Gene4HL: An Integrated Genetic Database for Hearing Loss
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ABSTRACT:
SUBMITTER: Huang S
PROVIDER: S-EPMC8558372 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Sensorineural hearing loss can result from dysfunction of the inner ear, auditory nerve, or auditory pathways in the central nervous system. Sensorineural hearing loss can be associated with age, exposure to ototoxic drugs or noise, or mutations in nuclear or mitochondrial genes. However, it is idiopathic in some patients. Although these disorders are mainly caused by dysfunction of the inner ear, little of the pathophysiology in sensorineural hearing loss is known due to inaccessibility of the living human inner ear for biopsy and pathological analysis. The inner ear has previously been thought of as an immune-privileged organ. We recently showed that a missense mutation of the NLRP3 gene is associated with autosomal-dominant sensorineural hearing loss with cochlear autoinflammation in two unrelated families. NLRP3 encodes the NLRP3 protein, a key component of the NLRP3 inflammasome that is expressed in immune cells, including monocytes and macrophages. Gain-of-function mutations of NLRP3 cause abnormal activation of the NLRP3 inflammasome leading to IL-1β secretion in a spectrum of autosomal dominant systemic autoinflammatory phenotypes termed cryopyrin-associated periodic syndromes. The affected subjects of our two families demonstrated atypical phenotypes compared with those reported for subjects with cryopyrin-associated periodic syndromes. These observations led us to test the hypothesis that macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The inflammasome can indeed be activated in macrophage/monocyte-like cells of the mouse cochlea, with secretion of IL-1β. The macrophage/monocyte-like cells in the cochlea were also found to be associated with hearing loss in a Slc26a4-insufficient mouse model of human deafness. This review addresses our understanding of genetic hearing loss mediated by autoinflammation and macrophage/monocyte-like cells in the cochlea.
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Project description:Hearing plays a crucial role in human development. Receiving and processing sounds are essential for the advancement of the speech ability during the early childhood and for a proper functioning in the society. Hearing loss is one of the most frequent disabilities that affect human senses. It can be caused by genetic or environmental factors or both of them. Calcium- and integrin-binding protein 2 (CIB2) is one of the recently identified genes, involved in HI pathogenesis. CIB2 is widely expressed in various human and animal tissues, mainly in skeletal muscle, nervous tissue, inner ear, and retina. The CIB2 protein is responsible for maintaining Ca2+ homeostasis in cells and interacting with integrins-transmembrane receptors essential for cell adhesion, migration, and activation of signaling pathways. Calcium signaling pathway is crucial for signal transduction in the inner ear, and integrins regulate hair cell differentiation and maturation of the stereocilia. To date, mutations detected in CIB2 are causative for nonsyndromic hearing loss (DFNB48) or Usher syndrome type 1 J. Patients harboring biallelic CIB2 mutations suffer from bilateral, early onset, moderate to profound HI. In the paper, we summarize the current status of the research on CIB2.
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Project description:Hearing impairment (HI) is highly heterogeneous with over 123 associated genes reported to date, mostly from studies among Europeans and Asians. Here, we performed a systematic review of literature on the genetic profile of HI in Africa. The study protocol was registered on PROSPERO, International Prospective Register of Systematic Reviews with the registration number "CRD42021240852". Literature search was conducted on PubMed, Scopus, Africa-Wide Information, and Web of Science databases. A total of 89 full-text records was selected and retrieved for data extraction and analyses. We found reports from only 17/54 (31.5%) African countries. The majority (61/89; 68.5%) of articles were from North Africa, with few reports found from sub-Saharan Africa. The most common method used in these publications was targeted gene sequencing (n = 66/111; 59.5%), and only 13.5% (n = 15/111) used whole-exome sequencing. More than half of the studies were performed in families segregating HI (n = 51/89). GJB2 was the most investigated gene, with GJB2: p.(R143W) founder variant only reported in Ghana, while GJB2: c.35delG was common in North African countries. Variants in MYO15A were the second frequently reported in both North and Central Africa, followed by ATP6V1B1 only reported from North Africa. Usher syndrome was the main syndromic HI molecularly investigated, with variants in five genes reported: USH2A, USH1G, USH1C, MYO7A, and PCDH15. MYO7A: p.(P1780S) founder variant was reported as the common Usher syndrome variant among Black South Africans. This review provides the most comprehensive data on HI gene variants in the largely under-investigated African populations. Future exomes studies particularly in multiplex families will likely provide opportunities for the discovery of the next sets of novel HI genes, and well as unreported variants in known genes to further our understanding of HI pathobiology, globally.
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Project description:Hearing loss is one of the most common concerns for presentation for a geneticist. Presentation prior to the age of one (congenital hearing loss), profound sensorineural hearing loss (SNHL), and bilateral hearing loss are sensitive and should raise concern for genetic causes of hearing loss and prompt referral for genetic testing. Genetic testing particularly in this instance offers the opportunity for anticipatory guidance including possible course of the hearing loss over time and also connection and evaluation for additional congenital anomalies that may be associated with an underlying syndrome vs. isolated genetic hearing loss.
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Project description:In the age of targeted genomic enrichment and massively parallel sequencing, there is no more efficient genetic testing method for the diagnosis of hereditary hearing loss. More clinical tests are on the market, which can make choosing good tests difficult.More and larger comprehensive genetic studies in patients with hearing loss have been published recently. They remind us of the importance of looking for both single nucleotide variation and copy number variation in all genes implicated in nonsyndromic hearing loss. They also inform us of how a patient's history and phenotype provide essential information in the interpretation of genetic data.Choosing the most comprehensive genetic test improves the chances of a genetic diagnosis and thereby impacts clinical care.
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Project description:Genome editing opens up a new frontier in developing personalized therapeutic solutions. With the unprecedented advance in the discovery and engineering of gene editing nucleases, it has now become potentially feasible to therapeutically influence up to 90% of all human genetic mutations. Hearing loss is one of the most well studied fields from the genetics perspective, with more than one hundred identified deafness genes. Novel viral and non-viral vectors have been established as safe and efficient modalities to deliver transgenes into cells of the cochlea and to the vestibular system in animal models. Recent studies demonstrated proof-of-concept for therapeutic genome and base editing in the mammalian inner ear and preclinical development is ongoing. This review summarizes important advances and future challenges for this transformative therapeutic modality for genetic and non-genetic hearing loss.
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Project description:According to the World Health Organization, hearing loss affects over 466 million people worldwide and is the most common human sensory impairment. It is estimated that genetic factors contribute to the causation of approximately 50% of congenital hearing loss. Yet, curative approaches to reversing or preventing genetic hearing impairment are still limited. The clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) systems enable programmable and targeted gene editing in highly versatile manners and offer new gene therapy strategies for genetic hearing loss. Here, we summarize the most common deafness-associated genes, illustrate recent strategies undertaken by using CRISPR-Cas9 systems for targeted gene editing and further compare the CRISPR strategies to non-CRISPR gene therapies. We also examine the merits of different vehicles and delivery forms of genome editing agents. Lastly, we describe the development of animal models that could facilitate the eventual clinical applications of the CRISPR technology to the treatment of genetic hearing diseases.
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Project description:Hearing loss is the most common sensory deficit in humans. The aim of this study was to clarify the genetic aetiology of nonsyndromic hearing loss in the Moravian-Silesian population of the Czech Republic. This study included 200 patients (93 males, 107 females, mean age 16.9 years, ranging from 4 months to 62 years) with nonsyndromic sensorineural hearing loss. We screened all patients for mutations in GJB2 and the large deletion del(GJB6-D13S1830). We performed further screening for additional genes (SERPINB6, TMIE, COCH, ESPN, ACTG1, KCNQ4, and GJB3) with Sanger sequencing on a subset of patients that were negative for GJB2 mutations. We detected biallelic GJB2 mutations in 44 patients (22%). Among these patients, 63.6%, 9.1% and 2.3% exhibited homozygous c.35delG, p.Trp24*, and p.Met34Thr mutations, respectively. The remaining 25% of these patients exhibited compound heterozygous c.35delG, c.-23+1G>A, p.Trp24*, p.Val37Ile, p.Met34Thr, p.Leu90Pro, c.235delC, c.313_326del14, p.Ser139Asn, and p.Gly147Leu mutations. We found a monoallelic GJB2 mutation in 12 patients (6.6%). We found no pathogenic mutations in the other tested genes. Conclusions: One fifth of our cohort had deafness related to GJB2 mutations. The del(GJB6-D13S1830), SERPINB6, TMIE, COCH, ESPN, ACTG1, GJB3, and KCNQ4 mutations were infrequently associated with deafness in the Moravian-Silesian population. Therefore, we suggest that del(GJB6-D13S1830) testing should be performed only when patients with deafness carry the monoallelic GJB2 mutation.
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Project description:Deafness is an etiologically heterogeneous trait with many known genetic, environmental causes or a combination thereof. The identification of more than 120 independent genes for deafness has provided profound new insights into the pathophysiology of hearing. However, recent findings indicate that a large proportion of both syndromic and non-syndromic forms of deafness in the Chinese population are caused by defects in a small number of genes. Studies of the genetic epidemiology and molecular genetic features revealed that there is a clear relevance of genes causing deafness in Chinese deaf patients as well as a unique spectrum of common and rare deafness gene mutations in the Chinese population. This review is focused on the genetic aspects of non-syndromic and mitochondrial deafness, in which unique molecular genetic features of hearing impairment have been identified in the Chinese population. The current China population is approximately 1.3 billion. It is estimated that 30,000 infants are born with congenital sensorineural hearing loss each year. Better understanding of the genetic causes of deafness in the Chinese population is important for accurate genetics counseling and early diagnosis for timely intervention and treatment options.
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Project description:AIM:Hearing loss is the most common sensory disorder that affects approximately one per 1000 live births. With this project, we aimed to identify gene variants that were common causes of hearing loss in Turkey to contribute to the planning of genetic screening programs for hearing loss, as well as to improve genetic counseling to affected families. MATERIAL AND METHODS:Twenty-one families with at least two affected individuals and parental consanguinity who presented with non-syndromic severe-to-profound sensorineural hearing loss were included in this study. We first screened for mutations in GJB2 and mitochondrial DNA 12S RNA genes. Subsequently, we genotyped the TMIE c.250C>T and SNP markers flanking the SLC26A4, MYO7A, MYO15A, OTOF, CDH23, TMIE, TECTA, PCDH15, TMC1, TMPRSS3, TMHS genes in the remaining twelve families without mutations in GJB2. RESULTS:Screening for mutations in GJB2 gene showed c.[35delG];[35delG] mutation in four families, c.[35delG];[507C>A] mutation in two families, c.[35delG];[-23+1G>A] mutation in one family, and c.457G>A heterozygous mutation in one family. Genotyping SNP markers showed the c.[250C>T];[250C>T] mutation in TMIE in one family. A homozygous region with SNP genotypes was detected with the OTOF gene in one family, the TMPRSS3 gene in another family, and also a homozygous region was detected with TMHS, OTOF, and TMPRSS3 genes in another family. CONCLUSIONS:Further research will be required to determine the genetic bases of hearing loss in families with non-syndromic hearing loss.
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