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Background: Biallelic pathogenic variants in USH2A lead to Usher syndrome or non-syndromic retinitis pigmentosa, and shown to have geographical and ethnical distribution in previous studies. This study provided a deeper understanding of the detailed clinical features using multimodal imaging, genetic spectrum, and genotype–phenotype correlations of USH2A-related retinal dystrophies in Taiwan. Results: In our cohort, the mean age at first visit was 47.66 ± 13.54 years, and the mean age at symptom onset, which was referred to the onset of nyctalopia and/or visual field constriction, was 31.21 ± 15.24 years. Among the variants identified, 23 (50%) were missense, 10 (22%) were splicing variants, 8 (17%) were nonsense, and 5 (11%) were frameshift mutations. The most predominant variant was c.2802T>G, which accounted for 21% of patients, and was located in exon 13. Patients with truncated alleles had significantly earlier symptom onset and seemly poorer disease progression regarding visual acuity, ellipsoid zone line length, and hypofluorescent lesions in the macula than those who had the complete gene. However, the clinical presentation revealed similar progression between patients with and without the c.2802T>G variant. During long-term follow-up, the patients had different ellipsoid zone line progression rates and were almost evenly distributed in the fast, moderate, and slow progression subgroups. Although a younger onset age and a smaller baseline intact macular area was observed in the fast progression subgroup, the results showed no significant difference. Conclusions: This is the first cohort study to provide detailed genetic and longitudinal clinical analyses of patients with USH2A-related retinal dystrophies in Taiwan. The mutated allele frequency in exon 13 was high in Taiwan due to the predominant c.2802T>G variant. Moreover, truncated variants greatly impacted disease progression and determined the length of therapeutic windows. These findings provide insight into the characteristics of candidates for future gene therapies. [ABSTRACT FROM AUTHOR]

Accurate detection of anti-SARS-CoV-2 antibodies provides a more accurate estimation of incident cases, epidemic dynamics, and risk of community transmission. We conducted a cross-sectional seroprevalence study specifically targeting different populations to examine the performance of pandemic control in Taiwan: symptomatic patients with epidemiological risk and negative qRT-PCR test (Group P), frontline healthcare workers (Group H), healthy adult citizens (Group C), and participants with prior virologically-confirmed severe acute respiratory syndrome (SARS) infection in 2003 (Group S). The presence of anti−SARS−CoV−2 total and IgG antibodies in all participants were determined by Roche Elecsys® Anti−SARS−CoV−2 test and Abbott SARS-CoV-2 IgG assay, respectively. Sera that showed positive results by the two chemiluminescent immunoassays were further tested by three anti-SARS-CoV-2 lateral flow immunoassays and line immunoassay (MIKROGEN recom Line SARS-CoV-2 IgG). Between June 29 and July 25, 2020, sera of 2,115 participates, including 499 Group P participants, 464 Group H participants, 1,142 Group C participants, and 10 Group S participants, were tested. After excluding six false-positive samples, SARS-CoV-2 seroprevalence were 0.4, 0, and 0% in Groups P, H, and C, respectively. Cross-reactivity with SARS-CoV-2 antibodies was observed in 80.0% of recovered SARS participants. Our study showed that rigorous exclusion of false-positive testing results is imperative for an accurate estimate of seroprevalence in countries with previous SARS outbreak and low COVID-19 prevalence. The overall SARS-CoV-2 seroprevalence was extremely low among populations of different exposure risk of contracting SARS-CoV-2 in Taiwan, supporting the importance of integrated countermeasures in containing the spread of SARS-CoV-2 before effective COVID-19 vaccines available. [ABSTRACT FROM AUTHOR]

Congenital cytomegalovirus (cCMV) infection is the leading environmental cause of childhood hearing impairment. However, its significance remains largely undocumented in many regions of the world. The purpose of this study was to investigate the prevalence and clinical features of cCMV infection in East Asia. Neonates born at a municipal hospital in Taipei were prospectively recruited and underwent concurrent hearing and CMV screenings. Those who failed the hearing screening or screened positive for CMV were subjected to a focused audiological and/or virological surveillance. The characteristics of the newborns and their mothers were compared between the CMV-positive and CMV-negative groups. Of the 1,532 newborns who underwent concurrent hearing and CMV screenings, seven (0.46%) were positive for cCMV infection. All seven CMV-positive newborns were asymptomatic at birth, and none of them developed hearing or other symptoms during a follow-up period of 14.4±6.3 months. The mothers of the CMV-positive newborns demonstrated higher gravidity (2.4 ± 1.4 vs. 2.1 ± 1.2) and parity (2.0 ± 1.2 vs. 1.6 ± 0.7) than those in the CMV-negative group; however, the difference did not reach statistical significance. The prevalence of cCMV infection in Taipei newborns was 0.46%, which is slightly lower than that of other populations and that of a previous report in the Taiwanese population. The relatively low prevalence in this study might be attributed to the improved public health system and decreased fertility rate in Taiwan. [ABSTRACT FROM AUTHOR]

Accurate epidemiological data on common deafness genes are essential to improve the efficiency and to reduce the cost of molecular diagnosis. They may depend on several factors, including a clear delineation of the source of patients being studied. In the present study, we hypothesize that patients with idiopathic sensorineural hearing loss recruited from different sources might reveal discrepancies in the epidemiological results of genetic screening, because patients from different sources might demonstrate distinct clinical or audiologic features and thus result in biased selection of subjects. To elucidate the relative importance of common deafness genes in Taiwanese and to verify our hypothesis, we conducted a prospective project screening mutations in GJB2, SLC26A4 and mitochondrial 12S rRNA gene in a total of 420 Taiwanese families with idiopathic bilateral sensorineural hearing loss, of which 325 families were recruited from hospitals and 95 from hearing rehabilitation facilities. Allele frequencies of common mutations in these three genes and distributions of the corresponding genotypes were then compared between the two groups. The allele frequencies of mutations in SLC26A4, GJB2 and mitochondrial 12S rRNA in the probands of the 420 families were 14.4, 21.7 and 3.8%, respectively. The allele frequency of SLC26A4 mutations in the hospital group was significantly higher than that in the rehabilitation facility group (16.2 vs. 8.4%, χ2-test, p < 0.05), whereas no difference in the frequencies of GJB2 mutations and mitochondrial 12S rRNA mutations was found between the two groups. Distributions of probands classified by SLC26A4 genotypes were also different between the two groups (χ2-test, p < 0.05). Accordingly, a discrepancy in the genetic screening results might exist between different sources of idiopathic hearing-impaired patients. Further analysis of audiological results and construction of a logistic regression model showed that different audiological features, namely hearing levels and hearing loss patterns, might be responsible for the unequal distributions of mutations and probands between the hospital and rehabilitation facility groups. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Since April 2022, waves of SARS-CoV-2 Omicron variant cases have surfaced in Taiwan and spread throughout the island. Using high-throughput sequencing of the SARS-CoV-2 genome, we analyzed 2,405 PCR-positive swab samples from 2,339 persons and identified the Omicron BA.2.3.7 variant as a major lineage within recent community outbreaks in Taiwan.

Recessive variants in GJB2 are the most common genetic cause of sensorineural hearing impairment. However, in many patients, only one variant in the GJB2 coding region is identified using conventional sequencing strategy (eg, Sanger sequencing), resulting in nonconfirmative diagnosis. Conceivably, there might be other unidentified pathogenic variants in the noncoding region of GJB2 or other deafness-causing genes in these patients. To address this, a next-generation sequencing-based diagnostic panel targeting the entire GJB2 gene and the coding regions of 158 other known deafness-causing genes was designed and applied to 95 patients with nonsyndromic sensorineural hearing impairment (including 81 Han Taiwanese and 14 Mongolian patients) in whom only a single GJB2 variant had been detected using conventional Sanger sequencing. The panel confirmed the genetic diagnosis in 24 patients (25.3%). Twenty-two of them had causative variants in several deafness-causing genes other than GJB2, including MYO15A, MYO7A, TECTA, POU4F3, KCNQ4, SLC26A4, OTOF, MT-RNR1, MITF, WFS1, and USH2A. The other two patients had causative variants in GJB2, including a Taiwanese patient with a mosaic maternal uniparental disomy c.235delC variant (approximately 69% mosaicism) and a Mongolian patient with compound heterozygous c.35dupG and c.35delG variants, which occurred at the same site. This study demonstrates the utility of next-generation sequencing in clarifying the genetic diagnosis of hearing-impaired patients with nonconfirmative GJB2 genotypes on conventional genetic examinations., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Hereditary hearing impairment (HHI) is a common but heterogeneous clinical entity caused by mutations in a plethora of deafness genes. Research over the past few decades has shown that the genetic epidemiology of HHI varies significantly across populations. In this study, we used different genetic examination strategies to address the genetic causes of HHI in a large Taiwanese cohort composed of >5000 hearing-impaired families. We also analyzed the clinical features associated with specific genetic mutations. Our results demonstrated that next-generation sequencing-based examination strategies could achieve genetic diagnosis in approximately half of the families. Common deafness-associated genes in the Taiwanese patients assessed, in the order of prevalence, included GJB2, SLC26A4, OTOF, MYO15A, and MTRNR1, which were similar to those found in other populations. However, the Taiwanese patients had some unique mutations in these genes. These findings may have important clinical implications for refining molecular diagnostics, facilitating genetic counseling, and enabling precision medicine for the management of HHI., Competing Interests: Declare conflicts of interest or state.

Objective: To evaluate the feasibility and potential benefits of incorporating genetic and cytomegalovirus (CMV) screenings into the current newborn hearing screening (NHS) programs., Study Design: Newborns were recruited prospectively from a tertiary hospital and a maternity clinic between May 2016 and December 2016 and were subjected to hearing screening, CMV screening, and genetic screening for 4 common mutations in deafness genes (p.V37I and c.235delC of GJB2 gene, c.919-2A>G of SLC26A4 gene, and the mitochondrial m.1555A>G). Infants with homozygous nuclear mutations or homoplasmic/heteroplasmic mitochondrial mutation (referred to as "conclusively positive genotypes") and those who tested positive for CMV received diagnostic audiologic evaluations., Results: Of the total 1716 newborns enrolled, we identified 20 (1.2%) newborns with conclusively positive genotypes on genetic screening, comprising 15 newborns (0.9%) with GJB2 p.V37I/p.V37I and 5 newborns (0.3%) with m.1555A>G. Three (0.2%) newborns tested positive on CMV screening. Twelve of the 20 newborns (60%) with conclusively positive genotypes and all 3 newborns who tested positive for CMV (100%) passed NHS at birth. Diagnostic audiologic evaluations conducted at 3 months confirmed hearing impairment in 6 of the 20 infants (30%) with conclusively positive genotypes., Conclusions: This study confirms the feasibility of performing hearing, genetic, and CMV screenings concurrently in newborns and provides evidence that the incorporation of these screening tests could potentially identify an additional subgroup of infants with impaired hearing that might not be detected by the NHS programs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Autosomal dominant non-syndromic hearing loss (ADNSHL) is genetically heterogeneous with more than 35 genes identified to date. Using a massively parallel sequencing panel targeting 159 deafness genes, we identified a novel missense variant of POU4F3 (c.982A>G, p.Lys328Glu) which co-segregated with the deafness phenotype in a three-generation Taiwanese family with ADNSHL. This variant could be classified as a "pathogenic variant" according to the American College of Medical Genetics and Genomics guidelines. We then performed subcellular localization experiments and confirmed that p.Lys328Glu compromised transportation of POU4F3 from the cytoplasm to the nucleus. POU3F4 p.Lys328Glu was located within a bipartite nuclear localization signal (NLS), and was the first missense variant in bipartite NLS of POU4F3 validated in functional studies. These findings expanded the mutation spectrum of POU4F3 and provided insight into the pathogenesis associated with aberrant POU4F3 localization.

Recent studies have confirmed the utility of massively parallel sequencing (MPS) in addressing genetically heterogeneous hereditary hearing impairment. By applying a MPS diagnostic panel targeting 129 known deafness genes, we identified a novel frameshift GATA3 mutation, c.149delT (p.Phe51LeufsX144), in a hearing-impaired family compatible with autosomal dominant inheritance. The GATA3 haploinsufficiency is thought to be associated with the hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome. The pathogenicity of GATA3 c.149delT was supported by its absence in the 5400 NHLBI exomes, 1000 Genomes, and the 100 normal hearing controls of the present study; the co-segregation of c.149delT heterozygosity with hearing impairment in 9 affected members of the family; as well as the nonsense-mediated mRNA decay of the mutant allele in in vitro functional studies. The phenotypes in this family appeared relatively mild, as most affected members presented no signs of hypoparathyroidism or renal abnormalities, including the proband. To our knowledge, this is the first report of genetic diagnosis of HDR syndrome before the clinical diagnosis. Genetic examination for multiple deafness genes with MPS might be helpful in identifying certain types of syndromic hearing loss such as HDR syndrome, contributing to earlier diagnosis and treatment of the affected individuals., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives/hypothesis: To explore the genetic characteristics of branchio-oto-renal (BOR) syndrome in an East Asian population., Study Design: Prospective clinical genetic study., Methods: Twelve families (total of 18 patients) who fulfilled the criteria for BOR syndrome were enrolled in this study. Mutation screening of the EYA1, SIX1, and SIX5 genes was performed by direct sequencing and quantitative polymerase chain reaction, and genotype-phenotype correlation was investigated., Results: Two novel EYA1 variants, c.466C>T (p.Q156X) and c.1735delG (p.D579fs), were identified in two multiplex families. The c.466C>T variant resulted in a truncated EYA1 protein, whereas the c.1735delG variant was predicted to encode an EYA1 protein with an abnormal C terminal. Neither variant was identified in a panel of 100 normal controls, and both were cosegregated with the BOR phenotype in the pedigrees, indicating that they were pathogenic mutations. No SIX1 and SIX5 mutations were detected in members of the remaining 10 families. Analysis of the genotype-phenotype correlation revealed a high phenotypic variability between and within BOR families., Conclusions: Two novel EYA1 mutations (c.466C>T and c.1735delG) were identified in two families with BOR syndrome. SIX1 and SIX5 mutations were not detected in the present study. Further investigation is warranted regarding the contribution of SIX1 and SIX5 mutations to BOR syndrome in East Asian populations., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Head and neck paragangliomas (HNPGLs) are rare, and frequently associated with germline mutations of the succinate dehydrogenase (SDH) genes, especially for familial cases. The purpose of the study is to explore SDH mutations in Chinese families with familial HNPGLs in Taiwan. Four unrelated families with familial HNPGLs were screened for germline mutations in the SDHB, SDHC and SDHD genes by direct sequencing. One hundred healthy subjects without a diagnosis or family history of HNPGLs were screened as normal controls. Immunohistochemistry with SDHB antibody was performed for a carotid body tumor. Two allele variants were identified, including p.Met1Val (c.1A>G) in the SDHD gene in one family and p.Met1Ile (c.3G>C) in the SDHD gene in the other three families. Both variants are considered pathogenic because of the absence of these variants in 100 normal controls, 100% evolutionary conservation of the p.Met1 residue, co-segregation of the variants with the phenotype of HNPGL in pedigrees, and predicted abolishment of the translation start site. The tumor cells obtained from one proband harboring c.3G>C mis-sense mutation were weak diffuse staining in the cytoplasm of tumors cells. This study demonstrates that two mis-sense mutations at the start codon of the SDHD gene, including p.Met1Val (c.1A>G) and p.Met1Ile (c.3G>C), might be mutation hotspots in Chinese patients with familial HNPGLs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Mutations in the OTOF gene have been found to be common causes of auditory neuropathy (AN) in Caucasians. However, the prevalence and spectrum of OTOF mutations in other populations have been inadequately documented. To explore the genetic characteristics of East Asian patients with AN, we screened for mutations in the OTOF gene by direct sequencing in 22 unrelated Taiwanese AN families (including 2 multiplex and 20 simplex families) and looked for genotype-phenotype correlations. Among the probands of the 22 AN families, a novel OTOF variant, p.E1700Q (c.5098G→C), was identified in 5 probands (23%), including 4 homozygotes and 1 heterozygote. By using restriction fragment length polymorphism to screen another 500 unrelated patients with idiopathic sensorineural hearing impairment, we further identified 1 p.E1700Q homozygote who also had clinical features compatible with AN. Furthermore, p.E1700Q was not identified in a panel of 100 normal controls, it cosegregated with the AN phenotype in the pedigrees, and the p.E1700 residue is evolutionarily conserved, consistent with its pathogenicity for AN. The associated audiologic features included progressive, prelingual, bilateral moderate-to-profound sensorineural hearing loss with a flat-type audiogram configuration. After genotyping single-nucleotide polymorphisms in the vicinity of p.E1700Q, we found that OTOF alleles with p.E1700Q shared a common haplotype, suggesting a founder effect for p.E1700Q. The predominance of the p.E1700Q mutation and the evidence of its founder effect indicate a distinct OTOF mutation spectrum in Taiwanese patients with AN., (Copyright © 2010 S. Karger AG, Basel.)

Objectives/hypothesis: To develop a cost-effective and robust genetic diagnostic tool for patients with idiopathic nonsyndromic sensorineural hearing impairment., Study Design: Development of a diagnostic tool and validation in a prospective cohort., Methods: Twenty common sequence variants in GJB2, SLC26A4, and the mitochondrial 12S rRNA gene were selected based on our previous epidemiological study. These variants were analyzed using the SNaPshot technique. The efficacies of the SNaPshot multiplex assays were determined by using a prospective cohort composed of 214 unrelated Taiwanese patients with idiopathic sensorineural hearing impairment. The results of the assays were compared to the results obtained by direct sequencing., Results: We developed a diagnostic technique consisting of two consecutive panels of SNaPshot multiplex assays, with each panel screening 10 common sequence variants. Theoretically, this design can detect more than 98% of the known deafness-associated sequence variants in Taiwanese individuals. A total of 126 (58.9%) patients were diagnosed as having at least one sequence variant using the SNaPshot multiplex assays. In total, the SNaPshot assays yielded an accuracy of more than 99%., Conclusions: The strengths of SNaPshot multiplex assays include high accuracy, high sensitivity, high flexibility (the examination panel can be easily expanded for additional mutations), low cost (less than US $10 per patient), and easy implementation for any institute with a DNA sequencer. Although only 20 to 30 mutations can be examined in two to three runs of the SNaPshot assay, this technology may be suitable for first-pass screening of deafness-associated mutations in populations with a relatively homogeneous ethnic background.

To investigate the effect of central obesity on the severity and characteristics of age-related hearing impairment (ARHI), we recruited 690 adult subjects with normal or symmetrical sensorineural hearing loss (SNHL). The effects of age, gender, morphometry, habits, systemic diseases, and environmental noise exposure on average pure tone hearing level at low frequencies (pure tone audiometry (PTA)-low) and high frequencies (PTA-high) were analyzed. After adjusting for age, gender, systemic disease, and other variables, waist circumference (WC) showed a significant positive association with PTA-low and PTA-high. In females, PTA-low and PTA-high only showed significant positive association with age, but not with WC or other variables. However, PTA-high showed a positive association with borderline significance with WC in female subjects older than 55. In males, WC as well as age and noise exposure showed significant positive associations with both PTA-low and PTA-high, primarily in subjects younger than 55. When both WC and BMI were taken into account in a backward stepwise multivariate linear regression analysis, WC, but not BMI, showed a significant positive association with PTA-low and PTA-high in males younger than 55, and with PTA-high with borderline significance in females older than 55. However, the audiogram patterns were not significantly affected by central obesity in either age or gender. Our results suggest that WC was, even after adjustment for BMI, an independent risk factor of ARHI, particularly for low and high frequencies in males younger than 55 and for high frequencies in female subjects older than 55.

Objective: The m.1555A>G mutation in the mitochondria 12S rRNA gene has been reported to be an important cause of nonsyndromic hereditary hearing loss. However, remarkable interfamilial and intrafamilial variations in the phenotypes of the mutation preclude precise prognosis during genetic counseling. Hence, this study was performed to explore the factors that might contribute to the differences in the phenotypes, including aminoglycoside exposure, mutation load and mitochondrial DNA (mtDNA) background. Also reported were the prevalence and the clinical features of the m.1555A>G mutation in the hearing-impaired Taiwanese patients., Design: Mutations in the 12S rRNA gene were screened in a panel of 315 unrelated Taiwanese families with idiopathic sensorineural hearing loss. The clinical features in families with m.1555A>G mutation were analyzed, and the roles of aminoglycoside exposure, mutation load and mtDNA background in disease expression were investigated. Penetrance was then compared among families with different mtDNA backgrounds., Results: The m.1555A>G mutation was identified in a total of 10 (3.2%) families, and was characterized clinically by progressive, postlingual and bilaterally symmetric sensorineural hearing loss and normal temporal bone radiological results. The m.1555A>G mutation was homoplasmic (i.e., all the mitochondrial DNA carries the mutation) in all the matrilineal relatives in these 10 pedigrees. Among the 44 hearing-impaired relatives of the 10 pedigrees, only two recalled definite episodes of aminoglycoside-induced hearing loss. mtDNA backgrounds in these 10 families could be categorized into 6 main haplogroups (A, B, D, F, M7, N*), including three families belonging to haplogroup F, two belonging to haplogroup A, two belonging to haplogroup M7, and three belonging to haplogroups B, N* and D, respectively. Penetrance differed among various haplogroups, and certain haplogroups appeared to be associated with a lower penetrance, like the three haplogroup F families, in which the penetrance ranged from 13 to 33%. Further analysis confirmed a heterogeneous distribution of hearing-impaired subjects among various haplogroups (Chi-square test, p = 0.018)., Conclusions: The mitochondrial m.1555A>G mutation accounted for 3.2% of the Taiwanese families (0% of the simplex families and 11% of multiplex families respectively) with sensorineural hearing impairment of unknown etiology. Since it was identified in a variety of mtDNA backgrounds, the mutation appeared to arise from multiple origins in Taiwanese. As subjects with various haplogroups demonstrated different penetrance, mtDNA background might exert effects on the disease expression of the m.1555A>G mutation.