otorinolaringologov i vrachei-otorinolaringologov.

The issues of medical ethics concern not only the doctor-patient relationship, but also the ethical aspects of the organization of the labor activity of medical specialists. Identifying and resolving ethical dilemmas can serve as the basis for preventing occupational stress and burnout and improving the effectiveness of medical care in the field of audiology. OBJECTIVE: Ethical analysis of work environment in audiology. MATERIAL AND METHODS: A 14-question questionnaire developed on the basis of demand-control and effort-reward models, an online survey was conducted using the Google Forms service among 111 specialists (43 audiologists, 13 otorhinolaryngologists, and 55 doctors combining work in both specialties).Results and discussion. The differences were revealed on the scales Effort and Reward depending on the specialty and clinic (public or private). The greatest effort was found among doctors combining both specialties, the least - among doctors of private clinics. 58% of the respondents consider the wages to be inadequate to the expended efforts. At the same time, a high respect level among patients, management and colleagues helps to compensate for the identified efforts. CONCLUSION: The analysis made it possible to identify ethical dilemmas in the work of audiologists for effective planning of specialty development.

Clinical features of hearing loss caused by STRC gene deletions/mutations in Russian population.

Congenital sensorineural hearing loss is related to mutations in numerous genes encoding the structures of the inner ear in majority of the cases. Mutations in GJB2 gene are the most frequently identified causes of congenital nonsyndromal hearing loss. GJB2 gene testing became a routine clinical tool. For GJB2-negative patients new genetic approaches including methods based on new generation sequencing give a chance to identify mutations in other genes. The frequent reason of mild-to-moderate hearing loss such as the deletions/mutations of the gene STRC encoding stereocilin protein were recognized (OMIM: 606440). OBJECTIVES: To evaluate the audiological features in hearing impaired patients with deletions and point mutations in the STRC gene. PATIENTS AND METHODS: The group of 28 patients from 21 unrelated families with pathological mutations in the STRC gene underwent audiological examination. The description and analysis of the results of full audiological examination was provided. RESULTS: All patients initially had bilateral nonsyndromal sensorineural hearing loss. Among 11 homozygotes of large deletion harboring STRC to CATSPER2 genes were 7 male individuals indicating the presence of male infertility syndrome. In general, 7 children failed audiological screening and 4 children underwent audiological assessment in the age of 3 and 6 months. The most frequently hearing thresholds were registered between 35 and 55 dB that corresponds to mild-to-moderate hearing impairment. The average age of diagnostics was 7.9 years (ranged from 3 months to 45 years). In the majority of patients the audiological profiles were flat or descending with elevation of thresholds at middle and high frequencies and relatively preserved thresholds at low frequencies. Hearing thresholds are symmetric and stable with age. CONCLUSION: STRC-linked hearing loss is congenital, of mild and moderate severity. Special clinical and genetic approach for children who failed newborn hearing screening with mild-to-moderate hearing loss is necessary.

[Hearing loss due to mutations or lack of the gene coding protein stereocillin]. / Narushenie slukha pri mutatsiyakh ili otsutstvii gena, kodiruyushchego belok stereotsilin.

OBJECTIVE: The description of a clinical picture and audiological features at the hearing loss caused by changes of a STRC gene, coding protein stereocillin (MIM: 606440). Mutations in the numerous genes responsible for the inner ear proteins are the reason for congenital sensorineural hearing loss. The main cause of congenital bilateral sensorineural hearing loss in the Russian Federation are mutations in GJB2 gene it reaches up 68% of cases identified in infancy. GJB2 gene tests already became routine around the world. Possibilities of new methods based on sequencing of new generation (NGS, next generation sequencing) allow to conduct a research of more rare genes connected with a hearing impairment. The most often among GJB2 negative patients reveal mutations and deletion of a gene of STRC. PATIENTS AND METHODS: Full audiological examination of 5 children and one adult with a hearing loss from 2 unrelated families is provided. Mutations in STRC gene were identified. All children are examined aged before 8 years, and 3 children failed universal audiological screening in maternity hospital, to two children screening was not carried out as they were born till 2009. RESULTS: The children with the sensorineural hearing loss connected with mutations and deletion of STRC gene failed hearing screening in maternity hospital because of the OAE is not registered, what indicates the congenital nature of a hearing loss. Recently it could not be noticed earlier because of slight increase of hearing thresholds and was regarded only as the early onset. Our data emphasize that the of thresholds from 35 to 60 dB in frequencies 0,5-4 kHz is common for mutations/deletions of STRC gene. CONCLUSION: The development of molecular genetics methods confirms the hereditary causes of GJB2-negative patients and expands indications for family counseling. Special approach for child with hearing loss so early revealed is necessary and the consultation of parents frightened of screening results is very important.

[OTOF-related auditory neuropathy spectrum disorder]. / Zabolevanie spektra auditornykh neiropatii, obuslovlennoe mutatsiyami v gene otoferlina (OTOF).

Otoferlin (OTOF) gene mutations are the most common cause of hereditary ANSD according to investigations in several countries. THE AIM: Of this study was to estimate the prevalence of OTOF mutations in Russian children with ANSD and evaluate audiological and clinical features of OTOF-related ANSD. PATIENTS AND METHODS: 28 children with bilateral ANSDwere enrolled in the investigation. Two step genetic testing was performed: first step - GJB2 gene testing to exclude GJB2-related hearing loss; second step - NGS-based sequencing to explore another 35 hearing loss genes (including OTOF). RESULTS: OTOF mutations, including 6 new variants, were found in 5 children with ANSD (18%). All 5 children had no risk factors for hearing loss and passed hearing screening. OAE and cochlear microphonics were present till the last testing at the age of 4-5 years. ABR were not detectable. The ASSR were measurable bilaterally at all frequencies in all cases, but they did not correlate with behavioral thresholds that revealed severe hearing loss. Hearing thresholds were stable during follow up period. 3 children underwent cochlear implantation. After cochlear implantation auditory nerve action potentials to electric stimulation were detected within normal range. CONCLUSION: Genetic testing of children with ANSD and first of all OTOF testing enables to reveal hearing loss etiology and provide the optimal rehabilitation approach, including cochlear implantation, as early as possible.

[Twenty years of clinical studies of GJB2-linked hearing loss in Russia]. / 20 let izucheniia klinicheskikh proiavlenii GJB2-obuslovlennoi tugoukhosti v Rossii.

The most common cause of congenital hereditary hearing loss was discovered 20 years ago in 1997 when GJB2 gene was revealed in the first locus of recessive hearing loss DFNB1. It encodes protein connexin 26, a structural component of the intercellular channels. Recessive mutations in this gene cause the congenital bilateral sensorineural hearing loss. For many years the aim of our work was to study the prevalence and clinical manifestations of hereditary hearing loss. Our research can be divided into three stages. In the beginning, we investigated the prevalence of GJB2 mutations in a healthy population and in the people suffering from hearing impairment. Further research was conducted in the field of clinical manifestations and evidence of the congenital character of GJB2-related hearing loss. Currently, we are working on the prevalence of mild and moderate hereditary hearing loss and the probability of its progression. Achievements in molecular genetics make it possible to establish the hereditary character of congenital hearing loss and to avoid repeated family cases. Primary prevention of hereditary hearing loss becomes real by raising the awareness of GJB2 mutations carriers.

[Epidemiology of hearing loss in children of the first year of life]. / Épidemiologiia narushenii slukha sredi detei 1-go goda zhizni.

The aim of this study was the investigation of the epidemiology of permanent hearing impairment in the children of first year of life in the Russian Federation after the implementation of the newborn universal hearing screening program. The prevalence of hearing loss in children in the first year of life was estimated at 2.5 per 1,000 based on the official statistical data and reports of hearing rehabilitation centres in 2016. A cohort of 405 children born in 2012 was examined at the age from 0 to 4 years of life. Among them 276 children were diagnosed with permanent congenital and prelingual hearing loss. 88% of the cases were bilateral, sensorineural hearing loss confirmed in 84% of the cases. The genetic cause of hearing loss was revealed in 58% of the patients assessed for the presence of GJB2 gene mutations. In preterm infants, the permanent hearing loss was detected in 70% of the cases. The comprehensive audiological assessment before 3 months of life was conducted only in 32% of the children; this finding is not consistent with the international newborn hearing screening recommendations. Only 70% of the cases of congenital and preverbal hearing loss were diagnosed during the first year of life.

[The analysis of the association of the polymorphic variants of the TPMT, COMT, and ABCC3 genes with the development of hearing disorders induced by the cisplatin treatment]. / Analiz assotsiatsii polimorfnykh variantov genov TPMT, COMT i ABCC3 c razvitiem narusheniia slukha, indutsirovannogo priemom tsisplatina.

Cisplatin and its derivatives are widely used chemotherapeutic agents for the treatment of many cancers, including hepatoblastoma, brain tumors, and germ-cell tumors. This therapy contributed to the dramatic increase in the survival rate. However, its use is restricted by the high incidence of irreversible ototoxicity associated with cisplatin application (in more than 60% of the children receiving it). Some studies have reported that genetic variants of TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) are conferring increased risk of developing cisplatin-induced hearing loss. However, in other studies the results were not replicated. In the present study, we replicated the previous studies based on an independent cohort of Russian patients. SNP genotypes for rs 12201199, rs4646316 and rs 1051640 were determined in DNA samples obtained from 16 patients who developed hearing loss and a group of 34 patients whose hearing was retained. The association between TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) variants and the hearing loss was not observed in our cohort.

[Results of molecular genetic testing in Russian patients with Pendred syndrome and allelic disorders].

Pendred syndrome is an autosomal recessive inherited disorder characterized by a combination of sensorineural hearing impairment and euthyroid goiter; its clinical manifestation in children is hardly distinguishable from nonsyndromic hearing loss. Pendred syndrome is one of the most frequent types of syndromic hearing loss. Hearing impairment is accompanied by abnormal development of the bony labyrinth­enlarged vestibular aqueduct (EVA) and occasionally combined with Mondini dysplasia. Mutations in the SLC26A4 gene, which encodes the pendrin protein, are responsible for both Pendred syndrome and for allelic disorder (nonsyndromic enlarged vestibular aqueduct). The present study for the first time conducted molecular genetic analysis in 20 Russian patients with Pendred syndrome, EVA and/or Mondini dysplasia. As a result, six pathogenic mutations in the SLC26A4 gene were revealed in four patients. The mutation c.222G>T (p.Trp74Cys) was detected for the first time. Mutations were found in patients with Pendred syndrome and nonsyndromic EVA with or without Mondini dysplasia. Mutations were not detected in patients with isolated Mondini dysplasia. One proband with clinical diagnosis Pendred syndrome was homozygous for the c.35delG mutation in the GJB2 gene. The absence of frequent mutations, including well-known ones or "hot" exons in the SLC26A4 gene, was reported. Therefore, the optimal method to search for mutations in the SLC26A4 gene in Russian patients is Sanger sequencing of all exons and exon-intron boundaries in the SLC26A4 gene.

[The Russian and international experience with the implementation of the programs of universal audiological screening of the newborn infants].

The problem of diagnostics of congenital hearing impairment has acquired special importance in the light of new possibilities for the early rehabilitation of the patients presenting with this condition. The implementation of the programs of universal audiological screening into the clinical practice of Russia and many other countries made it possible to significantly reducethe time necessary to confirm congenital impairment of hearing and begin the rehabilitative treatment. The present paper was designed to analyze the international experience with the implementation of the programs of universal audiological screening of the newborn infants as exemplified by such countries as Great Britain, USA, Germany, and Poland. The main indicators of the quality and the efficiency of such programs are considered taking into account the results of the epidemiological studies on the prevalence of congenital hearing impairment. A total of 1.8 mln newborn infants were examined in Russia during 2013. The first stage of screening involved 96.7% of the children, and only 2.9% of them remained uncovered by the examination. As many as 5,659 children were found to present with the congenital loss of hearing,with the prevalence of this condition being 3 per 1.000 newborn infants and the prevalence of deafness 0.6 per 1.000. The principal problem to be resolved for the organization of the management of these patients, both in Russia and other countries, remains the enhancement of the availability of comprehensive diagnostic examination and the timelyreferral of the patients to such examination (if appropriate based on the results of the screening). The successful solution of this problem requires personalized recording of the screening data with the use of the commonly accepted medical information systems.

Phenotype in a patient with p.D50N mutation in GJB2 gene resemble both KID and Clouston syndromes.

Keratitis-ichthyosis-deafness (KID) syndrome (OMIM 148210) is a rare ectodermal dysplasia syndrome characterized by vascularizing keratitis, congenital profound sensorineural hearing loss, and progressive erythrokeratoderma. We have found a 148G-A transition in the GJB2 gene, resulting in an asp50-to-asn (D50N) substitution in a girl with congenital deafness. This finding allowed us to diagnose а KID syndrome. But clinical features were uncommon because of a mild skin manifestation, lack of keratitis and unusual appearance resembling Clouston syndrome. Molecular genetic tests showed that it was de novo mutation because parents have normal genotype. Several autosomal dominant mutations in the GJB2 gene (сonnexin 26) now established to underlie many of the affected cases, with the majority of patients harboring the p.D50N mutation. Skin disease-associated mutation of connexin proteins can cause functional disturbances in gap junction intercellular conductance. It is likely that multiple disease mechanisms are involved across the wide spectrum of hereditary diseases relating to connexin proteins. The clinical data may provide additional insights into the dysregulation mechanisms of mutations result in the disease.

[The results of cochlear implantation in the patient with hereditary and non-hereditary hearing loss]. / Rezul'taty kokhlearnoi implantatsii u patsientov s nasledstvennymi i nenasledstvennymi formami tugoukhosti.

The objective of the present study was to evaluate the effectiveness of rehabilitation of the patients after cochlear implantation in the early and late periods after operation taking into consideration the etiology of congenital deafness. The comprehensive clinico-audiological examination performed during the period from 2010 to 2015 involved 246 children who had undergone cochlear implantation (CI). All children were operated at the National Research Center for Audiology and Hearing Rehabilitation in the period from 2003 to 2013. 83 (56%) patients were aged 1 to 3 years at the time of surgery. Their age varied from 3 to 18 years when they underwent the clinico-audiological examination. Thus, the study is based on the experience with cochlear implantation varying from 3 to 12 years. The genetic analysis revealed mutations in the GJB2 gene in 49% of the children, in agreement with the data of earlier studies. 85% of all the children with GJB2 deafness surgically treated at the age under 4 years attend ordinary institutions of learning. Within 24 months after the onset of the observations the majority of the children with hereditary deafness (63%) were referred to the groups with good and excellent results of the rehabilitation and only 6 (12%) patients presented with unsatisfactory results. It was shown that the acquired causes of the loss of hearing including severe prenatal pathology have a negative influence on the long-term outcomes of rehabilitation. The results of the genetic analysis for the elucidation of the cause of impaired hearing can be employed as a prognostic criteria not only for the prediction but also for the guarantee of the success of cochlear implantation provided the rehabilitative process was initiated in a proper time.

[The clinical definition and etiology of Pendred syndrome (a review of the literature and clinical observations)]. / Sindrom Pendreda (obzor literatury i klinicheskie nablyudeniya).

The aim of this work was a clinical study of the patients with mutations in the SLC26A4 gene and clinical diagnosis of the Pendred syndrome. The Pendred syndrome is a hereditary autosomal recessive disorder characterized by combined pathology of the inner ear and the thyroid gland. CT of the temporal bones demonstrates the Mondini-type structural anomaly in the inner ear and enlarged vestibular aqueduct. Examination of the thyroid gland reveals hypothyroidism and euthyroid goiter. A total of 20 unrelated children at the age from 2 to 16 years presenting with the hearing loss of different severity were available for the examination. High-resolution CT of the temporal bones demonstrated abnormal development of the inner ear including the Mondini-type structural anomaly and enlarged vestibular aqueduct. Five children with congenital hypothyroidism suffered from bilateral sensorineural impairment of hearing. The routine methods of audiological and molecular genetic examination were used throughout the study. RESULTS: As a result of molecular genetic studies, four out of the 20 patients were found to carry six recessive mutations of the SLC26A4 gene in the compound heterozygous and one such gene in the homozygous state which confirmed the hereditary nature of the disease. The children suffered the hearing loss of varying severity diagnosed at different age. The thyroid hypofunction in one child was identified when it was 2 years of age, and in two children at the age of 8 and 9 years. CONCLUSION: The first step in the diagnosis of the Pendred syndrome among children with congenital hearing loss was a CT scan of the temporal bones that showed incomplete separation of the curls of the cochlea and enlarged vestibular aqueduct. It is necessary to continue to study epidemiology, clinical and molecular genetics of the Pendred syndrome in the Russian population.

[Application of the mathematical model for prognosis in the rehabilitation of children after cochlear implantation]. / Ispol'zovanie matematicheskoi modeli dlya opredeleniya prognoza reabilitatsii u detei posle kokhlearnoi implantatsii.

Despite the variety of etiological factors, cochlear implantation (CI) remains the only effective method for the rehabilitation of the patients presenting with total deafness. The aim of this study was the enhancement of the efficiency of selection of the candidates for CI, the improvement of the quality of rehabilitation of the patients with cochlear implants, and the determination of the prognostic criteria for clinical trials. PATIENTS AND METHODS: (CI). The decision-making support system (DMSS) based on the artificial neural networks (ANNs) has been created to enhance the efficiency of rehabilitation of the patients with cochlear implants and increase the effectiveness of the selection of candidates for cochlear implantation. The results of the children's rehabilitation after CI have been analyzed by using a mathematical model of artificial neural networks (Kohonen layer). The basis for the assessment of ANNs was formed by the results of the observations of audioverbal perception in 110 patients aged from 6 months to 17 years. The initial data were the average values obtained with the use of the Russian-language version of the Nottingham children's implant profile's test T1 - T3. The testing was performed before CI and 3, 6, 12, 18, and 24 months after it. MAIN RESULTS: The work yielded the four-cluster data structure. It made it possible to estimate the effectiveness of the clinical trials in selected classes depending on the etiology of the disease, the age of the patients, and their experience with the application of hearing aids. The reliable estimation of the dynamics of auditory perception at the stage of rehabilitation and prognosis of the outcomes of CI made it possible to take additional preventive and therapeutic measures in the combination with complementary psychological and educational procedures.

[The audiological phenotype and the prevalence of GJB2-related sensorineural loss of hearing in the infants suffering acoustic disturbances].

The objective of the present work was to study specific features of the audiological phenotype and the prevalence of GJB2-related sensorineural hearing loss (SNHL) in the infants suffering acoustic disturbances. The study included 264 children with bilateral non-syndromic sensorineural loss of hearing diagnosed during the first year of life by means of detailed audiological examination that included tympanometry, registration of short-latency auditory action potentials (SLAAP), delayed evoked otoacoustic emission (DEOAE), distortion product-frequency otoacoustic emission (DPFOAE), and auditory brain-stem response (ABR). In addition, stationary acoustically evoked responses (SAER) were recorded in 38 children presenting with hearing impairment associated with GJB2-related sensorineural loss of hearing. The follow-up dynamic study involved 113 children subjected to repeated audiological examination. The study revealed the genotype with pathological mutations in 182 (69.0%) children including 171 (64.8%) ones with biallelic mutations and 11 (4.2%) with a single mutation (heterozygous genotype). Eighty two (31.0%) children had genotype without mutations. A total of 21 different mutations and 30 different genotypes were identified. Analysis of the family histories of the children showed that neither the absence of relatives suffering from hearing impairment nor the presence of risk factors of acquired hearing impairment excludes the possibility of GJB2-related sensorineural loss of hearing in the infants. Otoacoustic emission fails to be registered in the majority of the children with the altered genotype (87%) during the stay in the maternity house. Mutations in the GJB2 gene are most frequently diagnosed in the patients with the moderate, moderately severe, and severe loss of hearing. At the same time, almost half of the infants presenting with the mild loss of hearing were found to exhibit changes in the GJB2 gene. The thresholds of registration of short-latency auditory action potentials remain stable in 90.0% of the children presenting with GJB2-related sensorineural loss of hearing which makes it possible to choose the strategy of their rehabilitative treatment (the use of hearing aids or cochlear implantation) during the very first months of life and predict the favourable outcome of cochlear implantation and hearing aid measures. The results of the present work illustrate the importance and practical significance of genetic studies (GJB2 gene tresting) of the infants suffering sensorineural loss of hearing and other acoustic disturbances for the elucidation of etiology of these conditions, prognosis of the disease, and the choice of the strategy for its treatment.

[The universal audiological screening of newborn infants: achievements and challenges].

The objective of the present study was to estimate the effectiveness of universal audiological screening of newborn infants in Russia based on the results of this procedure obtained in 2011-2012 by the analysis of the activities of surdological centres in 15 regions of the country. It was shown, that the main indicators of the effectiveness of the screening are the technical equipment of maternity houses, newborn coverage at the first stage of screening, and its continuity. The study revealed 3.14% of the infants who failed to be involved in the first stage of screening. Hearing impairment was diagnosed in two of each 1,000 newborn infants at the second stage of screening, the frequency of severe forms of hearing impairment was estimated as three cases per 10,000 infants. The disadvantages of the current system of identification of newborn infants suffering congenital loss of hearing are discussed. The importance of the improvement of data collection methods is emphasized.

[Johanson-Blizzard syndrome: audiological features and results of cochlear implantation].

Johanson-Blizzard syndrome is a rare congenital autosomal recessive disease characterized by the association of congenital deficiency of the exocrine pancreatic function and multiple malformations. One of the most common manifestations of this pathology is sensorineural hearing loss of different severity and anomalous development of the inner ear. The case of cochlear implantation in the patient presenting with bilateral sensorineural deafness, congenital malformation of the inner ear, and stenosis of the internal auditory canal is reported.

[The mutation spectrum of the GJB2 gene in Belarussian patients with hearing loss. Results of pilot genetic screening of hearing impairment in newborns].

A total of 111 unrelated probands and their 8 sibs from Grodno oblast (Belarus) with bilateral isolated sensorineural hearing impairment were studied for the presence of mutations in the connexin 26--GJB2gene. Mutations were detected in 51 probands (46% of the sample). A significantly higher frequency of the GJB2gene mutations was observed in familial cases of the disease with the autosomal recessive type of inheritance (in 78% of families). Detected peculiarities of the GJB2 gene mutation spectrum demonstrated that use of the algorithm, which was developed for Russian patients, is optimal for the molecular study of patients from Be- larus. In the sample of patients with hearing loss, the highest (among other similar samples studied in the world) allele frequency of c.313_326de114 mutation (7% out of all pathological GJB2 alleles) was registered; Polish origin of this deletion was suggested. It was demonstrated that detection of the GJB2 gene mutation on only one patient's chromosome is insufficient to confirm a molecular genetic diagnosis of hearing loss of the DFNB1 genetic type (autosomal recessive hearing loss caused by the GJB2 gene mutations). Pilot screening in the presence of GJB2 gene mutations in newborns from Grodno oblast was conducted. The material from 235 children was studied during the screening; nine heterozygous carriers of the mutation were found. The c.35delG mutation was detected in a homozygous state in a single newborn (hearing loss of moderate severity was subsequently audiologically confirmed in this child).

[New recurrent extended deletion, including GJB2 and GJB6 genes, results in isolated sensorineural hearing impairment with autosomal recessive type of inheritance].

Hereditary hearing loss with the autosomal recessive type of inheritance of the DFNB 1 genetic type, caused by mutations in the GJB2 gene, is the main reason of innate non-syndromal hearing impairment in most developed countries of the world (including Russia). Intragenic point mutations prevail among the GJB2 gene defectors; however, extended deletions in the DFNB1 locus are also found with considerable frequency in some populations (for example, Spain, Great Britain, France, United States, and Brazil). Among the four known extended deletions, only one deletion affects directly the GJB2 gene sequence and was described in a single family. A new extended deletion in the GJB2 and GJB6 gene sequences (approximately 101 kb in size; NC_000013.10:g.20,757,021_20,858,394del), detected in three unrelated Russian patients, was described and characterized. Ingush origin of this mutation is assumed. If the new deletion is frequent, its detection is very important for the genetic consulting of families with hereditary hearing impairment.