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1.
Am J Hum Genet ; 103(5): 679-690, 2018 11 01.
Article in English | MEDLINE | ID: mdl-30401457

ABSTRACT

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154∗) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10-7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154∗, and p.Arg202∗-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.


Subject(s)
Fucosyltransferases/genetics , Genetic Variation/genetics , Otitis Media/genetics , Animals , COS Cells , Cell Line , Chlorocebus aethiops , Ear, Middle/microbiology , Exome/genetics , Female , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Microbiota/physiology , Otitis Media/microbiology , Pedigree , Galactoside 2-alpha-L-fucosyltransferase
2.
Hum Mutat ; 40(8): 1156-1171, 2019 08.
Article in English | MEDLINE | ID: mdl-31009165

ABSTRACT

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.


Subject(s)
Down-Regulation , Gene Expression Profiling/methods , Mutation , Otitis Media/genetics , Sequence Analysis, DNA/methods , alpha-Macroglobulins/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Finland , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Infant , Male , Middle Aged , Pakistan , Pedigree , Philippines , Sequence Analysis, RNA , Signal Transduction , United States , Young Adult
3.
Genet Test Mol Biomarkers ; 27(1): 12-17, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36719978

ABSTRACT

Background: Many indigenous peoples are at elevated risk for otitis media, however there is limited information on hearing loss due to OM in these communities. An Indigenous Filipino community that has previously been described with an elevated prevalence of OM that is due to rare A2ML1 variants and a common FUT2 variant underwent additional phenological testing. In this study, we describe the audiologic profiles in A2ML1- and FUT2-related otitis media and the validity of otoscopy and genotyping for A2ML1 and FUT2 variants in screening for otitis media and hearing loss. Method: We analyzed A2ML1 and FUT2 genotypes together with demographic, otologic and audiologic data from tympanometry and hearing level assessments of 109 indigenous individuals. Results: We confirmed previous findings of a spectrum of nonsyndromic otitis media as associated with A2ML1 variants. A2ML1 and FUT2 variants were associated with high-frequency hearing loss at 4000 Hz. As expected, young age was associated with flat tympanograms, and eardrum perforations due to chronic otitis media were associated with severe-to-profound hearing loss across frequencies. Adding A2ML1 or FUT2 genotypes improved the validity of otoscopy as a screening test to rule out moderate-to-profound hearing loss. Conclusion: Continued multi-disciplinary management and audiologic follow-up using tympanometry and screening audiometry are needed to document and treat otitis media and prevent permanent hearing loss in the indigenous community.


Subject(s)
Deafness , Hearing Loss , Otitis Media , Humans , alpha-Macroglobulins/genetics , Genotype , Hearing Loss/genetics , Hearing Loss/diagnosis , Otitis Media/genetics , Otoscopy , Galactoside 2-alpha-L-fucosyltransferase
4.
Acta Med Philipp ; 57(9): 116-120, 2023 Sep 28.
Article in English | MEDLINE | ID: mdl-37990697

ABSTRACT

Objective: Recent advances in epigenetic studies continue to reveal novel mechanisms of gene regulation and control, however little is known on the role of epigenetics in sensorineural hearing loss (SNHL) in humans. We aimed to investigate the methylation patterns of two regions, one in RB1 and another in GJB2 in Filipino patients with SNHL compared to hearing control individuals. Methods: We investigated an RB1 promoter region that was previously identified as differentially methylated in children with SNHL and lead exposure. Additionally, we investigated a sequence in an enhancer-like region within GJB2 that contains four CpGs in close proximity. Bisulfite conversion was performed on salivary DNA samples from 15 children with SNHL and 45 unrelated ethnically-matched individuals. We then performed methylation-specific real-time PCR analysis (qMSP) using TaqMan® probes to determine percentage methylation of the two regions. Results: Using qMSP, both our cases and controls had zero methylation at the targeted GJB2 and RB1 regions. Conclusion: Our study showed no changes in methylation at the selected CpG regions in RB1 and GJB2 in the two comparison groups with or without SNHL. This may be due to a lack of environmental exposures to these target regions. Other epigenetic marks may be present around these regions as well as those of other HL-associated genes.

5.
Genes (Basel) ; 12(4)2021 04 13.
Article in English | MEDLINE | ID: mdl-33924653

ABSTRACT

Background: Hearing loss remains an important global health problem that is potentially addressed through early identification of a genetic etiology, which helps to predict outcomes of hearing rehabilitation such as cochlear implantation and also to mitigate the long-term effects of comorbidities. The identification of variants for hearing loss and detailed descriptions of clinical phenotypes in patients from various populations are needed to improve the utility of clinical genetic screening for hearing loss. Methods: Clinical and exome data from 15 children with hearing loss were reviewed. Standard tools for annotating variants were used and rare, putatively deleterious variants were selected from the exome data. Results: In 15 children, 21 rare damaging variants in 17 genes were identified, including: 14 known hearing loss or neurodevelopmental genes, 11 of which had novel variants; and three candidate genes IST1, CBLN3 and GDPD5, two of which were identified in children with both hearing loss and enlarged vestibular aqueducts. Patients with variants within IST1 and MYO18B had poorer outcomes after cochlear implantation. Conclusion: Our findings highlight the importance of identifying novel variants and genes in ethnic groups that are understudied for hearing loss.


Subject(s)
Gene Regulatory Networks , Genetic Variation , Hearing Loss/genetics , Hearing Loss/surgery , Temporal Bone/abnormalities , Child , Child, Preschool , Cochlear Implantation , Female , Genetic Predisposition to Disease , Humans , Male , Myosins/genetics , Nerve Tissue Proteins/genetics , Oncogene Proteins/genetics , Phenotype , Phosphoric Diester Hydrolases/genetics , Tumor Suppressor Proteins/genetics
6.
Int J Pediatr Otorhinolaryngol ; 128: 109704, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31606683

ABSTRACT

OBJECTIVE: This study compared otoacoustic emission (OAE) and automated auditory brainstem response (AABR) in terms of concordance and cost impact for newborn hearing screening (NBHS) in the Philippine setting. METHODS: This was a prospective observational study to assess concordance between OAE and AABR involving 253 infants. Each infant underwent OAE and AABR testing. Infants who passed both tests were not required to follow up for additional testing. Infants who failed in any test were scheduled for repeat screening and diagnostic ABR after 1 month. Concordance was computed using B-statistic. FOR COST ANALYSIS: 4 scenarios were compared to 1-step both tests scenario: (1) OAE alone, (2) AABR alone, (3) 2-step OAE, and (4) 2-step AABR in terms of number of infants with hearing loss (HL) detected, cost of diagnosis, and economic loss from lack of treatment. RESULTS: There was high concordance between OAE and AABR (B-statistic = 0.8). AABR had a higher refer rate (18.58%) than OAE (10.27%) but higher number of detected babies with HL. Cost analysis favored an AABR alone scenario while the 2-step OAE protocol fared poorly. CONCLUSION: A change from 2-step OAE to AABR alone is worth considering in our institution.


Subject(s)
Evoked Potentials, Auditory, Brain Stem , Neonatal Screening/economics , Neonatal Screening/methods , Otoacoustic Emissions, Spontaneous , Algorithms , Costs and Cost Analysis , Female , Hearing Loss/diagnosis , Humans , Infant, Newborn , Male , Philippines , Prospective Studies , Tertiary Care Centers
7.
Article in English | MEDLINE | ID: mdl-17539266

ABSTRACT

The objectives of this study were to determine the agreement between the ear examination findings of the otorhinolaryngologist (trainer) and the elementary school nurse (trainee) after training with the use of a penlight and to determine the mean sound pressure level (SPL) produced by school nurses as a standard parameter for hearing screening using a 512 tuning fork after training on tuning fork testing by the otorhinolaryngologist. Training workshops in ear examination using a penlight and hearing screening using a 512 tuning fork were conducted for school nurses. Data for assessment of ear examination skills and production of SPL were collected by questionnaire and observation of performance. Kappa statistics were used to assess agreement between trainees' and trainer's responses. Mean and standard deviation were determined for the assessment of the SPL produced. Results showed an excellent agreement between the school nurses' and otorhinolaryngologist's observations on ear examination. These included observations of the ear canal, visualization of the tympanic membrane and identification of unusual findings such as wax and discharge. The majority of nurses responded positively in terms of the ease and confidence in performance of the procedure. Regarding tuning fork testing, the nurses were able to produce significant SPL. The mean SPL produced by the nurses using a 512 tuning fork was 56.316 dB.


Subject(s)
Education , Hearing Loss/diagnosis , Hearing Tests/methods , Mass Screening/methods , Otolaryngology/education , School Nursing/education , Clinical Competence , Data Collection , Humans , Philippines
8.
Infect Dis Poverty ; 5(1): 97, 2016 Nov 01.
Article in English | MEDLINE | ID: mdl-27799062

ABSTRACT

BACKGROUND: Previously rare A2ML1 variants were identified to confer otitis media susceptibility in an indigenous Filipino community and in otitis-prone US children. The goal of this study is to describe differences in the middle ear microbiome between carriers and non-carriers of an A2ML1 duplication variant that increases risk for chronic otitis media among indigenous Filipinos with poor health care access. METHODS: Ear swabs were obtained from 16 indigenous Filipino individuals with chronic otitis media, of whom 11 carry the A2ML1 duplication variant. Ear swabs were submitted for 16S rRNA gene sequencing. RESULTS: Genotype-based differences in microbial richness, structure, and composition were identified, but were not statistically significant. Taxonomic analysis revealed that the relative abundance of the phyla Fusobacteria and Bacteroidetes, and genus Fusobacterium were nominally increased in carriers compared to non-carriers, but were non-significant after correction for multiple testing. We also detected rare bacteria including Oligella that was reported only once in the middle ear. CONCLUSIONS: These findings suggest that A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome. Knowledge of middle ear microbial profiles according to genetic background can be potentially useful for therapeutic and prophylactic interventions for otitis media and can guide public health interventions towards decreasing otitis media prevalence within the indigenous Filipino community.


Subject(s)
DNA, Bacterial/genetics , Ear, Middle/microbiology , Genes, Duplicate/genetics , Microbiota , Otitis Media/genetics , RNA, Ribosomal, 16S/genetics , alpha-Macroglobulins/genetics , Adolescent , Child , Child, Preschool , Female , Humans , Male , Otitis Media/microbiology , Philippines , Population Groups , Sequence Analysis, DNA , Young Adult , alpha-Macroglobulins/metabolism
9.
Otolaryngol Head Neck Surg ; 155(5): 856-862, 2016 11.
Article in English | MEDLINE | ID: mdl-27484237

ABSTRACT

OBJECTIVE: To identify genetic and environmental risk factors for otitis media in an indigenous Filipino population. STUDY DESIGN: Cross-sectional study. SETTING: Indigenous Filipino community. SUBJECTS AND METHODS: Clinical history and information on breastfeeding, tobacco smoke exposure, and swimming were obtained from community members. Heads of households were interviewed for family history and personal beliefs on ear health. Height and weight were measured. Otoscopic findings were described for the presence and character of perforation or discharge. An A2ML1 duplication variant that confers otitis media susceptibility was Sanger sequenced in all DNA samples. Co-occurrence of middle ear bacteria detected by 16S rRNA gene sequencing was determined according to A2ML1 genotype and social cluster. RESULTS: The indigenous Filipino population has a ~50% prevalence of otitis media. Young age was associated with otitis media (4 age strata; P = .004); however, age was nonsignificant as a bistratal or continuous variable. There was no association between otitis media and sex, body mass index, breastfeeding, tobacco exposure, or deep swimming. In multivariate analyses, A2ML1 genotype is the strongest predictor of otitis media, with an odds ratio of 3.7 (95% confidence interval: 1.3-10.8; P = .005). When otitis media diagnoses were plotted across ages, otitis media was observed within the first year of life, and chronic otitis media persisted up to adulthood, particularly in A2ML1-variant carriers. CONCLUSION: Among indigenous Filipinos, A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype.


Subject(s)
Environmental Exposure/adverse effects , Otitis Media/epidemiology , Otitis Media/genetics , alpha-Macroglobulins/genetics , Adolescent , Adult , Child , Child, Preschool , Cross-Sectional Studies , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Microbiota , Otitis Media/microbiology , Otoscopy , Philippines/epidemiology , Prevalence , Risk Factors
11.
Nat Genet ; 47(8): 917-20, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26121085

ABSTRACT

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.


Subject(s)
Gene Duplication , Genetic Predisposition to Disease/genetics , Otitis Media/genetics , alpha-Macroglobulins/genetics , Animals , Base Sequence , Child , Cochlea/metabolism , Cochlea/pathology , Exome/genetics , Family Health , Female , Gene Frequency , Genotype , Haplotypes , Humans , Male , Mice, Inbred C57BL , Models, Molecular , Otitis Media/pathology , Pedigree , Principal Component Analysis , Protein Conformation , Sequence Analysis, DNA , alpha-Macroglobulins/chemistry
12.
Acta Medica Philippina ; : 11-17, 2012.
Article in English | WPRIM | ID: wpr-633775

ABSTRACT

OBJECTIVES: To determine the effect of age, ex and body index on selected static tests of balance and to generate referance normtive data among the different population groups. METHODS: In this cross-sectional study, 100 asymptomatic normal adult Filipino volunteers, aged 20 to 69 years were tasked to perform selected static balance tests. These tests included classic Romberg (CR), Romberg with Jendrassik (RJ) maneuver, tandem Romberg (TR), standing on foam with feet apart (SOFFA), standing on foam with feet together (SOFFT) and standing on one leg (SOL). All tests were done with eyes opened (EO) followed by eyes closed (EC) for 30 seconds each. Volunteers were grouped into age groups by decades, normative values were obtained and effects of age, sex and body mass index, if any, on performance of the various tests were determined. RESULTS: All volunteers were able to do the CR and RJ maneuver for 30 seconds. All were able to perform for 30 seconds the TREO, SOFFA EO and SOFFT EO procedures. Some volunteers were unable to complete the TREC, SOFFA EC, SOFFT EC, SOL EO and SOL EC procedures. The mean performance duration values for TREC, SOFFA EC, SOFFT EC, SOL EO AND SOL EC were significantly negatively correlated with age. Although majority of tests were negatively correlated with body mass index, the correlations were not statistically significant. CONCLUSION: Age significantly affects selected static balance performance whereas sex and body mass index do not significantly affect selected static balance performance. The normative values generated in this study are inconclusive because of inadequate sample size, particularly in the older age group. The results, however, showed the potential value of the 5th percentile as a normative norm in systematically assessing the involvement of the vesticular, visual and proprioceptive organs i balance function.


Subject(s)
Humans , Male , Female , Aged , Middle Aged , Adult , Young Adult , Sample Size , Body Mass Index , Posture , Foot , Volunteers
13.
Article in English | WPRIM | ID: wpr-632697

ABSTRACT

@#<p style="text-align: justify;"><strong>OBJECTIVES:</strong> To  report  a  case  of  congenital  oval  window  aplasia  (COWA)  in  a  Filipino  adult presenting   with      unilateral   maximal   conductive   hearing   loss   and   discuss   the   diagnostic considerations, pathophysiology and management.<br /><strong>METHODS:</strong><br /><strong>Design:</strong> Case Report<br /><strong>Setting:</strong> Tertiary Public Referral Center<br /><strong>Patient:</strong> One <br /><strong>RESULTS:</strong> Audiometric evaluation showed a maximal unilateral left conductive hearing loss. High resolution temporal bone CT showed absence of the oval window on the left along with facial and stapes  abnormalities.    Exploratory  tympanotomy  showed  an  aberrant  facial  nerve,  monopodal and  abnormally  located  stapes  and  absent  oval  window. Postoperative  hearing  gain  achieved after a neo-oval window and Schuknecht piston wire prosthesis remained stable over two years.<br /><strong>CONCLUSION:</strong> A congenital minor ear anomaly classified as Cremers Class 4a in which a congenital oval  window  aplasia  was  associated  with  an  aberrant  facial  nerve  anomaly  and  a  monopodal stapes is reported. Recent literature supported the view that congenital oval window aplasia can in selected cases be amenable to various surgical approaches and a stable postoperative hearing gain is achievable in the long term.</p>


Subject(s)
Humans , Male , Female , Adult , Ear, Middle , Hearing
14.
Acta Medica Philippina ; : 39-45, 2010.
Article in English | WPRIM | ID: wpr-632917

ABSTRACT

OBJECTIVES:To determine the agreement between 1) ear examination findings of the otorhinolaryngologist using an otoscope and trained elementary school nurses using a penlight, 2) hearing screening findings of the otorhinolaryngologist and elementary school nurses, both using the Philippine National Ear Institute (PNEI) Method of 512 Hz Tuning Fork Test (TFT) and 3) PNEI Method of 512 Hz TFT findings and screening audiometry findings.METHODS:In this continuing study, nurses residing in the venue of the study, and previously trained in ear examination using a penlight and hearing screening using the PNEI 512 Hz TFT, conducted these in school children who attended the hearing screening and medical mission. Otoscopy, PNEI Method of 512 Hz TFT, and screening audiometry were then conducted on the children by the otolaryngologist. The nurses and the otolaryngologist performed independent and blinded assessments.RESULTS:Eighteen nurses and ninety children participated in the study. Data subjected to Kappa statistics showed good agreement between nurses and otorhinolaryngologist's findings in the examination of the external canal and tympanic membrane and in PNEI Method of 512 Hz TFTs, and between the PNEI Method of 512 Hz TFT and screening audiometry.CONCLUSION:PNEI methods of penlight ear examination and 512 Hz TFT may be effective tools for early detection of common ear conditions and hearing screening in Filipino school children. These may be conducted in the school setting not only by otorhinolaryngologists but also by adequately trained school nurses.


Subject(s)
Humans , Male , Female , Middle Aged , Adult , Young Adult , Adolescent , Child , Child , Humans , Diagnosis , Nurses , Hearing , Audiometry , Ear Diseases , Early Diagnosis , Otolaryngologists , Otoscopes , Otoscopy , Philippines , Religious Missions , Schools , Tympanic Membrane , Hearing Tests
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