RESUMO
Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.
Assuntos
Surdez , Mutação de Sentido Incorreto , Linhagem , Receptores de Superfície Celular , Estereocílios , Animais , Feminino , Humanos , Masculino , Surdez/genética , Sequenciamento do Exoma , Genes Recessivos , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Modelos Moleculares , Receptores de Superfície Celular/genética , Estereocílios/metabolismo , Estereocílios/patologia , Estereocílios/genéticaRESUMO
In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. In 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription factors TBX2 and MEF2C, respectively. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of seven individuals with likely developmental etiologies due to lncRNA disruptions.
Assuntos
Fatores de Transcrição MEF2 , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Fatores de Transcrição MEF2/genética , Feminino , Aberrações Cromossômicas , Masculino , Genoma Humano , Fenótipo , Mutação em Linhagem GerminativaRESUMO
Synonymous variants have been shown to alter the correct splicing of pre-mRNAs and generate disease-causing transcripts. These variants are not an uncommon etiology of genetic disease; however, they are frequently overlooked during genetic testing in the absence of functional and clinical data. Here, we describe the occurrence of a synonymous variant [NM_005422.4 (TECTA):c.327C>T, p.(Gly109=)] in seven individuals with hearing loss from six unrelated families. The variant is not located near exonic/intronic boundaries but is predicted to impact splicing by activating a cryptic splicing donor site in exon 4 of TECTA. In vitro minigene assays show that the variant disrupts the reading frame of the canonical transcript, which is predicted to cause a premature termination codon 48 amino acids downstream of the variant, leading to nonsense-mediated decay. The variant is present in population databases, predominantly in Latinos of African ancestry, but is rare in other ethnic groups. Our findings suggest that this synonymous variant is likely pathogenic for TECTA-associated autosomal recessive hearing loss and seems to have arisen as a founder variant in this specific Latino subpopulation. This study demonstrates that synonymous variants need careful splicing assessment and support from additional testing methodologies to determine their clinical impact.
Assuntos
Surdez , Perda Auditiva , Humanos , Sítios de Splice de RNA , Splicing de RNA/genética , Perda Auditiva/genética , Surdez/genética , Éxons/genética , Proteínas da Matriz Extracelular/genética , Proteínas Ligadas por GPI/genéticaRESUMO
Since the discovery of the first human deafness gene a quarter of a century ago, our approach to clinical evaluation of children with hearing loss has changed dramatically. What was once a low-yield scattershot approach has changed to a clearly definable pathway involving genetic testing, imaging, and congenital cytomegalovirus testing. There still however is a great deal of work to be done to expand the correct use of this testing, particularly genetic testing.
Assuntos
Infecções por Citomegalovirus , Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Criança , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/genética , Surdez/diagnóstico , Surdez/genética , Testes Genéticos , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Perda Auditiva Neurossensorial/genética , HumanosRESUMO
Structural variation includes a change in copy number, orientation, or location of a part of the genome. Copy number variants (CNVs) are a common cause of genetic hearing loss, comprising nearly 20% of diagnosed cases. While large deletions involving the gene STRC are the most common pathogenic CNVs, a significant proportion of known hearing loss genes also contain pathogenic CNVs. In this review, we provide an overview of currently used methods for detection of CNVs in genes known to cause hearing loss including molecular techniques such as multiplex ligation probe amplification (MLPA) and digital droplet polymerase chain reaction (ddPCR), array-CGH and single-nucleotide polymorphism (SNP) arrays, as well as techniques for detection of CNVs using next-generation sequencing data analysis including targeted gene panel, exome, and genome sequencing data. In addition, in this review, we compile published data on pathogenic hearing loss CNVs to provide an up-to-date overview. We show that CNVs have been identified in 29 different non-syndromic hearing loss genes. An understanding of the contribution of CNVs to genetic hearing loss is critical to the current diagnosis of hearing loss and is crucial for future gene therapies. Thus, evaluation for CNVs is required in any modern pipeline for genetic diagnosis of hearing loss.
Assuntos
Surdez , Perda Auditiva , Variações do Número de Cópias de DNA , Surdez/genética , Exoma , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genéticaRESUMO
PURPOSE: The ClinGen Variant Curation Expert Panels (VCEPs) provide disease-specific rules for accurate variant interpretation. Using the hearing loss-specific American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, the Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in variant interpretation. METHODS: A total of 157 variants across nine HL genes, previously submitted to ClinVar, were curated by the HL VCEP. The curation process involved collecting published and unpublished data for each variant by biocurators, followed by bimonthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific ACMG/AMP guidelines to reach a final classification. RESULTS: Before expert curation, 75% (117/157) of variants had single or multiple variants of uncertain significance (VUS) submissions (17/157) or had conflicting interpretations in ClinVar (100/157). After applying the HL-specific ACMG/AMP guidelines, 24% (4/17) of VUS and 69% (69/100) of discordant variants were resolved into benign (B), likely benign (LB), likely pathogenic (LP), or pathogenic (P). Overall, 70% (109/157) variants had unambiguous classifications (B, LB, LP, P). We quantify the contribution of the HL-specified ACMG/AMP codes to variant classification. CONCLUSION: Expert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study highlights the utility of ClinGen VCEPs in supporting more consistent clinical variant interpretation.
Assuntos
Genoma Humano , Perda Auditiva , Humanos , Testes Genéticos , Variação Genética/genética , Perda Auditiva/diagnóstico , Perda Auditiva/genéticaRESUMO
PURPOSE: Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo. METHODS: Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish. RESULTS: We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1-/- knockouts. CONCLUSION: Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.
Assuntos
Perda Auditiva , Lisina-tRNA Ligase/genética , Transtornos do Neurodesenvolvimento , Alelos , Animais , Modelos Animais de Doenças , Perda Auditiva/genética , Humanos , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Peixe-Zebra/genéticaRESUMO
Recognition of distinct phenotypic features is an important component of genetic diagnosis. Although CHARGE syndrome, Kabuki syndrome, and a recently delineated KMT2D Ex 38/39 allelic disorder exhibit significant overlap, differences on neuroimaging may help distinguish these conditions and guide genetic testing and variant interpretation. We present an infant clinically diagnosed with CHARGE syndrome but subsequently found to have a de novo missense variant in exon 38 of KMT2D, the gene implicated in both Kabuki syndrome and a distinct KMT2D allelic disorder. We compare her brain and inner ear morphology to a retrospective cohort of 21 patients with classic Kabuki syndrome and to typical CHARGE syndrome findings described in the literature. Thirteen of the 21 Kabuki syndrome patients had temporal bone imaging (5/13 CT, 12/13 MRI) and/or brain MRI (12/13) which revealed findings distinct from both CHARGE syndrome and the KMT2D allelic disorder. Our findings further elucidate the spectrum of inner ear dysmorphology distinguishing Kabuki syndrome and the KMT2D allelic disorder from CHARGE syndrome, suggesting that these three disorders may be differentiated at least in part by their inner ear anomalies.
Assuntos
Anormalidades Múltiplas/genética , Síndrome CHARGE/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Predisposição Genética para Doença , Doenças Hematológicas/genética , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Síndrome CHARGE/diagnóstico por imagem , Síndrome CHARGE/patologia , DNA Helicases/genética , Face/diagnóstico por imagem , Face/patologia , Feminino , Doenças Hematológicas/diagnóstico por imagem , Doenças Hematológicas/patologia , Histona Desmetilases/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação/genética , Neuroimagem , Fenótipo , Estudos Retrospectivos , Doenças Vestibulares/diagnóstico por imagem , Doenças Vestibulares/patologiaRESUMO
OBJECTIVES: To identify the incidence of specific abnormal impedance patterns or electrode faults, and determine their implication and significance, in a pediatric population of cochlear implant recipients. DESIGN: Nine hundred fifty-six cochlear implant devices (621 recipients) were included in this retrospective study. Devices were included if the implantation surgery was performed at our tertiary care hospital, and the recipient was 21 years of age or younger at the time the device was implanted. Device models incapable of producing impedance measures by telemetry were excluded from the study. Individual devices with abnormal impedance measures indicating an open circuit (OC), short circuit (SC), or partial short circuit (partial SC) were included in the study, unless these abnormalities occurred only in the OR and not postoperatively. Device and patient characteristics were examined to determine their relationship to increased incidence of electrode faults or atypical patterns. RESULTS: The incidence of software-identified electrode faults in our exclusively pediatric population was similar to that reported in the literature containing mixed-age cohorts. Nine percent of devices experienced at least one OC or one pair of SCs. Although higher incidence of these faults was seen in some specific device models, the long-term average of these faults was equivalent across manufacturers. No factors examined in this study increased the likelihood of experiencing a software-identified electrode fault. Within the study period under examination (October 1997 to March 2018), partial SCs (presenting as zig-zag or low-flat impedance patterns) were only observed in Cochlear devices. While the incidence of these partial SC abnormalities (non-software-identified faults) was 6% across all models of Cochlear devices, the CI24RCS experienced the highest incidence of partial SCs. The incidence of this pattern was lower in models manufactured after CI24RCS. CONCLUSIONS: This study provides incidence of various cochlear implant electrode impedance abnormalities across a large cohort of pediatric recipients. The incidence of all electrode abnormalities was relatively low, particularly partial SCs, which are less well recognized and not currently identified by clinician-accessible software. Incidence of software-identified electrode faults (i.e., SCs and OCs) in our pediatric-only study is similar to the incidence reported in other mixed-population and adult-only studies. These common electrode faults generally are not associated with device failure, and clinicians should feel comfortable reassuring families that an individual electrode fault does not imply an impending device failure. Conversely, those atypical impedance patterns not currently flagged by the programming software as abnormal, but visible to the clinician's eye (i.e., partial SCs in zig-zag or low-flat patterns), have a higher likelihood of device damage and failure. Performance in patients with electrode arrays exhibiting these atypical patterns should be closely monitored for any functional decrement, and proactively managed to maintain performance whenever possible.
Assuntos
Implante Coclear , Implantes Cocleares , Adolescente , Criança , Eletrodos Implantados , Humanos , Incidência , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: To determine the utility of ophthalmology evaluation, dark-adapted threshold, and full-field electroretinogram for early detection of Usher syndrome in young patients with bilateral sensorineural hearing loss. METHODS: We identified 39 patients with secure genetic diagnoses of Usher Syndrome. Visual acuity, spherical equivalent, fundus appearance, dark-adapted threshold, and full-field electroretinogram results were summarized and compared to those in a group of healthy controls with normal hearing. In those Usher patients with repeated measures, regression analysis was done to evaluate for change in visual acuity and dark-adapted threshold with age. Spherical equivalent and full-field electroretinogram responses from dark- and light-adapted eyes were evaluated as a function of age. RESULTS: The majority of initial visual acuity and spherical equivalent results were within normal limits for age. Visual acuity and dark-adapted threshold worsened significantly with age in Usher type 1 but not in Usher type 2. At initial test, full-field electroretinogram responses from dark- and light-adapted eyes were abnormal in 53% of patients. Remarkably, nearly half of our patients (17% of Usher type 1 and 30% of Usher type 2) would have been missed by tests of retinal function alone if evaluated before age 10. CONCLUSIONS: Although there is an association of abnormal dark-adapted threshold and full-field electroretinogram at young ages in Usher patients, it appears that a small but important proportion of patients would not be detected by tests of retinal function alone. Thus, genetic testing is needed to secure a diagnosis of Usher syndrome.
Assuntos
Síndromes de Usher , Criança , Eletrorretinografia , Humanos , Retina , Síndromes de Usher/diagnóstico , Síndromes de Usher/genética , Acuidade Visual , Testes de Campo VisualRESUMO
The use of "big data" for pediatric hearing research requires new approaches to both data collection and research methods. The widespread deployment of electronic health record systems creates new opportunities and corresponding challenges in the secondary use of large volumes of audiological and medical data. Opportunities include cost-effective hypothesis generation, rapid cohort expansion for rare conditions, and observational studies based on sample sizes in the thousands to tens of thousands. Challenges include finding and forming appropriately skilled teams, access to data, data quality assessment, and engagement with a research community new to big data. The authors share their experience and perspective on the work required to build and validate a pediatric hearing research database that integrates clinical data for over 185,000 patients from the electronic health record systems of three major academic medical centers.
Assuntos
Audiologia , Criança , Estudos de Coortes , Bases de Dados Factuais , Audição , HumanosRESUMO
IMPORTANCE: Hearing loss in children is common and by age 18 years, affects nearly 1 of every 5 children. Without hearing rehabilitation, hearing loss can cause detrimental effects on speech, language, developmental, educational, and cognitive outcomes in children. OBSERVATIONS: Consequences of hearing loss in children include worse outcomes in speech, language, education, social functioning, cognitive abilities, and quality of life. Hearing loss can be congenital, delayed onset, or acquired with possible etiologies including congenital infections, genetic causes including syndromic and nonsyndromic etiologies, and trauma, among others. Evaluation of hearing loss must be based on suspected diagnosis, type, laterality and degree of hearing loss, age of onset, and additional variables such as exposure to cranial irradiation. Hearing rehabilitation for children with hearing loss may include use of hearing aids, cochlear implants, bone anchored devices, or use of assistive devices such as frequency modulating systems. CONCLUSIONS AND RELEVANCE: Hearing loss in children is common, and there has been substantial progress in diagnosis and management of these cases. Early identification of hearing loss and understanding its etiology can assist with prognosis and counseling of families. In addition, awareness of treatment strategies including the many hearing device options, cochlear implant, and assistive devices can help direct management of the patient to optimize outcomes.
Assuntos
Implantes Cocleares , Auxiliares de Audição , Perda Auditiva , Criança , Pré-Escolar , Implantes Cocleares/economia , Diagnóstico Tardio , Auxiliares de Audição/economia , Perda Auditiva/diagnóstico , Perda Auditiva/etiologia , Perda Auditiva/genética , Perda Auditiva/terapia , Humanos , Lactente , Recém-Nascido , Desenvolvimento da LinguagemRESUMO
PURPOSE: Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene-disease relationships. The Clinical Genome Resource (ClinGen) has developed a semiquantitative framework to assign clinical validity to gene-disease relationships. METHODS: The ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene-disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss. RESULTS: The final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website ( https://search.clinicalgenome.org/kb/gene-validity ). CONCLUSION: This gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.
Assuntos
Surdez/genética , Testes Genéticos/métodos , Perda Auditiva/genética , Curadoria de Dados/métodos , Bases de Dados Genéticas , Testes Genéticos/normas , Variação Genética , Genoma Humano , Genômica/métodos , Humanos , Mutação , Reprodutibilidade dos TestesRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
PURPOSE: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. METHODS: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed. RESULTS: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants. CONCLUSION: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
Assuntos
Conexinas/genética , Perda Auditiva/genética , Alelos , Estudos de Casos e Controles , Conexina 26/genética , Conexinas/metabolismo , Surdez/genética , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Char syndrome is characterized by persistent patent ductus arteriosus (PDA) associated with hand-skeletal abnormalities and distinctive facial dysmorphism. Pathogenic variants in the transcription factor gene TFAP2B have been shown to cause Char syndrome; however, there is significant phenotypic variability linked to variant location. Here, we report a pediatric patient with a novel de novo variant in the fifth exon of TFAP2B, c.917C > T (p.Thr306Met), who presented with PDA, patent foramen ovale, postaxial polydactyly of the left fifth toe and clinodactyly of the left fourth toe, sensorineural hearing loss, scoliosis, dental anomalies, and central diabetes insipidus (CDI). CDI, scoliosis, and hearing loss have not previously been reported in a patient with Char syndrome, and while the association may be coincidental, this report expands the genotypes and potentially phenotypes associated with this syndrome.
Assuntos
Anormalidades Múltiplas/genética , Diabetes Insípido/genética , Permeabilidade do Canal Arterial/genética , Face/anormalidades , Dedos/anormalidades , Mutação de Sentido Incorreto , Fator de Transcrição AP-2/genética , Adolescente , Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 10 , Feminino , Genótipo , Humanos , FenótipoRESUMO
Due to the high genetic heterogeneity of hearing loss (HL), current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of HL. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants in HL genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP HL rules. Three rules remained unchanged, four rules were removed, and the remaining 21 rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and disease experts. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These HL-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with HL.
Assuntos
Testes Genéticos/métodos , Genoma Humano/genética , Perda Auditiva/genética , Frequência do Gene/genética , Variação Genética/genética , Genômica/métodos , Humanos , Mutação/genética , Análise de Sequência de DNA , Sociedades Médicas , Estados UnidosRESUMO
OBJECTIVE: To examine the long-term trend of otitis media (OM)-associated ambulatory visits from 1997 to 2014 and to evaluate the impact of 7-valent and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) on OM ambulatory visits. STUDY DESIGN: We examined OM-associated ambulatory visits in children, using the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey. RESULTS: A total of 24 148 OM-related visits were identified from 363 240 ambulatory visits. OM visits accounted for 9.5% of all ambulatory visits in 1997-1999, 7.1% in 2002-2009, and 5.5% in 2012-2014. Between the pre-PCV7 and the post-PCV13 period, annual physician's office visits for OM declined from 826 to 387 visits per 1000 children among children younger than 2 years of age. Compared with the pre-PCV7 period, office visit rates for OM significantly declined by 51% (95% CI 42%-58%) among children younger than 2 years of age and by 37% (95% CI 23%-48%) among children 2-4 years of age during the post-PCV13 period. Among children younger than 2 years of age, emergency department visits for OM declined by 47% (95% CI 36%-55%) during the post-PCV13 period, and hospital outpatient visits declined by 30% (95% CI 8%-48%) during the PCV13-transition period. OM-related visits declined across sex, race/ethnicity, health insurance status, and geographic region. CONCLUSION: Our nationwide study shows that ambulatory visits for OM have declined following the introduction of PCV7 and PCV13. Future research on the evolving microbiology of OM and continued monitoring of the epidemiology of pneumococcal disease are needed.