RESUMO
BACKGROUND: EYA4 variants are responsible for DFNA10 deafness. Due to its insidious onset and slow progression, hearing loss in autosomal dominant non-syndromic hearing loss (ADNSHL) is usually challenging to detect early in clinical settings, with limited intervention options. Genetic testing can aid in early detection of hearing loss, enabling timely intervention to reduce disability rates and improve the quality of life. METHODS: In this study, we report the case of a Chinese family with postlingual and progressive hearing loss that was passed down for four generations. Whole-exome sequencing (WES) was performed on DNA samples from the proband. Candidate variants identified in the proband and family members were confirmed via Sanger sequencing. In silico prediction tools and co-segregation analyses were used to assess the pathogenicity of identified variants. A literature review of known EYA4 variants was performed, analysing variant frequency, distribution characteristics across different populations, and genotype-phenotype correlations. RESULTS: We identified a novel EYA4 variant, c.1745_1748del (p.Glu582ValfsTer6), in a Chinese family with ADNSHL, and co-segregation with the family's phenotype was confirmed. The audiometry showed mid-to-high frequency downsloping hearing loss. To date, 52 pathogenic variants of EYA4 have been reported, with majority identified in Asian populations. Most observed are the missense and frameshift variants. CONCLUSIONS: A novel variant of EYA4 was identified in a Chinese family with postlingual hearing loss, contributing to the expanding spectrum of EYA4 variants. The audiological features of EYA4 variants are highly heterogeneous and often challenging to detect early in clinical settings. Our findings highlight the significance of genetic testing in patients presenting with postlingual hearing loss.
Assuntos
Linhagem , Transativadores , Humanos , Masculino , Feminino , Transativadores/genética , Povo Asiático/genética , Adulto , Sequenciamento do Exoma , Perda Auditiva Neurossensorial/genética , Mutação , China , População do Leste AsiáticoRESUMO
Advances in next-generation sequencing technologies have led to elucidation of sensorineural hearing loss genetics and associated clinical impacts. However, studies on the functional pathogenicity of variants of uncertain significance (VUS), despite their close association with clinical phenotypes, are lacking. Here we identified compound heterozygous variants in ESRRB transcription factor gene linked to DFNB35, specifically a novel splicing variant (NM_004452.4(ESRRB): c.397 + 2T>G) in trans with a missense variant (NM_004452.4(ESRRB): c.1144C>T p.(Arg382Cys)) whose pathogenicity remains unclear. The splicing variant (c.397 + 2T>G) caused exon 4 skipping, leading to premature stop codon formation and nonsense-mediated decay. The p.(Arg382Cys) variant was classified as a VUS due to its particularly higher allele frequency among East Asian population despite disease-causing in-silico predictions. However, functional assays showed that p.(Arg382Cys) variant disrupted key intramolecular interactions, leading to protein instability. This variant also reduced transcriptional activity and altered expression of downstream target genes essential for inner ear function, suggesting genetic contribution to disease phenotype. This study expanded the phenotypic and genotypic spectrum of ESRRB in DFNB35 and revealed molecular mechanisms underlying ESRRB-associated DFNB35. These findings suggest that variants with high allele frequencies can also possess functional pathogenicity, providing a breakthrough for cases where VUS, previously unexplored, could be reinterpreted by elucidating their functional roles and disease-causing characteristics.
Assuntos
Perda Auditiva Neurossensorial , Receptores de Estrogênio , Feminino , Humanos , Masculino , Códon sem Sentido/genética , Frequência do Gene , Predisposição Genética para Doença , Perda Auditiva/genética , Perda Auditiva Neurossensorial/genética , Mutação de Sentido Incorreto , Linhagem , Splicing de RNA/genética , Receptores de Estrogênio/genéticaRESUMO
We present the case of a 37-year-old woman who underwent bilateral penetrating keratoplasty for congenital hereditary endothelial dystrophy at the age of 10 years. Over the subsequent 27 years, the patient's vision slowly deteriorated. Our examination revealed decompensation of the right corneal graft. We addressed this with regraft surgery. We then learned that the patient had been suffering from progressive hearing loss since adolescence. Tonal audiometry revealed hearing per ceptive deafness of 25 dB, which was more prominent in the left ear. Because the patterns of progressive sensorineural hearing loss and congenital hereditary endothelial dystrophy have both been linked to the same gene, slc4a11, we tested our patient for mutations in this gene. The test was positive for a heterozygous slc4a11 gene fifth exon mutation on chromosome 20p13-p12, which causes a frameshift. A combined clinical and genetic evaluation confirmed a diagnosis of Harboyan syndrome. After the genetic diagnosis of the disease, she was evaluated for the need for a hearing aid due to her hearing loss. The patient was also informed about genetic counseling.
Assuntos
Distrofias Hereditárias da Córnea , Perda Auditiva Neurossensorial , Humanos , Feminino , Perda Auditiva Neurossensorial/genética , Adulto , Distrofias Hereditárias da Córnea/genética , Proteínas de Transporte de Ânions/genética , Síndrome , Mutação da Fase de Leitura/genética , AntiportersRESUMO
BACKGROUND/OBJECTIVE: The genetic landscape of sensorineural hearing impairment (SNHI) varies across populations. In Mongolia, previous studies have shown a lower prevalence of GJB2 mutations and a higher frequency of variants in other deafness-related genes. This study aimed to investigate the genetic variants associated with idiopathic SNHI in Mongolian patients. METHODS: We utilized the next-generation sequencing for investigating the causative mutations in 99 Mongolian patients with SNHI. RESULTS: We identified pathogenic variants in 53 of the 99 SNHI patients (54%), with SLC26A4 being the most frequently mutated gene. The c.919-2A>G variant in SLC26A4 was the most prevalent, accounting for 46.2% of the mutant alleles. In addition, we identified 19 other known and 21 novel mutations in a total of 21 SNHI genes in autosomal recessive or dominant inheritance patterns. CONCLUSIONS: Our findings expand the understanding of the genetic landscape of SNHI in Mongolia and highlight the importance of considering population-specific variations in genetic testing and counseling for SNHI.
Assuntos
Perda Auditiva Neurossensorial , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Transportadores de Sulfato , Humanos , Mongólia/epidemiologia , Masculino , Feminino , Perda Auditiva Neurossensorial/genética , Transportadores de Sulfato/genética , Conexina 26/genética , Adulto , Criança , Adolescente , Pré-Escolar , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
RATIONALE: Deafness is associated with both environmental and genetic factors, with hereditary deafness often caused by mutations in deafness-related genes. Identifying and analyzing deafness-related genes will aid in early diagnosis and pave the way for treating inherited deafness through gene therapy in the future. PATIENT CONCERNS: A 15-month-old girl underwent audiological examination at the outpatient clinic of the hospital due to hearing loss and her brother was diagnosed with profound bilateral sensorineural hearing loss at the age of 3. DIAGNOSES: The diagnosis was determined as extremely severe sensorineural hearing loss caused by genetic factors. INTERVENTIONS: Clinical data of the patient were collected, and peripheral blood samples were obtained from both the patient and her family members for DNA extraction and sequencing. OUTCOMES: By utilizing targeted capture next-generation sequencing to further screen for deafness-related genes, 2 novel variants in CDH23 were identified as the causative factors for the patient's deafness. LESSONS: This study identified 2 novel heterozygous mutations in a Chinese family. Both the proband and her sibling have non-syndromic hearing loss (NSHL) and carry distinct heterozygous mutations of cadherin-like 23 (CDH23). One mutation, CDH23:c.2651 A>G, originated from their mother and paternal family, affecting the exon23 domain of CDH23. The other mutation, CDH23:c.2113 G>T, was inherited from their paternal grandmother, impacting the exon19 domain of CDH23. These 2 novel mutations likely cause NSHL by affecting protein function. This finding suggests that identifying 2 novel mutations in CDH23 contributes to the genetic basis of NSHL.
Assuntos
Caderinas , Perda Auditiva Neurossensorial , Humanos , Feminino , Caderinas/genética , Lactente , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Linhagem , Mutação , Povo Asiático/genética , China , Masculino , Proteínas Relacionadas a Caderinas , Sequenciamento de Nucleotídeos em Larga Escala , População do Leste AsiáticoRESUMO
PURPOSE OF REVIEW: To summarize indications, methods, and diagnostic yields for genetic testing for pediatric hearing loss. RECENT FINDINGS: Genetic testing has become a cornerstone of clinical care for children with sensorineural hearing loss. Recent studies have shown the efficacy of gene panels and exome sequencing for any child with sensorineural hearing loss. Recent findings have underscored the importance of a diagnosis in clinical care. Clinical trials for gene therapy for hearing loss have begun. SUMMARY: Genetic testing has become critical for personalized care for children with hearing loss. Recent studies have shown a 43% overall diagnostic yield for genetic testing for pediatric hearing loss, though the diagnostic yield may range from 10 to 60% depending on clinical features. Syndromic diagnoses comprise 25% of positive genetic tests for pediatric sensorineural hearing loss. While diagnostic yield is lower for children with unilateral or asymmetric sensorineural hearing loss, the likelihood of syndromic hearing loss finding is higher. An early and accurate genetic diagnosis is required for participating in clinical trials for gene therapy for hearing loss.
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Testes Genéticos , Terapia Genética , Perda Auditiva Neurossensorial , Humanos , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/terapia , Perda Auditiva Neurossensorial/diagnóstico , Criança , Terapia Genética/métodosRESUMO
INTRODUCTION: Sensorineural hearing impairment (SNHI), a common childhood disorder with heterogeneous genetic causes, can lead to delayed language development and psychosocial problems. Next-generation sequencing (NGS) offers high-throughput screening and high-sensitivity detection of genetic etiologies of SNHI, enabling clinicians to make informed medical decisions, provide tailored treatments, and improve prognostic outcomes. AREAS COVERED: This review covers the diverse etiologies of HHI and the utility of different NGS modalities (targeted sequencing and whole exome/genome sequencing), and includes HHI-related studies on newborn screening, genetic counseling, prognostic prediction, and personalized treatment. Challenges such as the trade-off between cost and diagnostic yield, detection of structural variants, and exploration of the non-coding genome are also highlighted. EXPERT OPINION: In the current landscape of NGS-based diagnostics for HHI, there are both challenges (e.g. detection of structural variants and non-coding genome variants) and opportunities (e.g. the emergence of medical artificial intelligence tools). The authors advocate the use of technological advances such as long-read sequencing for structural variant detection, multi-omics analysis for non-coding variant exploration, and medical artificial intelligence for pathogenicity assessment and outcome prediction. By integrating these innovations into clinical practice, precision medicine in the diagnosis and management of HHI can be further improved.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Testes Genéticos/métodos , Triagem Neonatal/métodos , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/terapia , Predisposição Genética para Doença , Recém-Nascido , Gerenciamento Clínico , Aconselhamento GenéticoRESUMO
Sensorineural hearing loss (SNHL), characterized by damage to the inner ear or auditory nerve, is a prevalent auditory disorder. This study explores the potential of Castanopsis echinocarpa (CAE) as a therapeutic agent for SNHL. In vivo experiments were conducted using zebrafish and mouse models. Zebrafish with neomycin-induced ototoxicity were treated with CAE, resulting in otic hair cell protection with an EC50 of 0.49 µg/mL and a therapeutic index of 1020. CAE treatment improved auditory function and protected cochlear sensory cells in a mouse model after noise-induced hearing loss (NIHL). RNA sequencing of NIHL mouse cochleae revealed that CAE up-regulates genes involved in neurotransmitter synthesis, secretion, transport, and neuronal survival. Real-time qPCR validation showed that NIHL decreased the mRNA expression of genes related to neuronal function, such as Gabra1, Gad1, Slc32a1, CaMK2b, CaMKIV, and Slc17a7, while the CAE treatment significantly elevated these levels. In conclusion, our findings provide strong evidence that CAE protects against hearing loss by promoting sensory cell protection and enhancing the expression of genes critical for neuronal function and survival.
Assuntos
Regulação da Expressão Gênica , Perda Auditiva Neurossensorial , Extratos Vegetais , Peixe-Zebra , Animais , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/induzido quimicamente , Camundongos , Extratos Vegetais/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Modelos Animais de Doenças , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neomicina/farmacologia , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Ototoxicidade/etiologia , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismoRESUMO
RATIONALE: Congenital sensorineural hearing loss is a significant global health issue, primarily driven by genetic factors, such as mutations in the GJB2 gene. This report presents a Chinese girl with congenital deafness and a novel mutation of the GJB2 gene. PATIENT CONCERNS: A newborn Chinese girl exhibited signs of congenital deafness. DIAGNOSIS: Congenital deafness was confirmed through comprehensive newborn hearing screenings that included otologic, audiologic, and physical examinations. Genetic analysis revealed a compound heterozygous mutation involving c.188delT and c.235delC in the GJB2 gene, indicating a genetic basis for her hearing loss. INTERVENTIONS: The patient underwent cochlear implantation, which resulted in stable auditory outcomes. OUTCOMES: Despite follow-up difficulties, stable auditory outcomes were achieved post-cochlear implantation, highlighting the potential efficacy of this intervention in GJB2-related hearing loss. LESSONS: This case study enriches our understanding of GJB2 mutations and underscores the critical role of genetic testing in diagnosing congenital sensorineural hearing loss. It emphasizes the necessity for early intervention and sustained interdisciplinary care to enhance the quality of life for patients with genetic hearing impairment.
Assuntos
Conexina 26 , Conexinas , Perda Auditiva Neurossensorial , Humanos , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Conexinas/genética , Recém-Nascido , Mutação , Implante Coclear , China , Povo Asiático/genética , População do Leste AsiáticoRESUMO
BACKGROUND: Cystic fibrosis (CF) is a severe hereditary disease with a multisystem lesion. Manifestations of CF include severe infectious purulent lesions of all parts of the respiratory tract, including purulent rhinosinusitis with nasal polyps. The involvement of the sinonasal region and the need for systemic use of ototoxic drugs (primarily aminoglycosides to treat resistant bacterial infection) potentially create a risk of both conductive and sensorineural hearing loss (SNHL). The available data on the epidemiology of hearing disorders in CF is contradictory. Currently, genetic determinants of the development of aminoglycoside SNHL have been identified. MATERIAL AND METHODS: For 136 CF patients (75 girls, 61 boys) aged 3 to 17 (9.4±3.9) years were performed audiological examination: tympanometry, transient-evoked otoacoustic emission and the pure tone threshold audiometry (standard frequency range) (n=126). History of systemic therapy with aminoglycosides was evaluated for each patient. Sequencing of c.35delG mutations in the GJB2 gene (nuclear DNA) and A1555G in the 12S rRNA gene (mitochondrial DNA) was performed in 215 patients with cystic fibrosis (the group partially overlaps with the audiological group), and as a control - 106 children with bronchial asthma and 103 healthy children, their age ranged from 3 to 17 (8.8±3.8) years. RESULTS: Audiological examination of CF children reveled a prevalence of conductive hearing loss comparable to the general population (2.4%). The frequency of SNHL was 1.6%, wich exceeds that of non-CF children. A genetic study revealed one case of heterozygous carriage of the c.35delG mutation in the GJB2 gene in a patient with bronchial asthma. In the group of patients with CF (n=215), mutations in the connexin 26 gene were not detected. No A1555G mutation was detected either in the group of patients with CF or in the control groups. CONCLUSIONS: Children with CF are at risk for the development of sensorineural, but not conductive hearing loss. Routine total screening for A1555G and c.35delG mutations probably seems not to be recommended.
Assuntos
Fibrose Cística , Humanos , Fibrose Cística/complicações , Fibrose Cística/epidemiologia , Criança , Feminino , Masculino , Adolescente , Federação Russa/epidemiologia , Pré-Escolar , Conexina 26 , Aminoglicosídeos/efeitos adversos , Conexinas/genética , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/genética , Medição de Risco/métodos , Audiometria de Tons Puros/métodos , MutaçãoRESUMO
Autosomal dominant hearing loss is represented by a large number of genetically determined forms. Over 50 genes associated with dominant nonsyndromic hearing impairments were described. Pathogenic variants in the CEACAM16 gene lead to the development of DFNA4B hearing loss. Currently, 8 pathogenic variants in this gene have been described. The objective of this study was to study the audiological and molecular genetic characteristics of a large family with CEACAM16-associated autosomal dominant nonsyndromic hearing loss. A detailed anamnesis was collected, and a comprehensive audiological examination was performed for 21 family members. Genetic testing was performed, including whole-genome sequencing for the proband's son and Sanger sequence analysis for the proband and for all available family members. In a large Russian family, including 5 generations, an autosomal dominant type of slowly progressing nonsyndromic late-onset hearing loss was observed. Eleven family members suffer from hearing impairment, which starts with tinnitus and threshold increase at high frequencies, since the age of 5-20 years. Hearing loss slowly progresses with age in each person and is similar to age-related hearing loss. We have detected the novel likely pathogenic variant Ñ.419С>T (p.(Thr140Ile)) in exon 3 of the CEACAM16 gene, which segregates with late-onset nonsyndromic hearing loss in this family. The clinical data obtained in the examined family correspond with the phenotype in previously described cases. In general, the study widened the mutation spectrum of the gene, allowing to carry out medical genetic counseling and to answer the questions about the hearing impairment prognosis for future generations.
Assuntos
Moléculas de Adesão Celular , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Feminino , Adulto , Pessoa de Meia-Idade , Moléculas de Adesão Celular/genética , Federação Russa , Adolescente , Criança , Antígenos CD/genética , Adulto Jovem , Idoso , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Genes Dominantes , Pré-Escolar , Proteínas Ligadas por GPI/genética , SurdezRESUMO
Autosomal recessive non-syndromic hearing loss (ARNSHL) can cause severe or very severe pre-speech hearing loss. Transmembrane channel-like 1 (TMC1) gene is the sixth deafness gene discovered, but the precise extent of its protein structure and function is unknown. First, history collection, audiology examination and imaging examination were performed on the proband and his family members. Peripheral blood of proband and family members was collected, genomic DNA was extracted, exon high-throughput sequencing technology was used to detect the deafness gene mutation of the proband, and Sanger sequencing was performed to verify the TMC1 gene of the proband's parents. The proband was born with hearing impairment, normal tympanic function, inability to induce acoustic reflex in both ears (acoustic reflex threshold is 100 dBHL), and severe sensorineural deafness. One of his sisters has severe sensorineural hearing loss, and neither his parents nor his other sister is hearing impaired. High-throughput sequencing of the proband identified mutations at c.741+3_741+6delAAGT (splicing) and c.884C>T (p.A295V) of the TMC1 gene, two of which were heterozygous mutations. Sanger sequencing confirmed that the c.884C > T mutation was inherited from the mother, while the c.741+3_741+6delAAGT mutation was derived from the father. Prediction of amino acid function suggested that both mutations were pathogenic mutations. In conclusion, we found a new pathogenic complex heterozygous mutation of the TMC1 gene, which enriched the mutation spectrum of the TMC1 gene and provided a basis for genetic counseling and prenatal diagnosis of ARNSHL.
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Heterozigoto , Proteínas de Membrana , Linhagem , Humanos , Masculino , Proteínas de Membrana/genética , Feminino , Mutação/genética , Surdez/genética , Sequenciamento de Nucleotídeos em Larga Escala , Genes Recessivos/genética , Perda Auditiva Neurossensorial/genética , Adulto , Sequência de BasesRESUMO
PURPOSE: To report the case of a young boy with early onset high myopia (eoHM), foveal hypoplasia and skeletal dysplasia due to a homozygous LOXL3 pathogenic variant. Atypically, this was from a paternal uniparental isodisomy (UPiD) of chromosome 2. CLINICAL CASE: Four-year-old boy with several months history of holding items close to his face was found to have reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed spondylo-epi-metaphyseal dysplasia. Whole-exome sequencing (WES) revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2. CONCLUSION: To our knowledge, this is the first reported case of LOXL3-associated eoHM, foveal hypoplasia and mild skeletal dysplasia due to the rare phenomenon of paternal UPiD of chromosome 2. This case further delineates the phenotype associated with LOXL3 pathogenic variants and supports truncating LOXL3 pathogenic variants being associated with a phenotypic spectrum; from isolated eoHM through to a Stickler syndrome-like phenotype.
Assuntos
Aminoácido Oxirredutases , Artrite , Doenças do Tecido Conjuntivo , Fenótipo , Humanos , Masculino , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/patologia , Artrite/genética , Artrite/diagnóstico , Pré-Escolar , Aminoácido Oxirredutases/genética , Descolamento Retiniano/genética , Descolamento Retiniano/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Instabilidade Articular/genética , Instabilidade Articular/diagnóstico , Sequenciamento do Exoma , Linhagem , MutaçãoRESUMO
BACKGROUND: Deafness autosomal dominant 2A (DFNA2A) is related to non-syndromic genetic hearing impairment. The KCNQ4 (Potassium Voltage-Gated Channel Subfamily Q Member 4) can lead to DFNA2A. In this study, we report a case of autosomal dominant non-syndromic hearing loss with six family members as caused by a novel variant in the KCNQ4 gene. METHODS: The whole-exome sequencing (WES) and pure tone audiometry were performed on the proband of the family. Sanger sequencing was conducted on family members to determine if the novel variant in the KCNQ4 gene was present. Evolutionary conservation analysis and computational tertiary structure protein prediction of the wild-type KCNQ4 protein and its variant were then performed. In addition, voltage-gated channel activity of the wild-type KCNQ4 protein and its variant were tested using whole-cell patch clamp. RESULTS: It was observed that the proband had inherited autosomal dominant, non-syndromic sensorineural hearing loss as a trait. A novel co-segregating heterozygous missense variant (c.902C>A, p.Ala301Asp) of the KCNQ4 gene was identified in the proband and other five affected family members. This variant was predicted to cause an alanine-to-aspartic acid substitution at position 301 in the KCNQ4 protein. The alanine at position 301 is well conserved across different species. Whole-cell patch clamp showed that there was a significant difference between the WT protein currents and the mutant protein currents in the voltage-gated channel activity. CONCLUSION: In the present study, performing WES in conjunction with Sanger sequencing enhanced the detection of a novel, potentially causative variant (c301 A>G; p.Ala301Asp) in exon 6 of the KCNQ4 gene. Therefore, our findings contributed to the mutation spectrum of the KCNQ4 gene and may be useful in the diagnosis and gene therapy of deafness autosomal dominant 2A.
Assuntos
Perda Auditiva Neurossensorial , Canais de Potássio KCNQ , Mutação de Sentido Incorreto , Linhagem , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , População do Leste Asiático/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Canais de Potássio KCNQ/genéticaRESUMO
Johanson-Blizzard syndrome (JBS) is an autosomal recessive disorder. We established an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells of a 2-year-old boy with Johanson-Blizzard syndrome carrying a compound heterozygous mutation of c.3167C>G (p.S1056X) and c.1911 + 14C>G(splicing) in the UBR1 gene. This iPSC line was free of exogenous gene, expressed stemness markers, exhibited differentiation potential, had normal karyotype and harbored the same mutations found in the patient. The iPSC cellline can serve as a disease model in drug development and novel personalized therapies.
Assuntos
Anus Imperfurado , Displasia Ectodérmica , Transtornos do Crescimento , Perda Auditiva Neurossensorial , Células-Tronco Pluripotentes Induzidas , Mutação , Ubiquitina-Proteína Ligases , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Ubiquitina-Proteína Ligases/genética , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Pré-Escolar , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Anus Imperfurado/genética , Anus Imperfurado/patologia , Heterozigoto , Nariz/patologia , Nariz/anormalidades , Linhagem Celular , Insuficiência Pancreática Exócrina/genética , Insuficiência Pancreática Exócrina/patologia , Surdez/genética , Surdez/patologia , Diferenciação Celular , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Hipotireoidismo , PancreatopatiasRESUMO
BACKGROUND: DNA methylation may have a regulatory role in monogenic sensorineural hearing loss and complex, polygenic phenotypic forms of hearing loss, including age-related hearing impairment or Meniere disease. The purpose of this systematic review is to critically assess the evidence supporting a functional role of DNA methylation in phenotypes associated with hearing loss. RESULTS: The search strategy yielded a total of 661 articles. After quality assessment, 25 records were selected (12 human DNA methylation studies, 5 experimental animal studies and 8 studies reporting mutations in the DNMT1 gene). Although some methylation studies reported significant differences in CpG methylation in diverse gene promoters associated with complex hearing loss phenotypes (ARHI, otosclerosis, MD), only one study included a replication cohort that supported a regulatory role for CpG methylation in the genes TCF25 and POLE in ARHI. Conversely, several studies have independently confirmed pathogenic mutations within exon 21 of the DNMT1 gene, which encodes the DNA (cytosine-5)-methyltransferase 1 enzyme. This methylation enzyme is strongly associated with a rare disease defined by autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Of note, rare variants in DNMT1 and DNMT3A genes have also been reported in noise-induced hearing loss. CONCLUSIONS: Evidence supporting a functional role for DNA methylation in hearing loss is limited to few genes in complex disorders such as ARHI. Mutations in the DNMT1 gene are associated with ADCA-DN, suggesting the CpG methylation in hearing loss genes deserves further attention in hearing research.
Assuntos
DNA (Citosina-5-)-Metiltransferase 1 , Metilação de DNA , Humanos , Metilação de DNA/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , Animais , Ilhas de CpG/genética , Epigênese Genética/genética , Perda Auditiva/genética , Mutação , Fenótipo , Regiões Promotoras Genéticas , Perda Auditiva Neurossensorial/genética , Narcolepsia/genéticaRESUMO
BACKGROUND: Mitochondrial proteins assume a pivotal role in the onset and progression of diverse diseases. Nonetheless, the causal interconnections with sensorineural hearing loss (SNHL) demand meticulous exploration. Mendelian randomization analysis is a method used in observational epidemiological studies to predict the relationship between exposure factors and outcomes using genetic variants as instrumental variables. In this study, we applied this analytical approach to two distinct samples to predict the causal impact of mitochondrial proteins on SNHL. METHODS: Two-sample Mendelian randomization analyses were executed to scrutinize the predicted associations between 63 mitochondrial proteins (nuclear-encoded) and SNHL, utilizing summary statistics derived from genome-wide association studies. Assessments of pleiotropy and heterogeneity were carried out to gauge the robustness of the obtained findings. RESULTS: Four mitochondrial proteins exhibited a suggestive causal relationship with the susceptibility to SNHL. Dihydrolipoamide dehydrogenase (DLD; OR = 0.9706, 95% CI = 0.9382-0.9953, p = 0.0230) was linked to a diminished risk of SNHL. Conversely, elevated levels of mitochondrial ribosomal protein L34 (MRPL34; OR = 1.0458, 95% CI = 1.0029-1.0906, p = 0.0362), single-pass membrane protein with aspartate-rich tail 1 (SMDT1; OR = 1.0619, 95% CI = 1.0142-1.1119, p = 0.0104), and superoxide dismutase 2 (SOD2; OR = 1.0323, 95% CI = 1.0020-1.0634, p = 0.0364) were associated with an elevated risk of SNHL. CONCLUSION: This research utilized Mendelian randomization analysis to predict the relationship between mitochondrial proteins and SNHL. It provides a potential viewpoint on the etiology and diagnosis.
Assuntos
Estudo de Associação Genômica Ampla , Perda Auditiva Neurossensorial , Análise da Randomização Mendeliana , Proteínas Mitocondriais , Humanos , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/epidemiologia , Proteínas Mitocondriais/genética , Predisposição Genética para Doença , Superóxido Dismutase/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Disease-related cells differentiated from patient-derived iPSCs are useful for elucidating the pathophysiological mechanisms underlying these diseases. In this study, four iPSC lines were established from independent patients with sensorineural hearing loss and a mutation in EYA4. These iPSCs showed pluripotency, the capacity to differentiate into three germ layers, and normal karyotypes, suggesting that these lines are useful for the pathological study of sensorineural hearing loss and drug screening for ear disorders.
Assuntos
Perda Auditiva Neurossensorial , Células-Tronco Pluripotentes Induzidas , Mutação , Humanos , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Linhagem Celular , Feminino , Transativadores/genética , Diferenciação Celular , Criança , CariótipoRESUMO
A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband's eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband's sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype-phenotype correlations in cardiomyopathy.
Assuntos
Linhagem , Humanos , Feminino , Masculino , Adulto , Cardiomiopatias/genética , Cardiomiopatias/diagnóstico , Sequenciamento do Exoma , Anormalidades Múltiplas/genética , Perda Auditiva Neurossensorial/genética , Fenótipo , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/diagnósticoRESUMO
BACKGROUND: Hereditary hearing loss is an important component of congenital hearing loss. MARVELD2 (OMIM ID:610572), located in the DFNB49 locus, which encodes a tight junction protein tricellulin playing an important role in the sensory epithelial barrier of the inner ear, may contribute to nonsyndromic autosomal recessive hereditary hearing loss. METHODS: Two Han Chinese pedigrees with hearing loss underwent clinical and genetic analyses. Variants were detected by targeted next-generation sequencing and sequencing data were compared with the Human Genome Reference (GRCh 37/hg 19) to identify mutant genes and loci. Furthermore, online tools such as RDDC, SpliceAI, and REVEL were used to predict risks from different variants. RESULTS: Both two probands failed neonatal hearing screening and were diagnosed with sensorineural hearing loss. A total of 3 mutations were detected in the two families, c.1331+1G>A, c.1325A>G, and c.782G>A. According to ACMG/AMP guidelines, they were judged to be pathogenic, uncertain significance, and uncertain significance, respectively. CONCLUSIONS: These findings contribute to a better understanding of the relationship between different variants of MARVELD2 and hearing. This could further expand the spectrum of deafness gene mutations and contribute to deafness patient management and genetic counseling.