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Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy-Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4-15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.

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Hearing loss is the most frequent sensory disorder, with an incidence of 1:1500 live newborns. In more than 50% of patients, it is associated with a genetic cause, while in up to 30% of cases, it is related to syndromic entities. We performed a literature review of studies on congenital hearing loss of genetic origin in the Mexican population. We identified eight reports that showed that the pathogenic variants most frequently associated with hearing loss are related to the GJB2 gene, although in a low percentage (3%). Other mutations were identified in the GJB6, SLC26A4, or CHD23 genes. On this basis, a possible diagnostic strategy in Mexican patients with hearing loss is to consider an initial screening of these three genes. If these genes were negative for pathogenic variants, the following steps would be to consider second-generation sequencing analysis focused on panels of genes associated with hearing loss, isolated or syndromic, and if necessary, to perform exome or whole-genome analysis. Establishing an etiologic cause is critical in clinically evaluating patients with congenital hearing loss and their families. It can help determine rehabilitation strategies, such as hearing aids or cochlear implants and provide information on disease progression and genetic counseling in this population.

La pérdida auditiva es la alteración sensorial más frecuente, con una incidencia de 1:1500 recién nacidos vivos. En más del 50% de los pacientes se asocia con una causa genética, mientras que en más del 30% de los casos se asocia con entidades sindrómicas. Se llevó a cabo una revisión de la literatura de las investigaciones sobre la pérdida auditiva congénita de origen genético en la población mexicana. Se identificaron ocho reportes en los que se demostró que las variantes patogénicas más frecuentemente asociadas con pérdida auditiva se encuentran en el gen GJB2, aunque en un porcentaje bajo (3%). Se identificaron otras mutaciones en los genes GJB6, SLC26A4 o CHD23. Con base en esta información, una posible estrategia diagnóstica en pacientes mexicanos con pérdida auditiva es considerar un primer paso en el tamiz diagnóstico con los tres genes mencionados. Si estos genes fueran negativos para variantes patogénicas, el siguiente paso sería considerar el análisis por secuenciación de segunda generación enfocado en paneles de genes asociados con pérdida auditiva, tanto aislada como sindrómica, y en caso necesario, realizar el análisis del exoma o del genoma completo. Establecer una causa etiológica es un componente crítico en la evaluación clínica de los pacientes con pérdida auditiva congénita, ya que puede ayudar a determinar las estrategias de manejo y rehabilitación, como el uso de auxiliares auditivos o implantes cocleares, proporcionar información sobre la progresión de la enfermedad y dar asesoramiento genético en esta población.

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Abstract Hearing loss is the most frequent sensory disorder, with an incidence of 1:1500 live newborns. In more than 50% of patients, it is associated with a genetic cause, while in up to 30% of cases, it is related to syndromic entities. We performed a literature review of studies on congenital hearing loss of genetic origin in the Mexican population. We identified eight reports that showed that the pathogenic variants most frequently associated with hearing loss are related to the GJB2 gene, although in a low percentage (3%). Other mutations were identified in the GJB6, SLC26A4, or CHD23 genes. On this basis, a possible diagnostic strategy in Mexican patients with hearing loss is to consider an initial screening of these three genes. If these genes were negative for pathogenic variants, the following steps would be to consider second-generation sequencing analysis focused on panels of genes associated with hearing loss, isolated or syndromic, and if necessary, to perform exome or whole-genome analysis. Establishing an etiologic cause is critical in clinically evaluating patients with congenital hearing loss and their families. It can help determine rehabilitation strategies, such as hearing aids or cochlear implants and provide information on disease progression and genetic counseling in this population.

Resumen La pérdida auditiva es la alteración sensorial más frecuente, con una incidencia de 1:1500 recién nacidos vivos. En más del 50% de los pacientes se asocia con una causa genética, mientras que en más del 30% de los casos se asocia con entidades sindrómicas. Se llevó a cabo una revisión de la literatura de las investigaciones sobre la pérdida auditiva congénita de origen genético en la población mexicana. Se identificaron ocho reportes en los que se demostró que las variantes patogénicas más frecuentemente asociadas con pérdida auditiva se encuentran en el gen GJB2, aunque en un porcentaje bajo (3%). Se identificaron otras mutaciones en los genes GJB6, SLC26A4 o CHD23. Con base en esta información, una posible estrategia diagnóstica en pacientes mexicanos con pérdida auditiva es considerar un primer paso en el tamiz diagnóstico con los tres genes mencionados. Si estos genes fueran negativos para variantes patogénicas, el siguiente paso sería considerar el análisis por secuenciación de segunda generación enfocado en paneles de genes asociados con pérdida auditiva, tanto aislada como sindrómica, y en caso necesario, realizar el análisis del exoma o del genoma completo. Establecer una causa etiológica es un componente crítico en la evaluación clínica de los pacientes con pérdida auditiva congénita, ya que puede ayudar a determinar las estrategias de manejo y rehabilitación, como el uso de auxiliares auditivos o implantes cocleares, proporcionar información sobre la progresión de la enfermedad y dar asesoramiento genético en esta población.

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Genetic variants in GJB2 and GJB6 genes are the most frequent causes of hereditary hearing loss among several deaf populations worldwide. Molecular diagnosis enables proper genetic counseling and medical prognosis to patients. In this study, we present an update of testing results in a cohort of Argentinean non-syndromic hearing-impaired individuals. A total of 48 different sequence variants were detected in genomic DNA from patients referred to our laboratory. They were manually curated and classified based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology ACMG/AMP standards and hearing-loss-gene-specific criteria of the ClinGen Hearing Loss Expert Panel. More than 50% of sequence variants were reclassified from their previous categorization in ClinVar. These results provide an accurately interpreted set of variants to be taken into account by clinicians and the scientific community, and hence, aid the precise genetic counseling to patients.

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Abstract Introduction: Deafness is the most frequent sensory deficit in humans. Incidence is estimated at 4:1000 births in Brazil. Specific programs for clinical care of patients with hearing loss are still scarce in Brazil and the issue is an important public health problem. Objective: To determine the frequency of 35delG and D13S1830 mutations in GJB2 and GJB6 genes respectively in patients with non-syndromic sensorineural hearing loss from Minas Gerais, Brazil. Methods: This research involved 53 individuals, who were assessed by a questionnaire for predicting the possibility of non-syndromic deafness and for data collecting. Samples were tested for the presence of the 35delG mutation in GJB2 gene and D13S1830 in GJB6 gene by polymerase chain reaction and restriction enzyme digestion. Results: Epidemiological research has shown that the majority of the subjects are unaware of the etiology and the pathogenesis of hearing loss. In 9 patients (16.98%), 35delG mutation was found in heterozygosis and the allele frequency was estimate to be around 8.5%. Although 9.61% of the patients reported having some degree of consanguinity between the parents and 12.08% reported other cases of deafness in their families, this mutation was not found in homozygosis. The D13S1830 mutation was not found in this study. Conclusion: This research describes for the first time the frequency of the 35delG and D13S1830 mutation in hearing-impaired individuals from Minas Gerais, Brazil, and the collected data reinforce the need for further studies in this population due to heterogeneity of hearing loss.

Resumo Introdução: A surdez é o déficit sensorial mais frequente em humanos. Estima-se que a incidência seja de 4:1.000 nascimentos no Brasil. Programas específicos para atendimento clínico de pacientes com perda auditiva são escassos no Brasil e a questão é um importante problema de saúde pública. Objetivo: Determinar a frequência das mutações 35delG no gene GJB2 e D13S1830 no GJB6 em pacientes deficientes auditivos de origem neurossensorial e não sindrômica de Minas Gerais, Brasil. Método: A pesquisa envolveu 53 indivíduos selecionados por meio de questionário o qual avaliou a possibilidade de surdez não sindrômica entre outros dados. As amostras foram testadas quanto à presença da mutação 35delG no gene GJB2 e D13S1830 no gene GJB6 por reação em cadeia da polimerase e digestão com enzima de restrição. Resultados: A pesquisa epidemiológica mostrou que a maioria dos indivíduos desconhece a etiologia da perda auditiva. Em 9 pacientes (16,98%), a mutação 35delG foi encontrada em heterozigose e a frequência alélica foi estimada em 8,5%. Embora 9,61% das pessoas tenham relatado algum grau de consanguinidade entre os pais e 12,08% relatassem outros casos de surdez em suas famílias, essa mutação não foi encontrada em homozigose. A mutação D13S1830 não foi encontrada neste estudo. Conclusão: Este trabalho descreve pela primeira vez a frequência da mutação 35delG e D13S1830 em deficientes auditivos de Minas Gerais, Brasil, e os dados coletados reforçam a necessidade de mais estudos nessa população devido à heterogeneidade da perda auditiva.

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INTRODUCTION: Deafness is the most frequent sensory deficit in humans. Incidence is estimated at 4:1000 births in Brazil. Specific programs for clinical care of patients with hearing loss are still scarce in Brazil and the issue is an important public health problem. OBJECTIVE: To determine the frequency of 35delG and D13S1830 mutations in GJB2 and GJB6 genes respectively in patients with non-syndromic sensorineural hearing loss from Minas Gerais, Brazil. METHODS: This research involved 53 individuals, who were assessed by a questionnaire for predicting the possibility of non-syndromic deafness and for data collecting. Samples were tested for the presence of the 35delG mutation in GJB2 gene and D13S1830 in GJB6 gene by polymerase chain reaction and restriction enzyme digestion. RESULTS: Epidemiological research has shown that the majority of the subjects are unaware of the etiology and the pathogenesis of hearing loss. In 9 patients (16.98%), 35delG mutation was found in heterozygosis and the allele frequency was estimate to be around 8.5%. Although 9.61% of the patients reported having some degree of consanguinity between the parents and 12.08% reported other cases of deafness in their families, this mutation was not found in homozygosis. The D13S1830 mutation was not found in this study. CONCLUSION: This research describes for the first time the frequency of the 35delG and D13S1830 mutation in hearing-impaired individuals from Minas Gerais, Brazil, and the collected data reinforce the need for further studies in this population due to heterogeneity of hearing loss.

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: Hearing loss (HL) is a common sensory disorder affecting over 5% of the global population. The etiology underlying HL includes congenital and acquired causes; genetic factors are the main cause in over 50% of congenital cases. Pathogenic variants in the GJB2 gene are a major cause of congenital non-syndromic hearing loss (NSHL), while their distribution is highly heterogeneous in different populations. To the best of our knowledge, there is no data regarding the genetic etiologies of HL in Peru. In this study, we screened 133 Peruvian families with NSHL living in Lima. We sequenced both exons of the GJB2 gene for all probands. Seven probands with familial NSHL that remained negative for GJB2 variants underwent whole genome sequencing (WGS). We identified biallelic pathogenic variants in GJB2 in 43 probands; seven were heterozygous for only one allele. The c.427C>T variant was the most common pathogenic variant followed by the c.35delG variant. WGS revealed three novel variants in MYO15A in two probands, one of them was predicted to affect splicing and the others produce a premature stop codon. The Peruvian population showed a complex profile for genetic variants in the GJB2 gene, this particular profile might be a consequence of the admixture history in Peru.

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El Nevo Poroqueratósico del Ostium y el Ducto Dérmico Ecrinos (NPODDE), es un raro hamartoma benigno de los conductos de las glándulas sudoríparas ecrinas, puede presentarse desde el nacimiento o también en edades posteriores. Su etiología plantea una alteración en la queratinización debido a una mutación somática en el gen GJB2 que codifica para una proteína de unión gap. Esta mutación también está relacionada con el síndrome KID por lo cual la asesoría genética es crucial en estos pacientes. Clínicamente puede presentarse como hoyuelos hiperqueratósicos en palmas y plantas que normalmente son asintomáticos. El diagnostico se confirma con la histopato-logía que muestra una laminilla cornoide sobre el conducto ecrino subyacente. La entidad es benigna y de difícil tratamiento siendo refractaria a varias modalidades terapéuticas. Se presenta un caso de un paciente adulto masculino con lesiones típicas en palmas y plantas, a quien con la biopsia de piel se le confirmó el diagnóstico de NPODDE. Dado la baja frecuencia de esta condición el objetivo de este artículo radica en actualizar los aspectos más relevantes de esta entidad.

Porokeratotic Eccrine Ostial and Dermal Duct Nevus (PEODDN) is a rare benign hamartoma of eccrine sweat gland ducts, it can present from birth or also at later ages. Its etiology implies an alteration in keratinization due to a somatic mutation in GJB2 gene, that codes for a gap junction protein. This mutation is also associated with KID syndrome so genetic counseling for parents is crucial. Clinically it can present as keratotic pits in palms and soles that are usually asymp-tomatic. The diagnosis is confirmed by histopathology that shows a cornoid lamellae on the underlying eccrine duct. The entity is benign and the treatment is difficult, being refractory to seve-ral therapeutic modalities. We present a case of a male adult patient with typical lesions on palms and soles, who was diagnosed with PEODDN by skin biopsy. Given the low frequency of this con-dition, the objective of this article is to update the most relevant aspects of this entity.

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GJB2 mutations are the leading cause of non-syndromic inherited hearing loss. GJB2 encodes connexin-26 (CX26), which is a connexin (CX) family protein expressed in cochlea, skin, liver, and brain, displaying short cytoplasmic N-termini and C-termini. We searched for CX26 C-terminus binding partners by affinity capture and identified 12 unique proteins associated with cell junctions or cytoskeleton (CGN, DAAM1, FLNB, GAPDH, HOMER2, MAP7, MAPRE2 (EB2), JUP, PTK2B, RAI14, TJP1, and VCL) by using mass spectrometry. We show that, similar to other CX family members, CX26 co-fractionates with TJP1, VCL, and EB2 (EB1 paralogue) as well as the membrane-associated protein ASS1. The adaptor protein CGN (cingulin) co-immuno-precipitates with CX26, ASS1, and TJP1. In addition, CGN co-immunoprecipitation with CX30, CX31, and CX43 indicates that CX association is independent on the CX C-terminus length or sequence. CX26, CGN, FLNB, and DAMM1 were shown to distribute to the organ of Corti and hepatocyte plasma membrane. In the mouse liver, CX26 and TJP1 co-localized at the plasma membrane. In conclusion, CX26 associates with components of other membrane junctions that integrate with the cytoskeleton.

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Abstract Introduction: Several studies have associated congenital sensorineural hearing loss in children with prolongation of the cardiac parameter QTc. The cause of this association is unknown. At the same time, mutations in GJB2, which encodes connexin 26, are the most common cause of congenital hearing impairment. Objective: To compare electrocardiographic parameters (PR interval, QRS complex, and QTc interval) in patients with hearing loss who were tested for mutations in GJB2 and GJB6 to investigate whether these mutations affect electrical activity of the heart. Methods: 346 patients (176 males, 170 females) with sensorineural hearing loss of 30 dB HL or more, aged 21.8 ± 19.9 years (including 147 children <14 years), underwent both genetic study for GJB2 and GJB6 mutations and electrocardiography. Results: Mutations in GJB2, including homozygotes and heterozygotes, were found in 112 (32%) patients. There were no significant differences in ECG parameters between groups of patients with and without mutations in GJB2. No differences were observed either in men (mean PR with mutation: 155 ± 16.6 vs. 153.6 ± 30.1 without; QRS: 99.9 ± 9.9 vs. 101.1 ± 15.4; QTc: 414.9 ± 29.9 vs. 412.4 ± 25.7) or women (mean PR with: 148.7 ± 21 vs. 143.8 ± 22.8 without; QRS: 94.8 ± 7.6 vs. 92.9 ± 9.6; QTc: 416.8 ± 20.6 vs. 424.9 ± 22.8). In similar fashion, we did we find any significant differences between groups of children with and without GJB2 mutations (mean PR with: 126.3 ± 19.6 vs. 127 ± 19.7 without; QRS: 80.7 ± 9.5 vs. 79.4 ± 11.6; QTc: 419.7 ± 23.5 vs. 419.8 ± 24.8). Conclusion: No association was found between the presence of GJB2 mutations encoding connexin 26 in patients with hearing loss and their ECG parameters (PR, QRS, QTc).

Resumo Introdução: Vários estudos têm associado a perda auditiva neurossensorial congênita em crianças ao prolongamento do parâmetro cardíaco QTc. A causa dessa associação é desconhecida. Ao mesmo tempo, as mutações no GJB2, que codifica a conexina 26, são a causa mais comum de deficiência auditiva congênita. Objetivo: Comparar parâmetros eletrocardiográficos (intervalo PR, complexos QRS e intervalo QTc) em pacientes com perda auditiva que foram testados para mutações no GJB2 e GJB6 para investigar se essas mutações afetam a atividade elétrica do coração. Método: Foram submetidos a estudo genético para mutações de GJB2 e GJB6 e eletrocardiograma 346 pacientes (176 homens, 170 mulheres) com perda auditiva neurossensorial de 30 dB ou mais, com média de 21,8 ± 19,9 anos (incluindo 147 crianças <14 anos). Resultados: Mutações no GJB2, inclusive homozigóticos e heterozigóticos, foram encontradas em 112 (32%) pacientes. Não houve diferenças significativas nos parâmetros de ECG entre grupos de pacientes com e sem mutações no GJB2. Não foram observadas diferenças em homens (PR médio com mutação: 155 ± 16,6 vs. 153,6 ± 30,1 sem mutação; QRS: 99,9 ± 9,9 vs. 101,1 ± 15,4; QTc: 414,9 ± 29,9 vs. 412,4 ± 25,7) nem em mulheres (PR médio com: 148,7 ± 21 vs. 143,8 ± 22,8, sem; QRS: 94,8 ± 7,6 vs. 92,9 ± 9,6; QTc: 416,8 ± 20,6 vs. 424,9 ± 22,8). Da mesma forma, encontramos diferenças significativas entre os grupos de crianças com e sem mutações de GJB2 (PR médio com: 126,3 ± 19,6 vs. 127 ± 19,7, sem; QRS: 80,7 ± 9,5 vs. 79,4 ± 11,6; QTc: 419,7 ± 23,5 vs. 419,8 ± 24,8). Conclusão: Não foi encontrada associação entre a presença de mutações de GJB2 que codificam conexina 26 em pacientes com perda auditiva e seus parâmetros de ECG (PR, QRS, QTc).

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INTRODUCTION: Several studies have associated congenital sensorineural hearing loss in children with prolongation of the cardiac parameter QTc. The cause of this association is unknown. At the same time, mutations in GJB2, which encodes connexin 26, are the most common cause of congenital hearing impairment. OBJECTIVE: To compare electrocardiographic parameters (PR interval, QRS complex, and QTc interval) in patients with hearing loss who were tested for mutations in GJB2 and GJB6 to investigate whether these mutations affect electrical activity of the heart. METHODS: 346 patients (176 males, 170 females) with sensorineural hearing loss of 30dB HL or more, aged 21.8±19.9 years (including 147 children <14 years), underwent both genetic study for GJB2 and GJB6 mutations and electrocardiography. RESULTS: Mutations in GJB2, including homozygotes and heterozygotes, were found in 112 (32%) patients. There were no significant differences in ECG parameters between groups of patients with and without mutations in GJB2. No differences were observed either in men (mean PR with mutation: 155±16.6 vs. 153.6±30.1 without; QRS: 99.9±9.9 vs. 101.1±15.4; QTc: 414.9±29.9 vs. 412.4±25.7) or women (mean PR with: 148.7±21 vs. 143.8±22.8 without; QRS: 94.8±7.6 vs. 92.9±9.6; QTc: 416.8±20.6 vs. 424.9±22.8). In similar fashion, we did we find any significant differences between groups of children with and without GJB2 mutations (mean PR with: 126.3±19.6 vs. 127±19.7 without; QRS: 80.7±9.5 vs. 79.4±11.6; QTc: 419.7±23.5 vs. 419.8±24.8). CONCLUSION: No association was found between the presence of GJB2 mutations encoding connexin 26 in patients with hearing loss and their ECG parameters (PR, QRS, QTc).

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The auditory neuropathy is a condition which there is a dyssynchrony in the nerve conduction of the auditory nerve fibers. There is no evidence about the relationship between patients with clinical auditory neuropathy spectrum disorder and mutations in GJB2 gene. There are only two studies about this topic in the medical literature. Connexin 26 (GJB2 gene) mutations are common causes of genetic deafness in many populations and we also being reported in subjects with auditory neuropathy. OBJECTIVE: To analyze the pattern of clinical relationship between patients with clinical diagnosis with auditory neuropathy spectrum disorder and GJB2 gene. PATIENTS AND METHODS: Study Design - Retrospective analysis and genetic evaluation. Setting - Tertiary referral center. Subjects - 40 patients with Auditory Neuropathy Spectrum Disorder. Intervention - Clinical information and genetic evaluation (GJB2 gene) were analyzed. RESULTS: Biallelic mutations that accounted for hearing loss (HL) were found in three patients, both with c.35delG mutation in homozygous state. The splice site mutation IVS1+1G>A was detected in heterozygous state in one individual. However, since the second mutant allele was not identified, it was not possible to establish its correlation with the phenotype. CONCLUSION: Mutations in GJB2 gene mutations were found in 7.5% of the patients with ANSD. We found no relationship between patients with clinical auditory neuropathy spectrum disorder and mutations in GJB2 gene (p>0.05).

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BACKGROUND: Keratitis-Ichthyosis-Deafness (KID) syndrome is a rare condition characterized by pre-lingual sensorineural deafness with skin hyperkeratinization. The primary cause of the disease is a loss-of-function mutation in the GJB2 gene. Mutations in Argentinean patients have not been described. CASE PRESENTATION: We studied a 2 year-old boy with bilateral congenital sensorineural deafness with dry skin over the entire body, hypotrichosis of the scalp, thin and light-blond hair. Analysis of the GJB2 gene nucleotide sequence revealed the substitution of guanine-148 by adenine predicted to result in an Asp50Asn amino acid substitution. CONCLUSION: This is the first KID report in a patient from Argentina. This de novo mutation proved to be the cause of keratitis-ichthyosis-deafness syndrome (KID-syndrome) in the patient, and has implications in medical genetic practice.

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Over 5% of the world's population has varying degrees of hearing loss. Mutations in GJB2 are the most common cause of autosomal recessive non-syndromic hearing loss (ARNHL) in many populations. The frequency and type of mutations are influenced by ethnicity. Guatemala is a multi-ethnic country with four major populations: Maya, Ladino, Xinca, and Garifuna. To determine the mutation profile of GJB2 in a ARNHL population from Guatemala, we sequenced both exons of GJB2 in 133 unrelated families. A total of six pathogenic variants were detected. The most frequent pathogenic variant is c.131G>A (p.Trp44*) detected in 21 of 266 alleles. We show that c.131G>A is associated with a conserved haplotype in Guatemala suggesting a single founder. The majority of Mayan population lives in the west region of the country from where all c.131G>A carriers originated. Further analysis of genome-wide variation of individuals carrying the c.131G>A mutation compared with those of Native American, European, and African populations shows a close match with the Mayan population.

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Hearing loss (HL) is the most common inherited sensory disorder affecting about 1 in 1000 births. The first locus for nonsyndromic autosomal recessive HL is on chromosome 13q11-22. The two genes, GJB2 and GJB6, are closely located on chromosome and are known to be co-expressed in the embryonic cochlea. Deletion mutations involving GJB6 were associated with autosomal-recessive nonsyndromic hearing loss (ARNSHL) and in combination with a GJB2 mutation with digenic ARNSHL. The objective of this study was to screen for the del (GJB6-D13S1830) and del (GJB6-D13s1854) mutations in GJB6 gene in patients with ARNSHL from Iran, using multiplex PCR and direct sequencing methods. Agarose gel electrophoresis and DNA sequencing of amplified fragment of the PCR reaction showed none of the patients was found to carry deletion in GJB6 gene which indicates that these deletions are restricted to certain populations and indicating a founder effect regarding these deletions.

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BACKGROUND: Sensorineural hearing loss (SNHL) is a genetically heterogeneous disease. GJB2 gene mutations seem to be the most frequent cause of hereditary hearing impairment in several populations. There is variability in the mutations in the GJB2 gene worldwide; this remarks the influence of ethnic background in SNHL. OBJECTIVE: To describe the presence of two trimutations in the GJB2 gene in two Mexican families with hereditary SNHL. MATERIALS AND METHODS: Two unrelated Mexican families with prelingual SNHL were included in the study. Analysis of the GJB2 gene through PCR and DNA direct sequencing analysis was performed in all members of the families and in 100 normal controls. RESULTS: Affected member of the family 1 showed the trimutation p.S19R/p.R32S/p.E47*, whereas affected members of the family 2 showed the trimutation p.F31I/p.W44*/p.V84M. Parents of both families were heterozygous with normal audition. CONCLUSION: We found a novel mutation in the GJB2 gene and two trimutations with SNHL not previously reported. This remarks the complexity in the pattern of mutations in the GJB2 gene in SNHL and enriches the spectrum of the type of molecular defects in the GJB2 gene.

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OBJECTIVES: Mutations in the DFNB1 locus are the most common cause of autosomal-recessive nonsyndromic hearing loss (ARNSHL) worldwide. The aim of this study was to identify the most frequent mutations in patients with ARNSHL who reside in Northeastern Mexico. METHODS: We determined the nucleotide sequence the coding region of GJB2 of 78 patients with ARNSHL. Polymerase chain reaction assays were used to detect the GJB2 IVS1+1G>A mutation and deletions within GJB6. RESULTS: GJB2 mutations were detected in 9.6% of the alleles, and c.35delG was the most frequent. Six other less-frequent mutations were detected, including an extremely rare variant (c.645_648delTAGA), a novel mutation (c.35G>A), and one of possible Mexican origin (c.34G>T). GJB6 deletions and GJB2 IVS1+1G>A were not detected. CONCLUSIONS: These data suggest that mutations in the DFNB1 locus are a rare cause of ARNSHL among the population of Northeastern Mexico. This confirms the genetic heterogeneity of this condition and indicates that further research is required to determine the other mechanisms of pathogenesis of ARNSHL in Mexicans.

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OBJECTIVE: The frequency of GJB2 mutations and of the del(GJB6-D13S1830) mutation has not been established among the Ecuadorian mestizo population diagnosed with autosomal recessive non-syndromic hearing loss. A genetic analysis was therefore designed in order to do so. METHODS: The sample population included 111 subjects of which 26 were autosomal recessive non-syndromic hearing loss probands. Posterior to PCR amplification, sequencing analysis of exon 2 was used for mutational detection of the GJB2 gene; a multiplex PCR method was used for detection of the del(GJB6-D13S1830) mutation. The ratio of subjects with a certain state of the mutation (heterozygous/homozygous) is expressed as a percentage and significant differences between probands and controls were calculated using Fisher's exact test; P<0.05 was considered significant. RESULTS: A total of 104 mutations belonging to 8 allelic variations were identified. The most common being the V27I (58.9%); however, as this variation is a non-pathogenic polymorphism, Q7X, with a total of 19 mutated alleles, was the most frequent mutation (18.3%). The V27I polymorphism was the only variation distributed homogenously among probands and controls (P=0.351). Based on physical analyses of multiple patients we confirm that Q7X causes a non-syndromic form of hearing loss and propose that it is a possible predominant mutation in the Ecuadorian population. CONCLUSIONS: This is the first study of its kind among the Ecuadorian population and a preliminary step in establishing GJB2 and del(GJB6-D13S1830) mutational frequencies in this population; it is also the first to report of such a high frequency of the Q7X mutation. The data presented here brings Ecuador a step closer to providing more efficient treatment for a broader number of patients; additionally, it contributes to a better understanding of the relationship between autosomal recessive non-syndromic hearing loss and mutations on the GJB2 gene.

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BACKGROUND: Hereditary sensorineural hearing loss (SNHL) is a genetically heterogeneous disorder worldwide. Mutations in the GJB2 gene are a frequent cause of hereditary SNHL. There is a prevalence of certain mutations in various populations which suggests that specific mutations may be influenced by ethnic background. OBJECTIVE: To analyze the prevalence of GJB2, GJB6 mutations in several geographic areas of Mexico in patients with hereditary SNHL. MATERIALS AND METHODS: One hundred and forty Mexican unrelated propositi with prelingual SNHL were included in the study. All patients had three previous generations born in Mexico and belonged to no specific ethnic group. Analyses of the GJB2 and GJB6 genes and mt.1555AG mutation was not detected. CONCLUSION: We found a great variety of mutations depending on the analyzed region in patients with SNHL; 57.86% of patients had affection in one or two alleles in GJB2 or GJB6 genes whereas 42.14% were wild-type. In some cases, allele distribution depended on region. Molecular studies of more genes involved in hereditary non-syndromic SNHL are required to completely confirm the molecular basis of hearing loss in Mexican population.

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RESUMO

Hearing loss is the most common inherited sensorial deficiency in humans; about 1 in 1000 children suffer from severe or profound hearing loss at birth. Mutations in the GJB2 gene are the most common cause of prelingual, non-syndromic autosomal recessive deafness in many populations; the c.35delG mutation is the most common in Caucasian populations. The frequency of the c.35delG mutation was estimated in two samples of deaf patients from Santiago, Chile. Unrelated non-syndromic sensorioneural deaf patients were examined: Group 1 consisted of 47 unrelated individuals with neurosensory deafness referred to the Chilean Cochlear Implant Program; Group 2 included 66 school children with prelingual deafness attending special education institutions for deaf people. Individuals with profound to moderate isolated neurosensory hearing loss with unknown etiology were included. The presence of the c.35delG mutation was evaluated by the allele-specific polymerase chain reaction method (PCR), and in some cases it was confirmed by direct DNA sequencing of the coding region of the GJB2 gene. Deaf relatives were present in 20.3% of the cases. We found 19.5% (22/113) patients with the c.35delG mutation, 6 of them homozygous; these rates are similar to frequencies found in other Latin American countries.

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