ABSTRACT
One nucleotide substitution in codon 320 of A*03:01:01:01 results in the novel allele, HLA-A*03:478.
Subject(s)
Alleles , Asian People , Exons , Histocompatibility Testing , Humans , Asian People/genetics , Republic of Korea , Sequence Analysis, DNA/methods , Base Sequence , Codon , HLA-A3 Antigen/genetics , HLA-A Antigens/genetics , Polymorphism, Single Nucleotide , Sequence AlignmentABSTRACT
KCNQ4 is a voltage-gated K+ channel was reported to distribute over the basolateral surface of type 1 vestibular hair cell and/or inner surface of calyx and heminode of the vestibular nerve connected to the type 1 vestibular hair cells of the inner ear. However, the precise localization of KCNQ4 is still controversial and little is known about the vestibular phenotypes caused by KCNQ4 dysfunction or the specific role of KCNQ4 in the vestibular organs. To investigate the role of KCNQ4 in the vestibular organ, 6-g hypergravity stimulation for 24 h, which represents excessive mechanical stimulation of the sensory epithelium, was applied to p.W277S Kcnq4 transgenic mice. KCNQ4 was detected on the inner surface of calyx of the vestibular afferent in transmission electron microscope images with immunogold labelling. Vestibular function decrease was more severe in the Kcnq4p.W277S/p.W277S mice than in the Kcnq4+/+ and Kcnq4+/p.W277S mice after the stimulation. The vestibular function loss was resulted from the loss of type 1 vestibular hair cells, which was possibly caused by increased depolarization duration. Retigabine, a KCNQ activator, prevented hypergravity-induced vestibular dysfunction and hair cell loss. Patients with KCNQ4 mutations also showed abnormal clinical vestibular function tests. These findings suggest that KCNQ4 plays an essential role in calyx and afferent of type 1 vestibular hair cell preserving vestibular function against excessive mechanical stimulation.
Subject(s)
Hair Cells, Vestibular , KCNQ Potassium Channels , Mice, Transgenic , Animals , KCNQ Potassium Channels/metabolism , KCNQ Potassium Channels/genetics , Hair Cells, Vestibular/metabolism , Hair Cells, Vestibular/pathology , Mice , Phenylenediamines/pharmacology , Carbamates/pharmacology , Vestibule, Labyrinth/metabolism , Vestibule, Labyrinth/pathology , Vestibule, Labyrinth/physiopathologyABSTRACT
Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019. In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virus-infected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105 PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.
ABSTRACT
Evaluation of the test performance of the Target enhanced whole-genome sequencing (TE-WGS) assay for comprehensive oncology genomic profiling. The analytical validation of the assay included sensitivity and specificity for single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs), revealing a revealed a sensitivity of 99.8% for SNVs and 99.2% for indels. The positive predictive value (PPV) was 99.3% SNVs and 98.7% indels. Clinical validation was benchmarked against established orthogonal methods and demonstrated high concordance with reference methods. TE-WGS provides insights beyond targeted panels by comprehensive analysis of key biomarkers and the entire genome encompassing both germline and somatic findings.
Subject(s)
Genomics , INDEL Mutation , Whole Genome Sequencing , Humans , Whole Genome Sequencing/methods , Genomics/methods , Polymorphism, Single Nucleotide , Neoplasms/genetics , Female , Male , Genome, Human , Middle Aged , Sensitivity and Specificity , High-Throughput Nucleotide Sequencing/methods , Aged , Adult , Reproducibility of ResultsABSTRACT
Background: The vestibular phenotypes of patients with genetic hearing loss are poorly understood. Methods: we performed genetic testing including exome sequencing and vestibular function tests to investigate vestibular phenotypes and functions in patients with genetic hearing loss. Results: Among 627 patients, 143 (22.8%) had vestibular symptoms. Genetic variations were confirmed in 45 (31.5%) of the 143 patients. Nineteen deafness genes were linked with vestibular symptoms; the most frequent genes in autosomal dominant and recessive individuals were COCH and SLC26A4, respectively. Vestibular symptoms were mostly of the vertigo type, recurrent, and persisted for hours in the genetically confirmed and unconfirmed groups. Decreased vestibular function in the caloric test, video head impulse test, cervical vestibular-evoked myogenic potential, and ocular vestibular-evoked myogenic potential was observed in 42.0%, 16.3%, 57.8%, and 85.0% of the patients, respectively. The caloric test revealed a significantly higher incidence of abnormal results in autosomal recessive individuals than in autosomal dominant individuals (p = 0.011). The genes, including SLC26A4, COCH, KCNQ4, MYH9, NLRP3, EYA4, MYO7A, MYO15A, and MYH9, were heterogeneously associated with abnormalities in the vestibular function test. Conclusions: In conclusion, diverse vestibular symptoms are commonly concomitant with genetic hearing loss and are easily overlooked.
ABSTRACT
BACKGROUND: Helping newly graduated registered nurses successfully adapt to clinical practice, evaluating work capabilities, identifying deficiencies, and continuously providing educational support to improve deficiencies are reported to be of paramount importance. OBJECTIVES: To develop a tailored nursing practice preparation improvement program for newly graduated registered nurses and assess its impact on the successful adaptation of nurses. DESIGN: A quasi-experimental study. SETTINGS: The study was performed at a tertiary general hospital in South Korea. PARTICIPANT: A total of 53 newly graduated registered nurses (experimental group = 28; comparison group = 25) participated. METHODS: The newly graduated registered nurses were recruited using purposive sampling to one of two groups. The study was conducted between February and May 2022. The experimental group underwent a 4-week education program that integrated various methods, whereas the control group underwent preceptor training in their department. Data were collected through a questionnaire survey and analyzed using the chi-square test, independent t-test, and analysis of covariance with the SPSS 26.0 program. RESULTS: The nursing practice readiness improvement program tailored for newly graduated registered nurses was effective in reducing the transition shock (F = 9.18, p = 0.004) of newly graduated registered nurses and improving nursing practice readiness (F = 19.90, p < 0.001), job satisfaction (F = 4.09, p = 0.049), and retention intention (F = 6.20, p = 0.016). CONCLUSIONS: This study presented an evidence based approach on the use of a nursing practice readiness improvement program for the successful adaptation of newly graduated registered nurses and the establishment of a nurse education system.
Subject(s)
Job Satisfaction , Nurses , Humans , Research Design , Republic of KoreaABSTRACT
BACKGROUND: Mutations in mitochondrial DNA (mtDNA) are associated with several genetic disorders, including sensorineural hearing loss. However, the prevalence of mtDNA mutations in a large cohort of Korean patients with hearing loss has not yet been investigated. Thus, this study aimed to investigate the frequency of mtDNA mutations in a cohort of with pre- or post-lingual hearing loss of varying severity. METHODS: A total of 711 Korean families involving 1,099 individuals were evaluated. Six mitochondrial variants associated with deafness (MTRNR1 m.1555A>G, MTTL1 m.3243A>G, MTCO1 m.7444G>A and m.7445A>G, and MTTS1 m.7471dupC and m.7511T>C) were screened using restriction fragment length polymorphism. The prevalence of the six variants was also analyzed in a large control dataset using whole-genome sequencing data from 4,534 Korean individuals with unknown hearing phenotype. RESULTS: Overall, 12 of the 711 (1.7%) patients with hearing loss had mtDNA variants, with 10 patients from independent families positive for the MTRNR1 m.1555A>G mutation and 2 patients positive for the MTCO1 m.7444G>A mutation. The clinical characteristics of patients with the mtDNA variants were characterized by post-lingual progressive hearing loss due to the m.1555A>G variant (9 of 472; 1.9%). In addition, 18/4,534 (0.4%) of the Korean population have mitochondrial variants associated with hearing loss, predominantly the m.1555A>G variant. CONCLUSION: A significant proportion of Korean patients with hearing loss is affected by the mtDNA variants, with the m.1555A>G variant being the most prevalent. These results clarify the genetic basis of hearing loss in the Korean population and emphasize the need for genetic testing for mtDNA variants.
Subject(s)
Hearing Loss, Sensorineural , Hearing Loss , Humans , Prevalence , Hearing Loss, Sensorineural/epidemiology , Hearing Loss, Sensorineural/genetics , Mutation , DNA, Mitochondrial/genetics , Republic of Korea/epidemiologyABSTRACT
BACKGROUND: Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML. METHODS: We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients. RESULTS: We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models. CONCLUSION: Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.
Subject(s)
Blast Crisis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Animals , Mice , Humans , Blast Crisis/drug therapy , Blast Crisis/genetics , Blast Crisis/pathology , Fusion Proteins, bcr-abl/genetics , Drug Resistance, Neoplasm/genetics , Signal Transduction , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Protein Kinase Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
Genetic hearing loss is the most common hereditary sensorial disorder. Though more than 120 genes associated with deafness have been identified, unveiled causative genes and variants of diverse types of hearing loss remain. Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration. CEP250 encodes C-Nap1 protein belonging to the CEP protein family, comprising 30 proteins that play roles in centrosome aggregation and cell cycle progression. The nonsense variant in CEP250 led to the early truncating protein of C-Nap1, which hindered centrosome localization; heterologous expression of CEP250 (c.3511C>T) in NIH3T3 cells within cilia expression condition revealed that the truncating C-Nap1 (p.Gln1171Ter) was not localized at the centrosome but was dispersed in the cytosol. In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells. Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response. In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice.
ABSTRACT
DQA1*03:50Q differs from DQA1*03:02:01:01 by a three-nucleotide insertion at gDNA position 3968 in exon 2.
Subject(s)
High-Throughput Nucleotide Sequencing , Humans , Alleles , Sequence Analysis, DNA , HLA-DQ alpha-Chains/genetics , Republic of KoreaABSTRACT
Background: A chemotherapy of rituximab, fludarabine and cyclophosphamide (R-FC) has been accepted as a promising frontline chemotherapy in selected patients with chronic lymphocytic leukemia (CLL). Although R-FC regimen is a relatively dose-dense regimen and neutropenia incidence is more than 50%, primary prophylactic pegfilgrastim was not fully recommended in the clinical field. Therefore, the study evaluated the prophylactic effectiveness of pegfilgrastim to reduce the incidence of febrile neutropenia associated with R-FC of patients with CLL. Patients and methods: A single-arm, multicenter, prospective phase II study was designed to assess the efficacy of prophylactic pegfilgrastim. Thirty-four CLL patients were enrolled and analyzed for neutropenia and other related factors, and comparative analysis was performed with historical cohort. Results: Compared with our historical cohort, incidence of grade 3-4 neutropenia and febrile neutropenia was remarkably reduced during any cycle of chemotherapy (14.7% vs. 48.2% of study cohort vs. historical cohort during C1, 5.9% vs. 65.8% during C2, 12.9% vs. 80.6% during C3, 10% vs. 84.6% during C4, 3.4% vs. 83.6% during C5, and 10.7% vs. 85.7% during C6, p <0.001). Also, cumulative incidence of disrupted chemotherapy was noticeably reduced in study cohort on any cycles of R-FC regimen (8.8% vs. 22.2% of study cohort vs. historical cohort on C2, 9.7% vs. 25.2% on C3, 13.4% vs. 26.9% on C4, 13.8% vs. 45.2% on C5, 17.9% vs. 47.3% on C6, p=0.007). In addition, treatment-related mortality was 5.9%, which significantly reduced compared to 9.6% of our historical cohort (HR 0.64, 95% CI 0.42-0.79, P = 0.032). Conclusion: Primary prophylactic pegfilgrastim is effective in the prevention of neutropenia/febrile neutropenia, and infection-related mortality during R-FC regimen in patients with CLL.
ABSTRACT
Pathogenic variants of KCNQ4 cause symmetrical, late-onset, progressive, high-frequency-affected hearing loss, which eventually involves all frequencies with age. To understand the contribution of KCNQ4 variants to hearing loss, we analyzed whole-exome and genome sequencing data from patients with hearing loss and individuals whose hearing phenotypes were unknown. In KCNQ4, we identified seven missense variants and one deletion variant in 9 hearing loss patients and 14 missense variants in the Korean population with an unknown hearing loss phenotype. The p.R420W and p.R447W variants were found in both cohorts. To investigate the effects of these variants on KCNQ4 function, we performed whole-cell patch clamping and examined their expression levels. Except for p.G435Afs*61, all KCNQ4 variants exhibited normal expression patterns similar to those of wild-type KCNQ4. The p.R331Q, p.R331W, p.G435Afs*61, and p.S691G variants, which were identified in patients with hearing loss, showed a potassium (K+) current density lower than or similar to that of p.L47P, a previously reported pathogenic variant. The p.S185W and p.R216H variants shifted the activation voltage to hyperpolarized voltages. The channel activity of the p.S185W, p.R216H, p.V672M, and p.S691G KCNQ4 proteins was rescued by the KCNQ activators retigabine or zinc pyrithione, whereas p.G435Afs*61 KCNQ4 proteins were partially rescued by sodium butyrate, a chemical chaperone. Additionally, the structure of the variants predicted using AlphaFold2 showed impaired pore configurations, as did the patch-clamp data. Our findings suggest that KCNQ4 variants may be overlooked in hearing loss that starts in adulthood. Some of these variants are medically treatable; hence, genetic screening for KCNQ4 is important.
Subject(s)
Deafness , Hearing Loss , Humans , Pedigree , Hearing Loss/genetics , Deafness/genetics , Hearing , Mutation, Missense , KCNQ Potassium Channels/geneticsABSTRACT
OBJECTIVES: Despite growing interest in the genetic contribution to cochlear implant (CI) outcomes, only a few studies with limited samples have examined the association of CI outcomes with genetic etiologies. We analyzed CI outcomes using known predictors and genetic testing results to obtain a comprehensive understanding of the impact of genetic etiologies. DESIGN: We retrospectively reviewed the medical records and images of patients who underwent cochlear implantation and genetic testing at a single tertiary medical institution, between May 2008 and December 2020. After excluding those whose speech test results were unavailable, and those in whom the implant was removed due to complications, such as infection or device failure, 203 patients were included in this study. The participants were categorized into adult (≥19 years), child (2-18 years), and infant (<24 months) groups. Outcomes were measured based on categories of auditory perception, monosyllable, disyllable, and sentence scores. For the infant group, the Infant-Toddler Meaningful Auditory Integration Scale score was used. RESULTS: Among the 203 participants, a causative genetic variant was identified in 117 (57.6%) individuals. The presence of a causative variant was significantly associated with better CI outcomes in the infant group (ß = 0.23; 95% confidence interval, 0.01 to 0.47; p = 0.044), but not in the child and adult groups. In the genetically confirmed patients without cochlear malformation, genetic variants involving the spiral ganglion was a poor prognostic factor in the child group (ß = -57.24; 95% confidence interval, -90.63 to -23.75; p = 0.004). CONCLUSIONS: The presence of known genetic etiology of hearing loss was associated with better CI outcomes in the infant group, but not in the child and adult groups. A neural-type genetic variant was a poor prognostic factor in the genetically diagnosed child subgroup without cochlear malformation. Careful genetic counseling should be performed before cochlear implantation.
Subject(s)
Cochlear Implantation , Cochlear Implants , Speech Perception , Adult , Infant , Humans , Cochlear Implantation/methods , Retrospective Studies , Treatment Outcome , Genetic TestingABSTRACT
BACKGROUND: Children in the affected area were exposed to large amounts of volatile organic compounds (VOCs) from the Hebei Spirit oil spill accident. OBJECTIVES: We investigated the lung function loss from the exposure to VOCs in a longitudinal panel of 224 children 1, 3, and 5 years after the VOC exposure event. METHODS: Atmospheric estimated concentration of total VOCs (TVOCs), benzene, toluene, ethylbenzene, and xylene for 4 days immediately after the accident were calculated for each village (n = 83) using a modeling technique. Forced expiratory volume in 1 s (FEV1) as an indicator of airway status was measured 1, 3, and 5 years after the exposure in 224 children 4~9 years of age at the exposure to the oil spill. Multiple linear regression and linear mixed models were used to evaluate the associations, with adjustment for smoking and second-hand smoke at home. RESULTS: Among the TVOCs (geometric mean: 1319.5 mg/m3·4 d), xylene (9.4), toluene (8.5), ethylbenzene (5.2), and benzene (2.0) were dominant in the order of air concentration level. In 224 children, percent predicted FEV1 (ppFEV1), adjusted for smoking and second-hand smoke at home, was 100.7% after 1 year, 96.2% after 3 years, and 94.6% after 5 years, and the loss over the period was significant (p < 0.0001). After 1 and 3 years, TVOCs, xylene, toluene, and ethylbenzene were significantly associated with ppFEV1. After 5 years, the associations were not significant. Throughout the 5 years' repeated measurements in the panel, TVOCs, xylene, toluene, and ethylbenzene were significantly associated with ppFEV1. CONCLUSIONS: Exposure to VOCs from the oil spill resulted in lung function loss among children, which remained significant up to 5 years after the exposure.
Subject(s)
Air Pollutants , Petroleum , Tobacco Smoke Pollution , Volatile Organic Compounds , Child , Humans , Volatile Organic Compounds/toxicity , Volatile Organic Compounds/analysis , Benzene/analysis , Benzene Derivatives/toxicity , Benzene Derivatives/analysis , Xylenes/toxicity , Xylenes/analysis , Toluene/toxicity , Toluene/analysis , Lung , Air Pollutants/analysis , Environmental Monitoring/methodsABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and potentially fatal virus. So far, most comprehensive analyses encompassing clinical and transcriptional manifestation have concentrated on the lungs. Here, we confirmed evident signs of viral infection in the lungs and spleen of SARS-CoV-2-infected K18-hACE2 mice, which replicate the phenotype and infection symptoms in hospitalized humans. Seven days post viral detection in organs, infected mice showed decreased vital signs, leading to death. Bronchopneumonia due to infiltration of leukocytes in the lungs and reduction in the spleen lymphocyte region were observed. Transcriptome profiling implicated the meticulous regulation of distress and recovery from cytokine-mediated immunity by distinct immune cell types in a time-dependent manner. In lungs, the chemokine-driven response to viral invasion was highly elevated at 2 days post infection (dpi). In late infection, diseased lungs, post the innate immune process, showed recovery signs. The spleen established an even more immediate line of defense than the lungs, and the cytokine expression profile dropped at 7 dpi. At 5 dpi, spleen samples diverged into two distinct groups with different transcriptome profile and pathophysiology. Inhibition of consecutive host cell viral entry and massive immunoglobulin production and proteolysis inhibition seemed that one group endeavored to survive, while the other group struggled with developmental regeneration against consistent viral intrusion through the replication cycle. Our results may contribute to improved understanding of the longitudinal response to viral infection and development of potential therapeutics for hospitalized patients affected by SARS-CoV-2.
Subject(s)
COVID-19 , Virus Diseases , Animals , Humans , Mice , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Cytokines , Disease Models, Animal , Gene Expression Profiling , Lung , Mice, Transgenic , SARS-CoV-2 , Spleen/metabolism , TranscriptomeSubject(s)
Leukemia, Promyelocytic, Acute , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 17/genetics , Humans , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Oncogene Proteins, Fusion/genetics , Promyelocytic Leukemia Protein , Translocation, GeneticABSTRACT
Following the original severe acute respiratory syndrome coronavirus 2 strain (Wuhan-Hu-1) in December 2019, the Delta variant in May 2021 and the Omicron variant in December 2021 were classified as variants of concern. The pandemic has been ongoing for more than two years, and the three-dose vaccination rate has reached approximately 50% in Korea. We analyzed anti-S antibodies (Abs) and neutralizing Abs (NAbs) in 32 healthcare workers at a university hospital, focusing on the first to third doses of ChAdOx1-ChAdOx1-BNT162b2, which is the most common vaccination regimen in Korea. Antibodies were analyzed at eight time points according to the vaccine regimen. The first to third doses of ChAdOx1-ChAdOx1-BNT162b2 produced high Ab concentrations; NAb concentrations after the third dose were predicted to remain high for a longer period than those after the first and second doses. The effectiveness of a second dose of ChAdOx1 in the real world was demonstrated by analyzing samples collected during an outbreak that occurred in the study period, 4-5 months after the second dose. The relative risk ratio was 88.0%, and the efficacy of the second ChAdOx1 dose was 12.0% (P<0.05). Therefore, maintaining appropriate Ab concentrations through regular vaccination will help protect against coronavirus disease-19.
Subject(s)
BNT162 Vaccine , COVID-19 , COVID-19/prevention & control , Health Personnel , Humans , Longitudinal Studies , Prospective Studies , SARS-CoV-2/genetics , Vaccines, Synthetic , mRNA VaccinesABSTRACT
Autosomal dominant hearing loss (ADHL) manifests as an adult-onset disease or a progressive disease. MYO7A variants are associated with DFNA11, a subtype of ADHL. Here, we examined the role and genotype-phenotype correlation of MYO7A in ADHL. Enrolled families suspected of having post-lingual sensorineural hearing loss were selected for exome sequencing. Mutational alleles in MYO7A were identified according to ACMG guidelines. Segregation analysis was performed to examine whether pathogenic variants segregated with affected status of families. All identified pathogenic variants were evaluated for a phenotype-genotype correlation. MYO7A variants were detected in 4.7% of post-lingual families, and 12 of 14 families were multiplex. Five potentially pathogenic missense variants were identified. Fourteen variants causing autosomal dominant deafness were clustered in motor and MyTH4 domains of MYO7A protein. Missense variants in the motor domain caused late onset of hearing loss with ascending tendency. A severe audiological phenotype was apparent in individuals carrying tail domain variants. We report two new pathogenic variants responsible for DFNA11 in the Korean ADHL population. Dominant pathogenic variants of MYO7A occur frequently in motor and MyTH4 domains. Audiological differences among individuals correspond to specific domains which contain the variants. Therefore, appropriate rehabilitation is needed, particularly for patients with late-onset familial hearing loss.
ABSTRACT
BACKGROUND: Most laboratories adopt the results of metaphase fluorescent in situ hybridization (FISH) for the diagnosis of microdeletion syndromes. To investigate the discrepancy between the results of interphase and metaphase, we compared the quantitative results of FISH for 5 kinds of microdeletion syndrome and gender determination disorders (SDD). METHODS: A total of 282 (135 for DiGeorge syndrome, 20 for Kalmann syndrome, 7 for Miller-Dieker syndrome, 38 for Prader Willi/Angelman syndrome, 62 for Williams syndrome, and 20 for SDD (SRY FISH)) were enrolled. For SRY FISH, we artificially mixed fresh blood of male and female with various ratios and then compared the results of metaphase and interphase SRY FISH. Using a bio-cell chip, we performed interphase FISH in 168 patients with microdeletion syndromes and compared the results with manual interphase. RESULTS: The concordance rate between the results of metaphase and interphase was 100% in microdeletion syndrome. In the disorders of gender development, SRY FISH showed 100% concordance between interphase and metaphase when we counted 50 metaphase cells and 100 interphase cells. Comparison with mixtures of male and female blood at various ratios also showed 100% concordance. The results of bio-cell chip showed 100% concordance between previous interphase FISH results. CONCLUSIONS: Considering the complete concordance between interphase and metaphase in microdeletion syndrome, the application of interphase FISH without performing metaphase FISH can be a screening test for microdeletion syndrome. Confirmation by metaphase FISH can be performed only in cases with abnormal results by interphase FISH.