Síndrome de Wildervanck: reporte de un caso clínico / Wildervanck syndrome: clinical case report

El síndrome de Wildervanck (cérvico-óculo-acústico) es una patología muy rara, caracterizada por la tríada clásica de fusión de vértebras cervicales o anomalía de Klippel-Feil, síndrome de Duane (paresia del VI par craneal) e hipoacusia. Se han descrito, además, otras afecciones a nivel vascular, cardíaco y musculoesquelético. En este caso clínico, describimos a una paciente que cumple la tríada cardinal, además de presentar datos clínicos adicionales que no han sido reportados con anterioridad, lo cual contribuye a la ampliación del fenotipo de la enfermedad. Asimismo, realizamos una revisión de la literatura respecto a este síndrome

Wildervanck syndrome (also known as cervico-oculo-acoustic dysplasia) is a very rare disease, characterized by the typical triad of cervical vertebral fusion or Klippel-Feil anomaly, Duane syndrome (paresis of the sixth cranial nerve), and hearing loss. Other vascular, cardiac, and musculoskeletal conditions have also been described. In this case report, we describe a patient who met the cardinal triad and also presented additional clinical data that have not been previously reported, which contribute to broadening the disease phenotype. We have also reviewed the bibliography related to this syndrome.

Analysis of genotypes on 850 newborns with SLC26A4 single-allele mutation and the phenotypes of those with second variant / 中华耳鼻咽喉头颈外科杂志

Objective: To clarify the phenotypes of the newborns with SLC26A4 single-allele mutation in deafness genetic screening and second variant; to analyze the SLC26A4 genotype and hearing phenotype. Methods: 850 newborns born in Beijing from April 2015 to December 2019 were included and there were 468 males and 382 females. They received genetic deafness screening for 9 or 15 variants, with the result of SLC26A4 single-allele mutation. Firstly, three step deafness gene sequencing was adopted in this work, i.e., the first step was "SLC26A4 gene whole exons and splice sites" sequencing; the second step was "SLC26A4 gene promoter, FOXI1 gene and KCNJ10 gene whole exons" sequencing; and the third step was detection for "SLC26A4 gene copy number variation". Secondly, we collected the results of newborn hearing screening for all patients with the second mutation found in the three step test, and conducted audiological examinations, such as acoustic immittance, auditory brainstem response and auditory steady state response. Thirdly, for novel/VUS mutations, we searched the international deafness gene database or software, such as DVD, ClinVar and Mutation Taster, to predict the pathogenicity of mutations according to the ACMG guideline. Lastly, we analyzed the relationship between genotype and phenotype of newborns with SLC26A4 single allele mutation. Results: Among 850 cases, the median age of diagnosis was 4 months. In the first step, 850 cases were sequenced. A total of 32 cases (3.76%, 32/850) of a second variants were detected, including 18 cases (2.12%, 18/850) with identified pathogenic variants; 832 cases were sequenced and 8 cases of KCNJ10 gene missense variants were detected among the second step. No missense mutations in the FOXI1 gene and abnormal SLC26A4 gene promoter were detected; the third step sequencing results were all negative. Genotypes and hearing phenotypes included 18 cases combined with the second clear pathogenic variant, 16 cases (16/18) referred newborn hearing screening and 2 cases (2/18) passed in both ears; degree of hearing loss consisted of 18 profound ears (18/36), 13 severe ears (13/36) and 5 moderate ears (5/36); audiogram patterns comprised 17 high frequency drop ears (17/36), 14 flat ears (14/36), 3 undistinguished ears (3/36), and 2 U shaped ears (2/36); 11 cases underwent imaging examination, all of which were bilateral enlarged vestibular aqueduct. As for 22 cases of other genotypes, all passed neonatal hearing screening and the hearing diagnosis was normal, including 9 cases with VUS or possibly novel benign variants, 8 cases with KCNJ10 double gene heterozygous variants, and 5 cases with double heterozygous variants. Conclusions: The probability of individuals with SLC26A4 single-allele variant who merge with a second pathogenic variant is 2.12%, all of which are SNV, which can provide scientific basis for the genetic diagnosis and genetic counseling of SLC26A4 variants. Those who have merged with second pathogenic variant are all diagnosed with sensorineural hearing loss. Patients with KCNJ10 gene mutations do not manifest hearing loss during the infancy, suggesting the need for further follow-up.

Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations / 中华耳鼻咽喉头颈外科杂志

Objective: To analyze the phenotypic-genotypic characteristics of hereditary deafness caused by OTOA gene variations. Methods: Family histories, clinical phenotypes and gene variations of six pedigrees were analyzed, which were diagnosed with hearing loss caused by OTOA gene variations at the PLA General Hospital from September 2015 to January 2022. The sequence variations were verified by Sanger sequencing and the copy number variations were validated by multiplex ligation-dependent probe amplification (MLPA) in the family members. Results: The hearing loss phenotype caused by OTOA variations ranged from mild to moderate in the low frequencies, and from moderate to severe in the high frequencies in the probands, which came from six sporadic pedigrees, among which a proband was diagnosed as congenital deafness and five were diagnosed as postlingual deafness. One proband carried homozygous variations and five probands carried compound heterozygous variations in OTOA gene. Nine pathogenic variations (six copy number variations, two deletion variations and one missense variation) and two variations with uncertain significance in OTOA were identified in total, including six copy number variations and five single nucleotide variants, and three of the five single nucleotide variants were firstly reported [c.1265G>T(p.Gly422Val),c.1534delG(p.Ala513Leufs*11) and c.3292C>T(p.Gln1098fs*)]. Conclusions: OTOA gene variations can lead to autosomal recessive nonsyndromic hearing loss. In this study, the hearing loss caused by OTOA defects mostly presents as bilateral, symmetrical, and postlingual, and that of a few presents as congenital. The pathogenic variations of OTOA gene are mainly copy number variations followed by deletion variations and missense variations.

Results of combined newborn hearing and deafness gene screening in Yuncheng area of Shanxi Province / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical significance of combined newborn hearing and deafness gene screening in Yuncheng area of Shanxi Province.@*METHODS@#Results of audiological examinations, including transient evoked otoacoustic emission and automatic discriminative auditory brainstem evoked potentials, for 6 723 newborns born in Yuncheng area from January 1, 2021 to December 31, 2021, were retrospectively analyzed. Those who failed one of the tests were considered to have failed the examination. A deafness-related gene testing kit was used to detect 15 hot spot variants of common deafness-associated genes in China including GJB2, SLC26A4, GJB3, and mtDNA12S rRNA. Neonates who had passed the audiological examinations and those who had not were compared using a chi-square test.@*RESULTS@#Among the 6 723 neonates, 363 (5.40%) were found to carry variants. These have included 166 cases (2.47%) with GJB2 gene variants, 136 cases (2.03%) with SLC26A4 gene variants, 26 cases (0.39%) with mitochondrial 12S rRNA gene variants, and 33 cases (0.49%) with GJB3 gene variants. Among the 6 723 neonates, 267 had failed initial hearing screening, among which 244 had accepted a re-examination, for which 14 cases (5.73%) had failed again. This has yielded an approximate prevalence of hearing disorder of 0.21% (14/6 723). Among 230 newborns who had passed the re-examination, 10 (4.34%) were found to have carried a variant. By contrast, 4 out of the 14 neonates (28.57%) who had failed the re-examination had carried a variant, and there was a significant difference between the two groups (P < 0.05).@*CONCLUSION@#Genetic screening can provide an effective supplement to newborn hearing screening, and the combined screening can provide a best model for the prevention of hearing loss, which can enable early detection of deafness risks, targeted prevention measures, and genetic counseling to provide accurate prognosis for the newborns.

A prospective study of genetic screening of 2 060 neonates by high-throughput sequencing / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of genetic screening by high-throughput sequencing (HTS) for the early diagnosis of neonatal diseases.@*METHODS@#A total of 2 060 neonates born at Ningbo Women and Children's Hospital from March to September 2021 were selected as the study subjects. All neonates had undergone conventional tandem mass spectrometry metabolite analysis and fluorescent immunoassay analysis. HTS was carried out to detect the definite pathogenic variant sites with high-frequency of 135 disease-related genes. Candidate variants were verified by Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA).@*RESULTS@#Among the 2 060 newborns, 31 were diagnosed with genetic diseases, 557 were found to be carriers, and 1 472 were negative. Among the 31 neonates, 5 had G6PD, 19 had hereditary non-syndromic deafness due to variants of GJB2, GJB3 and MT-RNR1 genes, 2 had PAH gene variants, 1 had GAA gene variants, 1 had SMN1 gene variants, 2 had MTTL1 gene variants, and 1 had GH1 gene variants. Clinically, 1 child had Spinal muscular atrophy (SMA), 1 had Glycogen storage disease II, 2 had congenital deafness, and 5 had G6PD deficiency. One mother was diagnosed with SMA. No patient was detected by conventional tandem mass spectrometry. Conventional fluorescence immunoassay had revealed 5 cases of G6PD deficiency (all positive by genetic screening) and 2 cases of hypothyroidism (identified as carriers). The most common variants identified in this region have involved DUOX2 (3.93%), ATP7B (2.48%), SLC26A4 (2.38%), GJB2 (2.33%), PAH (2.09%) and SLC22A5 genes (2.09%).@*CONCLUSION@#Neonatal genetic screening has a wide range of detection and high detection rate, which can significantly improve the efficacy of newborn screening when combined with conventional screening and facilitate secondary prevention for the affected children, diagnosis of family members and genetic counseling for the carriers.

The clinical phenotype and gene analysis of syndromic deafness with PTPN11 gene mutation / 中华耳鼻咽喉头颈外科杂志

Objective: To analyze the clinical phenotype and screen the genetic mutations of hereditary deafness in three deaf families to clarify their molecular biology etiology. Methods: From January 2019 to January 2020, three deaf children and family members were collected for medical history, physical examination, audiology evaluation, electrocardiogram and cardiac color Doppler ultrasound, temporal bone CT examination, and peripheral blood DNA was obtained for high-throughput sequencing of deafness genes. Sanger sequencing was performed to verify the variant sites among family members. The pathogenicity of the variants was evaluated according to the American College of Medical Genetics and Genomics. Results: The probands in the three families had deafness phenotypes. In family 1, proband had multiple lentigines, special facial features, growth retardation, pectus carinatum, abnormal skin elasticity, cryptorchidism and other manifestations. In family 2, proband had special facial features, growth retardation and abnormal heart, and the proband in family 3 had growth retardation and abnormal electrocardiogram. Genetic testing of three families detected three heterozygous mutations in the PTPN11 gene: c.1391G>C (p.Gly464Ala), c.1510A>G (p.Met504Val), c.1502G>A (p.Arg501Lys). All three sites were missense mutations, and the mutation sites were highly conserved among multiple homologous species. Based on clinical manifestations and genetic test results, proband 1 was diagnosed with multiple lentigines Noonan syndrome, and probands 2 and 3 were diagnosed with Noonan syndrome. Conclusion: Missense mutations in the PTPN11 gene may be the cause of the disease in the three deaf families. This study enriches the clinical phenotype and mutation spectrum of the PTPN11 gene in the Chinese population.

Identification of novel pathogenic variants of TRIOBP gene in a pedigree affected with non-syndromic deafness / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with non-syndromic hearing loss (NSHL).@*METHODS@#Commercialized gene chip was applied to detect common mutations associated with congenital deafness. Whole exome sequencing was carried out for patients for whom gene chip yielded a negative result. Candidate variants were verified by Sanger sequencing.@*RESULTS@#Two patients from the pedigree were discovered to carry compound heterozygous variants of the TRIOBP gene, namely c.3299C>A and c.5185-2A>G. Their parents had normal hearing and were both heterozygous carriers of the above variants. Both variants had co-segregated with the disease phenotype in the pedigree and were unreported previously.@*CONCLUSION@#Pathogenic variants of the TRIOBP gene comprise an important factor for NSHL. The novel c.5185-2A>G and c.3299C>A variants discovered in this study have enriched the mutational spectrum of the TRIOBP gene and enabled molecular diagnosis and genetic counseling for the family.

Analysis of TMC1 gene variants and prenatal diagnosis in four Chinese families affected with deafness / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of four Chinese families affected with deafness.@*METHODS@#All probands were subjected to next generation sequencing (NGS). Suspected variant were verified by Sanger sequencing among the family members. Prenatal diagnosis was provided for three couples through Sanger sequencing.@*RESULTS@#All probands were found to carry pathogenic variants of the TMC1 gene, which included c.100C>T (p.R34X) and c.642+4A>C in family 1, c.582G>A (p.W194X) and c.589G>A (p.G197R) in family 2, c.1396_1398delAAC and c.1571T>C (p.F524S) in family 3, and homozygosity of c.2050G>C (p.D684H) in family 4. All parents were heterozygous carriers of the variants. The c.642+4A>C and c.1571T>C (p.F524S) were unreported previously. Prenatal diagnosis revealed that none of the fetuses were affected. Follow-up confirmed that all newborns had normal hearing.@*CONCLUSION@#Variant of the TMC1 gene probably underlay the deafness in the four families. Above findings have enhanced our understanding of the function of the TMC1 gene and enriched its variant spectrum. The results also facilitated genetic counseling and prenatal diagnosis for the families.

Analysis of results of concurrent hearing and deafness genetic screening and follow up of 33 911 newborns / 中华医学遗传学杂志

OBJECTIVE@#To analyze the results of concurrent hearing and deafness genetic screening and follow up of newborns.@*METHODS@#In total 33 911 babies born to 5 designated hospitals in Nanshan District of Shenzhen city from October 2017 to December 2019 were included. All subjects underwent concurrent hearing and deafness genetic screening covering 21 variants of 4 genes including GJB2, SLC26A4, GJB3 and Mt12SrRNA. For those with positive results, Sanger sequencing was carried out for confirmation.@*RESULTS@#93.32% subjects passed the first-round hearing screening, and 87.01% passed the recheck testing. The overall detection rate was 4.18%. The detection rates for GJB2, SLC26A4, GJB3 and Mt12srRNA variants were 1.98%, 1.58%, 0.37% and 0.25%, respectively. 126 and 84 subjects were found with high risk for delayed-onset and drug-induced hearing loss, respectively. In addition, 4 and 5 subjects were found to harbor homozygous/compound heterozygous variants of the GJB2 and SLC26A4 genes, respectively. Concurrent screening showed that subjects (with heterozygous variants) who did not passed the two round hearing test were as follows: GJB2 with 6.75% in the first round and 2.61% in the second round testing, SLC26A4 (3.3%/1.2%), GJB3 (0.72%/0.14%) and 12SrRNA (0.36%/Nil), respectively. Moreover, the No-pass rate in the subjects with homozygous or compound variants in single gene, heterozygous variant in single gene, heterozygous variant in multiple genes, and homozygous variant in GJB3 gene were significantly higher than the subjects with negative results of genetic screening.@*CONCLUSION@#Concurrent newborn genetic screening can enhance the effectiveness of hearing screening and enable earlier identification and intervention for children with hearing impairment. Follow-up can improve the diagnostic rate for children who are positive for the concurrent screening. Nevertheless, genetic and hearing screening cannot replace the diagnostic testing. It is necessary to conduct comprehensive analysis for the results of genetic and hearing screening and radiological examinations. Sanger sequencing and next-generation sequencing are critical for ascertain the diagnosis.

Genetic testing of a Chinese pedigree affected with non-syndromic autosomal dominant deafness 15 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a Chinese pedigree affected with progressive non-syndromic sensorineural hearing loss.@*METHODS@#High-throughput DNA sequencing was carried out to analyze 415 genes associated with hereditary deafness in the proband. Sanger sequencing was carried out to verify the suspected variants among her family members.@*RESULTS@#The proband was found to carry a heterozygous c.842T>A (p.Ile281Asn) variant of the POU4F3 gene. The same variant was found among all other patients from the pedigree including the proband's mother, brother, aunt and maternal grandfather, but not among those with normal hearing. Based on the standards and guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, the c.842T>A(p.Ile281Asn) variant of the POU4F3 gene was predicted as likely pathogenic (PM2+PM5+PP1+PP3+PP4).@*CONCLUSION@#A Chinese pedigree affected by a rare type autosomal dominant deafness-15 (DFNA15) due to a novel c.842T>A (p.Ile281Asn) variant of the POU4F3 gene was identified. The result has facilitated genetic counseling and risk assessment for the pedigree.

Analysis of result of gene screening of neonatal deafness in Huizhou and surrounding urban areas / 中华医学遗传学杂志

OBJECTIVE@#To detect common pathogenic variants associated with congenital deafness among neonates from Huizhou and surrounding areas and discuss its implications.@*METHODS@#Thirteen hot-spot mutations in four most common pathogenic genes were screened among 20 934 neonates from March 2017 to December 2019.@*RESULTS@#In total 760 neonates were found to carry common pathogenic variants (3.63%). Sixty two neonates have carried homozygous/compound heterozygous variants or homoplasmy/heteroplasmy mutations of mtDNA (0.29%). Further analysis of five abnormal cases revealed that 3 of them have carried compound heterozygous mutations of GJB2 gene, and 2 were due to compound heterozygous variants of the CDH23 gene.@*CONCLUSION@#Genetic testing has a great clinical significance for the prevention and reduction of congenital hearing loss, but the scope needs to be updated and redefined by removing mutation sites with a very low rate, adding new significant sites, and improvement of the technical strategies.

New deafness gene: Progress of research on ABCC1 in biological barriers / 中华医学遗传学杂志

ABCC1 gene is expressed in various tissues and organs of the human body, and can transport substrates including drugs, heavy metals, toxic substances and organic anions. Previous research on ABCC1 gene has mostly focused on tumor multidrug resistance. Recently, ABCC1 has been proposed as a candidate gene for hereditary hearing impairment, which has attracted much attention. ABCC1-associated deafness may be related to its role in biological barriers. This article has summarized recent progress in the study of the role of ABCC1 in the blood-testis barrier, placental barrier, blood-brain barrier, blood-labyrinth barrier, which may provide insight into its biological functions.

Variation analysis of genes associated with Usher syndrome type 1 in 136 Chinese deafness families / 中华耳鼻咽喉头颈外科杂志

Objective: To investigate the variation of genes associated with Usher syndrome type 1(USH1)in 136 Chinese deafness families from Henan province. Methods: The data of 136 deafness families tested by next-generation sequencing(NGS) which identified in the center of genetics and prenatal diagnosis of the First Affiliated Hospital of Zhengzhou University from November 2016 to December 2019 were analysized and the variation frequency of six genes related to Usher syndrome type 1(MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2) were summarized. Results: Five deafness families were detected nine pathogenic or likely pathogenic variations in two genes, accounting for 3.7% of all families. Among them, four families were caused by MYO7A variations and one family was caused by CDH23 variation. Meanwhile, seven variations of two genes were reported for the first time. They were c.313delG, c.5257dupA, c.5435A>T, c.5636G>C, c.5722T>G of MYO7A, and c.155_166del, c.4802delA of CDH23. The patients' vision of family 2 and family 3 had no obvious abnormality at present, but according to genetic diagnosis and walking dealy, they were considered to be USH1. Conclusions: MYO7A is the most common caustive gene associated with USH1 in Henan deafness patients, the application of next-generation sequencing technology can make USH1 patients diagnosed earlier before the visual symptoms appear.

Result of Sanger sequencing for newborn carriers of single heterozygous variants of GJB2 or SLC26A4 gene by genechip analysis / 中华医学遗传学杂志

OBJECTIVE@#To detect additional variants for newborn carriers of single heterozygous variants of the GJB2 or SLC26A4 gene by genechip analysis in Changsha area, and explore the variation spectrum of deafness-related genes in this region.@*METHODS@#For 462 newborns carrying single heterozygous variants of the GJB2 or SLC26A4 gene, all exons of the genes were subjected to Sanger sequencing. The pathogenicity of the variants was analyzed by database and literature search.@*RESULTS@#For 305 newborns carrying a heterozygous GJB2 variant, 143 (46.49%) were found to carry additional variants, including 29 (9.51%) with c.109G>A likely pathogenic variant, and 1 (6.48%) with c.551G>A pathogenic variant. Among 153 newborns carrying single heterozygous variant of the SLC26A4 gene, 2 (1.31%) were found with a c.281C>T variant, and 1 (0.65%) with a c.1547_1548ins pathogenic variant. Among 4 newborns simultaneously carrying GJB2 and SLC26A4 variants, two were found to carry c.109G>A and c.844T>C variants (clinical significance unknown), respectively.@*CONCLUSION@#For newborns carrying single heterozygous variants of the GJB2 or SLC26A4 gene by genechip analysis, the detection rate for other variants is quite high. Sanger sequencing can significantly improve the detection rate of high-risk newborns and enrich the variant spectrum of deafness genes.

Frequency of GJB2 mutations in patients with nonsyndromic hearing loss from an ethnically characterized Brazilian population / Frequência de mutações de GJB2 em pacientes com perda auditiva não sindrômica em uma população brasileira etnicamente caracterizada

Abstract Introduction: In different parts of the world, mutations in the GJB2 gene are associated with nonsyndromic hearing loss, and the homozygous 35delG mutation (p.Gly12Valfs*2) is a major cause of hereditary hearing loss. However, the 35delG mutation is not equally prevalent across ethnicities, making it important to study other mutations, especially in multiethnic countries such as Brazil. Objective: This study aimed to identify different mutations in the GJB2 gene in patients with severe to profound nonsyndromic sensorineural hearing loss of putative genetic origin, and who were negative or heterozygote for the 35delG mutation. Methods: Observational study that analyzed 100 ethnically characterized Brazilian patients with nonsyndromic severe to profound sensorineural hearing loss, who were negative or heterozygote for the 35delG mutation. GJB2 mutations were detected by DNA-based sequencing in this population. Participants' ethnicities were identified as Latin European, Non-Latin European, Jewish, Native, Turkish, Afro-American, Asian and Others. Results: Sixteen participants were heterozygote for the 35delG mutation; 14 participants, including three 35delG heterozygote's, had nine different alterations in the GJB2 gene. One variant, p.Ser199Glnfs*9, detected in two participants, was previously unreported. Three variants were pathogenic (p.Trp172*, p.Val167Met, and p.Arg75Trp), two were non-pathogenic (p.Val27Ile and p.Ile196Thr), and three variants were indeterminate (p.Met34Thr, p.Arg127Leu, and p.Lys168Arg). Three cases of compound heterozygosity were detected: p.[(Gly12Valfs*2)];[(Trp172*)], p.[(Gly12Valfs*2)](;)[(Met34Thr)], and p.[(Gly12Valfs*2)(;)[(Ser199Glnfs*9)]). Conclusion: This study detected previously unclassified variants and one case of previously unreported compound heterozygosity.

Resumo Introdução: Em diferentes partes do mundo, mutações do gene GJB2 estão associadas a perda auditiva não sindrômica e a mutação homozigótica 35delG (p.Gly12Valfs*2) é uma das principais causas de perda auditiva hereditária. No entanto, a mutação 35delG não é igualmente prevalente em todas as etnias, faz com que seja importante estudar outras mutações, especialmente em países multiétnicos, como o Brasil. Objetivo: Identificar diferentes mutações no gene GJB2 em pacientes com perda auditiva neurossensorial grave ou profunda não sindrômica de origem genética putativa e negativos ou heterozigotos para a mutação 35delG. Método: Estudo observacional que analisou 100 pacientes brasileiros caracterizados etnicamente, com perda auditiva neurossensorial grave ou profunda não sindrômica, negativos ou heterozigotos para a mutação 35delG. As mutações de GJB2 foram detectadas por sequenciamento baseado no DNA nessa população. As etnias dos participantes foram identificadas como latino-europeia, não latino-europeia, judaica, nativa, turca, negra, asiática e outras. Resultados: Dezesseis participantes eram heterozigotos para a mutação 35delG e 14, incluindo três heterozigotos para 35delG, apresentaram nove alterações no gene GJB2. Uma variante, p.Ser199Glnfs*9, detectada em dois participantes, não havia sido relatada anteriormente. Três variantes eram patogênicas (p.Trp172*, p.Val167Met, e p.Arg75Trp), duas não patogênicas (p.Val27Ile e p.Ile196Thr) e três indeterminadas (p.Met34Thr, p.Arg127Leu, e p.Lys168Arg). Três casos de heterozigosidade composta foram detectados: p.[(Gly12Valfs*2)];[(Trp172*)], p.[(Gly12Valfs*2)](;)[(Met34Thr)], e p.[(Gly12Valfs*2)(;)[(Ser199Glnfs*9)]). Conclusão: Este estudo detectou variantes não classificadas anteriormente e um caso de heterozigosidade composta ainda não relatada.

Cochlear Implantation in Isolated Large Vestibular Aqueduct Syndrome: Report of Three Cases and Literature Review

Introduction Large vestibular aqueduct syndrome (LVAS) is characterized by the enlargement of the vestibular aqueduct associated with sensorineural hearing loss. It is the most common radiographically detectable inner ear anomaly in congenital hearing loss. LVAS may occur as an isolated anomaly or in association with other inner ear malformations. Objective To report three cases of isolated LVAS with a focus on preoperative assessment, surgical issues, and short-term postoperative follow-up with preliminary auditory habilitation outcomes. Resumed Report One girl and two boys with LVAS were assessed and cochlear implantation was performed for each. Various ways of intraoperative management of cerebrospinal fluid gusher and postoperative care and outcomes are reported. Conclusion Cochlear implantation in the deaf children with LVAS is feasible and effective.(AU)

GJB2 gene; Its contribution to genetic deafness?: a review

This article reviews the most prevalent sensory illness of mammals especially humans - Genetic Deafness or hearing loss [HL]. For genetic hearing loss more than 100 candidate genes have been discovered. The most common candidate gene of these all that is found all around the world is GJB2 gene. Different types of mutations are found in GJB2 gene. Some of these mutations are non-sense while some are sense mutations. This study is focus on mutation in GJB2 gene and its prevalence in different region of the world

Heteroplasmia de la mutación del ADN mitocondrial m.3243A>G en la diabetes y sordera de herencia materna / Mitochondrial DNA heteroplasmy of the m.3243A>G mutation in maternally inherited diabetes and deafness

Maternally Inherited Diabetes and Deafness (MIDD) is caused by mutations in mitochondrial DNA (mtDNA), mainly m.3243A>G. Severity, onset and clinical phenotype of MIDD patients are partially determined by the proportion ofmutant mitochondrial DNA copies in each cell and tissue (heteroplasmy). The identification ofMIDD allows a corred treatment with insulin avoiding drugs that may interfere with mitochondrial electrón chain transpon. We estimated the degree of heteroplasmy ofthe mutation m.3243A>G from blood, saliva, hair root and a muscle biopsy using quantitative PCR (qPCR) in a femóle adult patient. For this purpose, PCR producís were inserted in a vector creatingplasmids with 3243A or G. Mutant and wild-type vectors were mixed in different proportions to créate a calibration curve used to interpólate heteroplasmy percentages with qPCR threshold cycles. The proportions of m.3243A>G heteroplasmy were 62% (muscle), 14% (saliva), 6% (blood leukocytes) and 3% in hair root. Quantitative analysis of heteroplasmy showed marked variations in different tissues (highest in muscle and lowest in blood). Given the relatively high heteroplasmy found in saliva, this type of biológical sample may represent an adequate non-invasive way for assessing the presence of m.3243A>G mutations in epidemiologic studies.

Investigation of the A1555G mutation in mitochondrial DNA (MT-RNR1) in groups of Brazilian individuals with nonsyndromic deafness and normal-hearing.

BACKGROUND: Mutations of mitochondrial DNA were described into two genes: The mitochondrially encoded 12S RNA (MT-RNR1) and the mitochondrially encoded tRNA serineucn (MT-TS1). The A1555G mutation in MT-RNR1 gene is a frequent cause of deafness in different countries. AIM: The aim of this work was to investigate the frequency of the A1555G mutation in the MT-RNR1 gene in the mitochondrial DNA in Brazilians individuals with nonsyndromic deafness, and listeners. MATERIALS AND METHODS: DNA samples were submitted to polymerase chain reaction and to posterior digestion with the Hae III enzyme. RESULTS: Seventy eight (78) DNA samples of deaf individuals were analyzed; 75 showed normality in the region investigated, two samples (2.5%) showed the T1291C substitution, which is not related to the cause of deafness, and one sample (1.3%) showed the A1555G mutation. Among the 70 non-impaired individuals no A1555G mutation or T1291C substitution was found. CONCLUSION: We can affirm that A1555G mutation is not prevalent, or it must be very rare in normal-hearing subjects in the State of Paraná, the south region of Brazil. The A1555G mutation frequency (1.3%) found in individual with nonsyndromic deafness is similar to those found in other populations, with nonsyndromic deafness. Consequently, it should be examined in deafness diagnosis. The investigation of the A1555G mutation can contribute towards the determination of the nonsyndromic deafness etiology, hence, contributing to the correct genetic counseling process.

Maternally-inherited diabetes with deafness (MIDD) and hyporeninemic hypoaldosteronism / Diabetes mitocondrial (MIDD) e hipoaldosteronismo hiporreninêmico

Maternally-inherited diabetes with deafness (MIDD) is a rare form of monogenic diabetes that results, in most cases, from an A-to-G transition at position 3243 of mitochondrial DNA (m.3243A>G) in the mitochondrial-encoded tRNA leucine (UUA/G) gene. As the name suggests, this condition is characterized by maternally-inherited diabetes and bilateral neurosensory hearing impairment. A characteristic of mitochondrial cytopathies is the progressive multisystemic involvement with the development of more symptoms during the course of the disease. We report here the case of a patient with MIDD who developed hyporeninemic hypoaldosteronism. Arq Bras Endocrinol Metab. 2012;56(8):574-7.

O diabetes mitocondrial (MIDD) é uma forma rara de diabetes monogênico resultante, na maioria dos casos, da mutação mitocondrial A3243G. Essa condição é caracterizada por diabetes de transmissão materna e disacusia neurossensorial. Uma característica das mitocondriopatias é o envolvimento progressivo de outros órgãos ou sistemas, levando ao aparecimento de diversos sintomas durante o curso da doença. Este relato descreve o caso de um paciente com MIDD que, durante o período de acompanhamento, apresentou hipoaldosteronismo hiporreninêmico. Arq Bras Endocrinol Metab. 2012;56(8):574-7.