GJB2 Mutations Research Articles

Management of Prenatal Expanded Genetic Carrier Screening Results for Autosomal Recessive Sensorineural Hearing Loss.

Expanded carrier screening (ECS) identified couples at-risk to have a baby with an autosomal recessive genetic condition. Several genes implicated in sensorineural hearing loss (SNHL) are included in prenatal or preconception genetics ECS testing. Early identification of SNHL risk may enable prognostication of hearing loss, early educational intervention, and minimization of unnecessary diagnostic testing. We sought to describe cases where ECS enabled early SNHL-risk identification. Retrospective chart review. Maternal-Fetal Care Center and Otolaryngology department at an academic tertiary hospital. Medical records of parent-infant dyads with positive ECS results for variants in autosomal recessive SNHL genes were reviewed. Data regarding genetic diagnostic testing, newborn hearing screening, time to HL diagnosis, audiological evaluation, and clinical consultations were compiled. Fifteen pregnant with positive ECS results for SNHL were referred for consultation with a pediatric otolaryngologist and genetic counselor. Generally, these couples were highly educated and adequately insured. 14 had pathogenic variants for GJB2 and 1 for USH2A. Four couples pursued prenatal genetic diagnosis via amniocentesis; 11 couples deferred genetic testing to the postnatal period or waited for initial hearing evaluation. Six babies inherited biallelic GJB2 mutations. Four were found to have SNHL on ABR by age 5 weeks and received follow-up management, 1 had a normal hearing evaluation despite being gene-positive, and 1 was lost to follow-up before hearing evaluation. Carrier screening and confirmatory prenatal or neonatal genetic testing provided considerable lead time for early audiometric testing and appropriate intervention services including hearing aid fitting.

The analysis of gene screening results for common hereditary hearing loss in 2 102 pregnant women in Dali area

Objective:By conducting genetic testing of hereditary hearing loss in pregnant women within 17 weeks of gestation in Dali areas, the importance of genetic testing and genetic counseling during pregnancy was emphasized. Methods:Twenty-one mutation sites of 4 hearing loss genes, including GJB2, GJB3, SLC26A4 and mtDNA, were detected by PCR amplification technology. The positive ratio, mutation ratio and ethnic distribution of positive samples were statistically described. Results:The positive ratios of GJB2 and SLC26A4 genes were 1.24% and 1.43%, respectively, with mutation rates of 40.62% and 46.88% in the positive samples, respectively. The positive ratio of GJB3gene was 0.19%, and mtDNA mutation genes accounted for 0.14%, and all of them were mtDNA（Heterozygous）. There was only one case of GJB2/SLC26A4 double positive multi-gene mutation, with a positive ratio of 0.05%. The frequency of GJB2 c. 235delC site was the highest, accounting for 65.38% of GJB2 mutation genes and 26.56% of mutation gene samples. Conclusion:GJB2 and SLC26A4 are the most common genes of hearing loss, and GJB2 c. 235delC site is the most common mutation site. Identifying the hearing loss mutation site is of great importance to prevent the birth of hereditary hearing loss children, and genetic diagnosis, genetic counseling, and appropriate intervention are crucial to alleviate congenital problems.

Auditory characteristics and disease progression trends of patients with common recessive deafness genes GJB2 and SLC26A4

Patients who aged≥6 years and had hearing loss due to GJB2 or SLC26A4 mutation from the Chinese Deafness Genome Project between January 2020 and December 2023 were included. A total of 43 patients with GJB2 mutation were detected, including 25 males and 18 females, with a mean age of (20.4±11.4) years. There were 20 patients with SLC26A4 mutation, including 9 males and 11 females, with a mean age of (15.7±9.1) years. The mean hearing threshold of GJB2 and SLC26A4 mutation patients was 54.1 (95%CI: 49.1-59.1) decibel hearing level (dB HL) and 66.1 (95%CI: 58.6-73.6) dB HL, respectively. The hearing threshold of GJB2 and SLC26A4 mutation patients increased at a rate of 0.21 (95%CI:-0.15-0.57) dB HL/year and 2.22 (95%CI: 1.46-2.99) dB HL/year, respectively. The current study indicates that patients with SLC26A4 mutation show a progressive trend of hearing decline with the increase of age.

Correlation between the etiology of severe hearing loss and endolymphatic hydrops.

This study aimed to investigate correlation between the presence of endolymphatic hydrops(EH) and factors such as causes of hearing loss, patient age, duration of deafness, and results of vestibular function tests. We retrospectively reviewed medical charts of 128 ears of cochlear implantees who were not considered relevant to Meniere's disease. When comparing group with genetic variants of GJB2, SLC26A4, LMX1A and other genetic mutation group, the proportion of vestibular EH and cochlear EH found in group with genetic variants of GJB2, SLC26A4, LMX1A was significantly higher than group with other genetic etiology (p < 0.01) or the group with all the other causes of hearing loss (p < 0.01). The rate of vestibular and cochlear EH detection was higher in younger patients (41.5% and 35.4%) than in older patients (25.4% and 20.6%). A higher ratio of vestibular and cochlear EH was observed in patients with a longer duration of deafness (37.5% and 31.3%) than those with a shorter duration of deafness (29.7% and 25.0%). The group with vestibular EH showed a higher incidence of abnormal findings in the caloric test (42.9%) than the group without vestibular EH (28.2%). Patients with genetic variants of GJB2, SLC26A4, LMX1A, younger patients, those with longer deaf durations showed a higher prevalence of vestibular and cochlear EH, implying EH appears to be formed as a developmental disorder in association with a certain set of genetic variants, rather than a phenotypic marker as a result of severe to profound hearing loss.

Genetic Basis of Hearing Loss in Mongolian Patients: A Next-Generation Sequencing Study.

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. We utilized the next-generation sequencing for investigating the causative mutations in 99 Mongolian patients with SNHI. 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. 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.

Etiologic Diagnosis of Genetic Hearing Loss in an Ethnically Diverse Deafness Cohort.

Hearing loss is a common sensory disorder that impacts patients across the lifespan. Many genetic variants have been identified that contribute to non-syndromic hearing loss. Yet, genetic testing is not routinely administered when hearing loss is diagnosed, particularly in adults. In this study, genetic testing was completed in patients with known hearing loss. A total of 104 patients who were evaluated for hearing loss were enrolled and received genetic testing. Of those 104 patients, 39 had available genetic testing, 20 had one missing allele, and 45 yielded no genetic diagnosis. Of the 39 cases with genetic testing data, 24 were simplex cases, and 15 were multiplex cases. A majority of patients presented with an autosomal recessive inheritance pattern (n = 32), 26 of whom presented with congenital hearing loss. 38% of cases were positive for GJB2 mutation with c.35delG being the most common pathogenic variant. These findings are consistent with previous literature suggesting GJB2 mutations are the most common causes of non-syndromic hearing loss. Given the frequency of genetic variants in patients with hearing loss, genetic testing should be considered a routine part of the hearing loss work-up, particularly as gene therapies are studied and become more widely available. Many genetic variants have been identified that contribute to non-syndromic hearing loss. Given the frequency of genetic variants in patients with hearing loss, genetic testing should be considered a routine part of the hearing loss work-up.

Novel GJB2 mutation c.188delT compound with c.235delC causing non-syndromic hearing loss in a Chinese family: A case report.

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. A newborn Chinese girl exhibited signs of congenital deafness. 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. The patient underwent cochlear implantation, which resulted in stable auditory 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. 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.

Genetic analysis of 106 sporadic cases with hearing loss in the UAE population

BackgroundHereditary hearing loss is a rare hereditary condition that has a significant presence in consanguineous populations. Despite its prevalence, hearing loss is marked by substantial genetic diversity, which poses challenges for diagnosis and screening, particularly in cases with no clear family history or when the impact of the genetic variant requires functional analysis, such as in the case of missense mutations and UTR variants. The advent of next-generation sequencing (NGS) has transformed the identification of genes and variants linked to various conditions, including hearing loss. However, there remains a high proportion of undiagnosed patients, attributable to various factors, including limitations in sequencing coverage and gaps in our knowledge of the entire genome, among other factors. In this study, our objective was to comprehensively identify the spectrum of genes and variants associated with hearing loss in a cohort of 106 affected individuals from the UAE.ResultsIn this study, we investigated 106 sporadic cases of hearing impairment and performed genetic analyses to identify causative mutations. Screening of the GJB2 gene in these cases revealed its involvement in 24 affected individuals, with specific mutations identified. For individuals without GJB2 mutations, whole exome sequencing (WES) was conducted. WES revealed 33 genetic variants, including 6 homozygous and 27 heterozygous DNA changes, two of which were previously implicated in hearing loss, while 25 variants were novel. We also observed multiple potential pathogenic heterozygous variants across different genes in some cases. Notably, a significant proportion of cases remained without potential pathogenic variants.ConclusionsOur findings confirm the complex genetic landscape of hearing loss and the limitations of WES in achieving a 100% diagnostic rate, especially in conditions characterized by genetic heterogeneity. These results contribute to our understanding of the genetic basis of hearing loss and emphasize the need for further research and comprehensive genetic analyses to elucidate the underlying causes of this condition.

Deficient Gap Junction Coupling in Two Common Hearing Loss-Related Variants of GJB2.

The aim of this study was to explore the functional consequences of two common variants, p.V37I and c.299-300delAT, in the hearing loss-associated gene GJB2. Connexin 26 expression and gap junctional permeability were studied in HEK 293T cells transfected with plasmids expressing GJB2 wild-type, p.V37I, or c.299-300delAT CX26 proteins tagged with fluorescent markers. Functional analyses of various GJB2 haplotypes were conducted to thoroughly evaluate alterations in ionic and small-molecule coupling. The p.V37I protein was localized at the plasma membrane, but it failed to effectively transport intercellular propidium iodide or Ca2+ efficiently, indicating an impairment in both biochemical and ionic coupling. The presence of GJB2 p.V37I seemed to increase the cells' sensitivity to H2O2 treatment. In contrast, the known variant c.299-300delAT protein was not transported to the cell membrane and was unable to form gap junctions, remaining confined to the cytoplasm. Both ionic and biochemical coupling were defective in cells transfected with c.299-300delAT. The p.V37I and c.299-300delAT GJB2 mutations resulted in deficient gap junction-mediated coupling. Additionally, environmental factors could influence the functional outcomes of the GJB2 p.V37I mutation. These findings could pave the way for the development of molecular therapies targeting GJB2 mutations to treat hearing loss.

Identification of novel and known genetic variants associated with hereditary hearing loss in iranian families using whole exome sequencing.

Hearing loss (HL) is a common sensory impairment worldwide, with genetic and environmental factors contributing to its occurrence. Next Generation Sequencing (NGS) plays a crucial role in identifying the genetic factors involved in this heterogeneous disorder. In this study, a total of 9 unrelated Iranian families, each having at least one affected individual who tested negative for mutations in GJB2, underwent screening using whole exome sequencing (WES). The pathogenicity and novelty of the identified variant was checked using various databases. Co-segregation study was also performed to confirm the presence of the candidate variants in parents. Plus, The pathogenicity of the detected variant was assessed through in silico analysis using a number of mutation prediction software tools. Among the 9 investigated families, hearing loss-causing genes were identified in 6 families. the mutations were observed in USH2A, CLRN1, BSND, SLC26A4, and MITF, with two of the identified mutations being novel. Discovering additional variants and broadening the range of mutations associated with hearing impairment has the potential to enhance the diagnostic effectiveness of molecular testing in patient screening, and can also lead to improved counseling aimed at reducing the risk of affected offspring for high-risk couples.

Unveiling a novel GJB2 dominant K22T mutation in a Chinese family with hearing loss.

Hearing loss constitutes one of the most prevalent conditions within the field of otolaryngology. Recent investigations have revealed that mutations in deafness-associated genes, including point mutations and variations in DNA sequences, can cause hearing impairments. With the ethology of deafness remaining unclear for a substantial portion of the affected population, further screenings for pathogenic mutations are imperative to unveil the underlying mechanisms. On this study, by using next-generation sequencing, we examine 129 commonly implicated deafness-related genes in a Chinese family with hearing loss, revealing a novel heterozygous dominant mutation in the GJB2 gene (GJB2: c.65T>G: p. Lys22Thr). This mutation consistently occurs in affected family members but is not detected in unaffected individuals, strongly suggesting its causative role in hearing loss. Structural analysis indicates potential disruption to the Cx26 gap junction channel's hydrogen bond and electrostatic interactions, aligning with predictions from the PolyPhen and SIFT algorithms. In conclusion, our study provides conclusive evidence that the identified heterozygous GJB2 mutation (GJB2: c.65T>G: p. Lys22Thr), specifically the K22T alteration, is the primary determinant of the family's deafness. This contribution enhances our understanding of the interplay between common deafness-associated genes and hearing loss, offering valuable insights for diagnostic guidance and the formulation of therapeutic strategies for this condition.

Audiological Phenotypes of Connexin Gene Mutation Patterns: A Glance at Different GJB2/GJB6 Gene Mutation Profiles.

GJB2 mutations are the most common cause of autosomal-recessive non-syndromic sensorineural hearing loss (SNHL). The available evidence shows large phenotypic variability across different genotypes and allelic variants. The aim of this study was to investigate the clinical and audiological features of a cohort of subjects with different GJB2/GJB6 gene mutation profiles from a tertiary referral center in Northeastern Italy. We considered 57 patients with GJB2/GJB6 mutations presenting with congenital, non-syndromic SNHL, mainly coming from the Veneto region (Italy). The samples were screened for mutations in exons 1 and 2 of the GJB2 gene and for the GJB6 gene deletion del (GJB6-D13S1830). Free-field and air-conduction frequency-specific thresholds and the pure-tone average (PTA) were considered in the statistical analysis. Five patients (8.87%) had connexin gene mutations in simple heterozygosis, 15 (26.31%) in compound heterozygosis, 34 (59.64%) in homozygosis, and 3 (5.26%) with digenic patterns. The frequency-specific air-conduction thresholds showed significantly different mean values across the different genotypes (Roy's largest-root test, p = 0.0473). Despite the evidence already available on genetic SNHL, many new insights are to be expected. Further large-scale prospective studies including different populations are necessary to confirm these preliminary findings about the clinical and audiological features of patients with different GJB2/GJB6 gene mutation patterns.

Unraveling the Diversity of GJB2 Mutations in Nonsyndromic Hearing Loss: A Comprehensive Study in the Moroccan Population

Introduction: Despite the high genetic heterogeneity of hearing loss, mutations in the GJB2 gene are a major cause of autosomal recessive nonsyndromic hearing loss (NSHL) worldwide. However, the mutation profile of GJB2 in NSHL is under-investigated in Morocco, especially among simplex cases. This study aimed to identify the spectrum and frequency of GJB2 mutations in the Moroccan population among simplex and multiplex families with NSHL. Methods: Moroccan families with NSHL were selected according to well-defined criteria. Selected families were screened for GJB2 gene variants using direct sequencing of the entire coding region of GJB2. Results: A total of 145 affected individuals from 115 families with NSHL were included in this study (49 simplex, 66 multiplex). Mutations in the GJB2 gene were noted in 28.69% of the families (33/115), of which 75.75% were multiplex families and 24.24% were simplex. In total, seven different mutations were detected: c.35delG(p.G12fs), c.551G>A(p.R184Q), c.139G>T(p.E47X), c.109G>A(p.V37I), c.167delT(p.L56fs), c.617A>G(p.N206S), c.94C>T(p.R32C). The last three mutations have not previously been reported in Morocco. The most common GJB2 mutation was c.35delG (21.73%), followed by p.V37I (2.60%) and p.E47X (1.73%). Conclusions: Our study confirms a high prevalence of GJB2 variants in the Moroccan population, particularly the c.35delG mutation. Additionally, we have identified previously unreported or rarely reported mutations, revealing a greater diversity of GJB2 mutations. These findings emphasize the importance of comprehensive screening beyond the 35delG mutation for patients with NSHL, regardless of their family history. Integrating this approach into clinical care will enhance diagnosis and management of hearing loss in the Moroccan population.

Episodic Neurological Dysfunction in X-Linked Charcot-Marie-Tooth Disease: Expansion of the Phenotypic and Genetic Spectrum.

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by peripheral neuropathy with or without episodic neurological dysfunction. We performed clinical, neuropathological, and genetic investigations of a series of patients with mutations of the gap-junction beta-1 gene (GJB1) to extend the phenotypic and genetic description of CMTX1. Detailed clinical evaluations, sural nerve biopsy, and genetic analysis were applied to patients with CMTX1. We collected 27 patients with CMTX1 with GJB1 mutations from 14 unrelated families. The age at onset (AAO) was 20.9±12.2 years (mean±standard deviation; range, 2-45 years). Walking difficulties, weakness in the legs, and pes cavus were common initial symptoms. Compared with female patients, males tended to have a younger AAO (males vs. females=15.4±9.6 vs. 32.0±8.8 years, p=0.002), a longer disease course (16.8±16.1 vs. 5.5±3.8 years, p=0.034), and more-severe electrophysiological results. Besides peripheral neuropathy, six of the patients had special episodic central nervous system (CNS) evidence from symptoms, signs, and/or reversible white-matter lesions. Neuropathology revealed the loss of large myelinated fibers, increased number of regenerated axon clusters with abnormally thin myelin sheaths, and excessively folded myelin. Genetic analysis identified 14 GJB1 variants, 6 of which were novel. These findings expand the phenotypic and genetic spectrum of CMTX1. Although CMTX1 was found to have high phenotypic and CNS involvement variabilities, detailed neurological examinations and nerve conduction studies will provide critical clues for accurate diagnoses. Further exploration of the underlying mechanisms of connexin 32 involvement in neuropathy or CNS dysfunction is warranted to develop promising therapies.

Bone Marrow, Laboratory, and Clinical Features in Pediatric Patients with RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM)

Background: Germline RUNX1 mutation is associated with an autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), most commonly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but lymphoblastic leukemias are also reported. FPDMM is characterized by thrombocytopenia from an early age associated with abnormal platelet function. Herein we report the bone marrow features, in addition to laboratory and clinical findings, of a large pediatric cohort (N=29) with RUNX1-FPDMM. These data have value in guiding early investigation of neonatal/pediatric thrombocytopenia, and baseline bone marrow interpretation to avoid overdiagnosis of MDS or misdiagnosis of immune-mediated thrombocytopenias. Design: The clinical, laboratory, bone marrow pathology, and molecular findings of 29 pediatric patients (&amp;lt;18 years) with germline RUNX1 mutation followed by the natural history study at the National Institutes of Health (NIH) (ClinicalTrials.gov Identifier: NCT03854318), were analyzed. Results : Among the patients, 13 were female and 16 male, in 21 pedigrees, with a median age at bone marrow biopsy of 6 years (range: 17 months to 17 years). Germline RUNX1 mutations were familial in 26 patients and de novo in 3 patients. Easy bruising and propensity for bleeding were common (87%). The median platelet count was 123 x 10 9/L (range: 38 - 244). Abnormal platelet aggregation assay was present in all 9 patients tested. Abnormal transmission electron microscopy of platelets was found in 14/21 (67%) patients tested; the majority had decreased platelet dense granules, with or without decreased alpha granules. Three patients had normal platelet counts. Hematologic neoplasm was identified in 4 patients: one with AML with JAK3 and KRAS mutations; one with B-lymphoblastic leukemia with EBF1::PDGFRB; one with T-lymphoblastic leukemia with a complex karyotype; and one with MDS with excess blasts and no detectable acquired genetic alterations. 3/4 of patients with malignancy had hypercellular marrows. Of the remaining patients, 19/25 (76%) had hypocellular bone marrows for age. The majority had normal numbers of megakaryocytes. Dysmegakaryopoiesis with features overlapping with “dysplasia” (small hypolobated, small with convoluted nuclei and minimal cytoplasm, separation of nuclear lobes) in greater than 10% of megakaryocytes was present in 92% of cases. At least one patient was previously misdiagnosed with immune thrombocytopenic purpura (ITP). 18 patients had eosinophilia in bone marrow sections, six of whom had peripheral blood eosinophilia. Flow cytometric analysis of the marrow commonly showed T-cells with inverted CD4:CD8 ratios (17/22) and increased eosinophils (16/22). The one patient with MDS had increased (10%) immunophenotypically abnormal myeloblasts expressing CD7 and CD123. 23/25 patients had targeted NGS: one patient had a pathogenic mutation in BCOR and the remaining had no pathogenic mutations in genes associated with hematologic malignancy; 15 patients had VUSs reported. At least four patients had large RUNX1 deletions that were not detected by conventional NGS. 23 patients tested had a normal karyotype except one female patient with monosomy X in 11/20 metaphases. Allergy (drug, food and seasonal) was present in 11 patients, and eczema was common. A spectrum of gastrointestinal (GI) symptoms was seen in 11 patients, including constipation, eosinophilic esophagitis, gastroesophageal reflux, and celiac disease. 2 patients were diagnosed with autism, 1 with coarse facies and KDM6B mutation, 1 with brachydactyly syndrome related to PRMT7 mutation, and 1 with non-syndromic hearing loss related to GJB2 mutation. Conclusion: Germline mutation in RUNX1 should be considered in pediatric patients with thrombocytopenia and/or abnormal platelet function and a hypocellular marrow with or without dysmegakaryopoiesis. Dysmegakaryopoiesis in the setting of RUNX1-FPDMM should not be overinterpreted as pediatric MDS without other supporting criteria such as MDS-defining cytogenetic/molecular abnormalities, multilineage dysplasia, or increased blasts. Patients with large deletions in RUNX1 may be missed on routine NGS testing hence proper germline testing in an experienced laboratory is recommended if suspicion is high. Close monitoring is crucial for early identification of emerging myeloid or lymphoid malignancy.

Hearing and Hearing Loss Progression in Patients with GJB2 Gene Mutations: A Long-Term Follow-Up.

We aimed to investigate whether the degree of hearing loss with GJB2 mutations could be predicted by distinguishing between truncating and non-truncating mutations and whether the genotype could predict the hearing loss level. Additionally, we examined the progression of hearing loss in individuals monitored for over 2 years for an average of 6.9 years. The proportion of truncating mutations was higher in patients with profound and severe hearing loss, but it was not accurate enough to predict the degree of hearing loss. Via genotype analysis, mutations of the p.Arg143Trp variants were associated with profound hearing loss, while mutations of the p.Leu79Cysfs*3 allele exhibited a wide range of hearing loss, suggesting that specific genotypes can predict the hearing loss level. Notably, there were only three cases of progression in four ears, all of which involved the p.Leu79Cysfs*3 mutation. Over the long-term follow-up, 4000 Hz was significant, and there was a trend of progression at 250 Hz, suggesting that close monitoring at these frequencies during follow-up may be crucial to confirm progression. The progression of hearing loss was observed in moderate or severe hearing loss cases at the time of the initial diagnosis, emphasizing that children with this level of hearing loss need regular follow-ups.

Characteristics of hearing loss-associated gene mutations: A multi-center study of 119,606 neonates in Gannan.

HL is the second most common congenital disability in China, and its high incidence brings a serious burden of medical and educational sequelae. HL genetic screening enables the identification of individuals with inherited HL and carriers in a large scale. This study aimed to measure the detection rates of hearing loss (HL)-associated gene mutations in the Gannan population. The molecular etiology and risk factors of hereditary HL were also analyzed. In total, 119,606 newborns from 18 districts of Gannan were enrolled in this multi-center study conducted between April 2019 and April 2021. Otoacoustic Emission (OAE) was used for primary hearing screening 3 days after birth in quiet conditions, and OAE combined with automated auditory brainstem response (AABR) was applied 29-42 days after birth for those who failed or missed the initial screening. Meanwhile, high-throughput sequencing of hotspot HL-associated mutations in GJB2, GJB3, MTRNR1, and SLC26A4 were performed. Among the 119,606 newborns, 7796 (6.52%) failed the hearing screening. Genetic screening revealed that 5092 neonates (4.26%) carried HL-associated mutations. The detection rate of GJB2, SLC26A4, MTRNR1 and GJB3 mutations were 2.09%, 1.51%, 0.42% and 0.24%, respectively. The most prevalent variant was GJB2 c.235delC (1.74%). The second most prevalent variant was SLC26A4 c.919-2A>G (0.93%). The population who failed the hearing screening had a lower proportion (24.64%) of SLC26A4 gene variants compared to the population who passed (37.46%). Genetic screening identified 4612 (3.86%) carriers who were normal in hearing screenings. The concurrent hearing and genetic screening identified 480 (0.40%) neonates at high risk for hereditary HL. The results of this study suggest that the concurrent hearing screening and high-throughput genetic screening would greatly improve the effectiveness of newborn HL programs. This integration also facilitates the management of congenital HL, and aids in the prevention of aminoglycoside antibiotics-induced HL.

Novel Pathogenic Variants in the Gene Encoding Stereocilin (STRC) Causing Non-Syndromic Moderate Hearing Loss in Spanish and Argentinean Subjects.

Non-syndromic hearing impairment (NSHI) is a very heterogeneous genetic condition, involving over 130 genes. Mutations in GJB2, encoding connexin-26, are a major cause of NSHI (the DFNB1 type), but few other genes have significant epidemiological contributions. Mutations in the STRC gene result in the DFNB16 type of autosomal recessive NSHI, a common cause of moderate hearing loss. STRC is located in a tandem duplicated region that includes the STRCP1 pseudogene, and so it is prone to rearrangements causing structural variations. Firstly, we screened a cohort of 122 Spanish familial cases of non-DFNB1 NSHI with at least two affected siblings and unaffected parents, and with different degrees of hearing loss (mild to profound). Secondly, we screened a cohort of 64 Spanish sporadic non-DFNB1 cases, and a cohort of 35 Argentinean non-DFNB1 cases, all of them with moderate hearing loss. Amplification of marker D15S784, massively parallel DNA sequencing, multiplex ligation-dependent probe amplification and long-range gene-specific PCR followed by Sanger sequencing were used to search and confirm single-nucleotide variants (SNVs) and deletions involving STRC. Causative variants were found in 13 Spanish familial cases (10.7%), 5 Spanish simplex cases (7.8%) and 2 Argentinean cases (5.7%). In all, 34 deleted alleles and 6 SNVs, 5 of which are novel. All affected subjects had moderate hearing impairment. Our results further support this strong genotype-phenotype correlation and highlight the significant contribution of STRC mutations to moderate NSHI in the Spanish population.

Follow-up of infants with mild-to-moderate sensorineural hearing loss over three years.

To observe and analyse the hearing outcome in infants with mild-to-moderate sensorineural hearing loss (SNHL) who failed universal newborn hearing screening (UNHS). This retrospective cohort analysis included infants with mild-to-moderate SNHL and with complete etiological diagnosis and followed up over three years. Out of 96 infants with mild-to-moderate SNHL 72 were stable (75%). Only one case was normal (1.04%), ten cases were improved (10.42%), and 13 were deteriorated (13.54%). The pathogenic mutation of GJB2 was the most common cause (50/96, 52.08%), and most of them were homozygous or complex heterozygous mutations of p.V37I (44/50, 88%). There were 11 cases (11.49%) with large vestibular aqueduct syndrome (LVAS) and nine cases (9.38%) with perinatal risk factors. Infants with GJB2 pathogenic mutation and those without certain etiology mostly had unchanged hearing levels, accounting for 84% (42/50) and 84.61% (22/26), respectively. Hearing deterioration in LVAS was associated with seven cases (63.64%). There was no difference in types of outcomes in perinatal risk factor infants, who were more likely to improve than the other groups, but there were three cases (33.3%) deteriorated to profound hearing loss. Comparison of outcomes of different etiologies showed statistically significant difference (Chi-square=28.673, p=0.000). Normal and improved hearing in infants with mild-to-moderate SNHL was rare before the age of three, unlike in many previous studies, and appropriate intervention is recommended. However, intervention should be adjusted according to the hearing outcomes because of the possibility of improvement or deterioration. The etiological diagnosis of infants with mild-to-moderate SNHL would be helpful for predicting the outcome and managing intervention.

Ocular phenotype and therapeutic interventions in keratitis-ichthyosis-deafness (KID) syndrome

ABSTRACT Background To report ocular manifestations, clinical course, and therapeutic management of patients with molecular genetically confirmed keratitis-ichthyosis-deafness syndrome. Methods Four patients, aged 19 to 46, with keratitis-ichthyosis-deafness syndrome from across the UK were recruited for a general and ocular examination and GJB2 (Cx26) mutational analysis. The ocular examination included best-corrected visual acuity, slit-lamp bio-microscopy, and ocular surface assessment. Mutational analysis of the coding region of GJB2 (Cx26) was performed by bidirectional Sanger sequencing. Results All four individuals had the characteristic systemic features of keratitis-ichthyosis-deafness syndrome. Each patient was found to have a missense mutation, resulting in the substitution of aspartic acid with asparagine at codon 50 (p.D50N). Main ophthalmic features were vascularizing keratopathy, ocular surface disease, hyperkeratotic lid lesions, recurrent epithelial defects, and corneal stromal scarring. One patient had multiple surgical procedures, including superficial keratectomies and lamellar keratoplasty, which failed to prevent severe visual loss. In contrast, oral therapy with ketoconazole stabilized the corneal and skin disease in two other patients with keratitis-ichthyosis-deafness syndrome. The patient who underwent intracorneal bevacizumab injection showed a marked reduction in corneal vascularization following a single application. Conclusions Keratitis-ichthyosis-deafness syndrome is a rare ectodermal dysplasia caused by heterozygous mutations in GJB2 (Cx26) with a severe, progressive vascularizing keratopathy. Oral ketoconazole therapy may offer benefit in stabilizing the corneal and skin disease.