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We review emerging strategies to protect the privacy of research participants in international epigenome research: open consent, genome donation, registered access, automated procedures, and privacy-enhancing technologies.
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Genómica/ética , Genómica/legislación & jurisprudencia , Difusión de la Información , Privacidad , Secuenciación de Nucleótidos de Alto Rendimiento , Proyecto Genoma Humano/ética , Proyecto Genoma Humano/legislación & jurisprudencia , Humanos , Análisis de Secuencia de ADNRESUMEN
Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases1,2. Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired3,4. However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination-a common type of DNA damage-with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing.
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Disparidad de Par Base , Daño del ADN , ADN de Cadena Simple , Análisis de Secuencia de ADN , Imagen Individual de Molécula , Humanos , Envejecimiento/genética , Desaminasas APOBEC/genética , Desaminasas APOBEC/metabolismo , Disparidad de Par Base/genética , Citidina Desaminasa/metabolismo , Citidina Desaminasa/genética , Citosina/metabolismo , Desaminación , Daño del ADN/genética , Reparación de la Incompatibilidad de ADN/genética , Replicación del ADN/genética , ADN de Cadena Simple/genética , Genoma Mitocondrial/genética , Mutación , Neoplasias/genética , Análisis de Secuencia de ADN/métodos , Análisis de Secuencia de ADN/normas , Imagen Individual de Molécula/métodos , Masculino , FemeninoRESUMEN
Next-generation sequencing has revolutionized the speed of rare disease (RD) diagnoses. While clinical exome and genome sequencing represent an effective tool for many RD diagnoses, there is room to further improve the diagnostic odyssey of many RD patients. One recognizable intervention lies in increasing equitable access to genomic testing. Rural communities represent a significant portion of underserved and underrepresented individuals facing additional barriers to diagnosis and treatment. Primary care providers (PCPs) at local clinics, though sometimes suspicious of a potential benefit of genetic testing for their patients, have significant constraints in pursuing it themselves and rely on referrals to specialists. Yet, these referrals are typically followed by long waitlists and significant delays in clinical assessment, insurance clearance, testing, and initiation of diagnosis-informed care management. Not only is this process time intensive, but it also often requires multiple visits to urban medical centers for which distance may be a significant barrier to rural families. Therefore, providing early, "direct-to-provider" (DTP) local access to unrestrictive genomic testing is likely to help speed up diagnostic times and access to care for RD patients in rural communities. In a pilot study with a PCP clinic in rural Kansas, we observed a minimum 5.5 months shortening of time to diagnosis through the DTP exome sequencing program as compared to rural patients receiving genetic testing through the "traditional" PCP-referral-to-specialist scheme. We share our experience to encourage future partnerships beyond our center. Our efforts represent just one step in fostering greater diversity and equity in genomic studies.
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Pruebas Genéticas , Genómica , Accesibilidad a los Servicios de Salud , Enfermedades Raras , Población Rural , Humanos , Pruebas Genéticas/métodos , Enfermedades Raras/genética , Enfermedades Raras/diagnóstico , Genómica/métodos , Niño , Masculino , Secuenciación de Nucleótidos de Alto Rendimiento , FemeninoRESUMEN
PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity of PPFIA3 variants in vivo, we generated transgenic fruit flies producing either human wild-type (WT) PPFIA3 or five missense variants using GAL4-UAS targeted gene expression systems. In the fly overexpression assays, we found that the PPFIA3 variants in the region encoding the N-terminal coiled-coil domain exhibited stronger phenotypes compared to those affecting the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of fly Liprin-α leads to embryonic lethality. This lethality is partially rescued by the expression of human PPFIA3 WT, suggesting human PPFIA3 function is partially conserved in the fly. However, two of the tested variants failed to rescue the lethality at the larval stage and one variant failed to rescue lethality at the adult stage. Altogether, the human and fruit fly data reveal that the rare PPFIA3 variants are dominant-negative loss-of-function alleles that perturb multiple developmental processes and synapse formation.
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Proteínas de Drosophila , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Adulto , Animales , Humanos , Alelos , Animales Modificados Genéticamente , Drosophila , Proteínas de Drosophila/genética , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular , Trastornos del Neurodesarrollo/genética , Proteínas Tirosina FosfatasasRESUMEN
TBC1D3 is a primate-specific gene family that has expanded in the human lineage and has been implicated in neuronal progenitor proliferation and expansion of the frontal cortex. The gene family and its expression have been challenging to investigate because it is embedded in high-identity and highly variable segmental duplications. We sequenced and assembled the gene family using long-read sequencing data from 34 humans and 11 non-human primate species. Our analysis shows that this particular gene family has independently duplicated in at least five primate lineages, and the duplicated loci are enriched at sites of large-scale chromosomal rearrangements on Chromosome 17. We find that all human copy number variation maps to two distinct clusters located at Chromosome 17q12 and that humans are highly structurally variable at this locus, differing by as many as 20 copies and ~1 Mbp in length depending on haplotypes. We also show evidence of positive selection, as well as a significant change in the predicted human TBC1D3 protein sequence. Lastly, we find that, despite multiple duplications, human TBC1D3 expression is limited to a subset of copies and, most notably, from a single paralog group: TBC1D3-CDKL These observations may help explain why a gene potentially important in cortical development can be so variable in the human population.
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Spinal muscular atrophy, a leading cause of early infant death, is caused by bi-allelic mutations of SMN1. Sequence analysis of SMN1 is challenging due to high sequence similarity with its paralog SMN2. Both genes have variable copy numbers across populations. Furthermore, without pedigree information, it is currently not possible to identify silent carriers (2+0) with two copies of SMN1 on one chromosome and zero copies on the other. We developed Paraphase, an informatics method that identifies full-length SMN1 and SMN2 haplotypes, determines the gene copy numbers, and calls phased variants using long-read PacBio HiFi data. The SMN1 and SMN2 copy-number calls by Paraphase are highly concordant with orthogonal methods (99.2% for SMN1 and 100% for SMN2). We applied Paraphase to 438 samples across 5 ethnic populations to conduct a population-wide haplotype analysis of these highly homologous genes. We identified major SMN1 and SMN2 haplogroups and characterized their co-segregation through pedigree-based analyses. We identified two SMN1 haplotypes that form a common two-copy SMN1 allele in African populations. Testing positive for these two haplotypes in an individual with two copies of SMN1 gives a silent carrier risk of 88.5%, which is significantly higher than the currently used marker (1.7%-3.0%). Extending beyond simple copy-number testing, Paraphase can detect pathogenic variants and enable potential haplotype-based screening of silent carriers through statistical phasing of haplotypes into alleles. Future analysis of larger population data will allow identification of more diverse haplotypes and genetic markers for silent carriers.
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Atrofia Muscular Espinal , Lactante , Humanos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/diagnóstico , Mutación , Dosificación de Gen , Linaje , Análisis de Secuencia , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genéticaRESUMEN
DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains unassociated with disease traits in OMIM. Using exome sequencing and family-based rare-variant analyses, we identified 20 individuals with de novo, ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative Human Phenotype Ontology (HPO) analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 was restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from an individual with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.Gly411Glu and p.Arg761Gln, altered DHX9 ATPase activity. The severe NDD-associated variant p.Arg141Gln did not affect DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9-/- mice exhibited hypoactivity in novel environments, tremor, and sensorineural hearing loss. All together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.
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Enfermedad de Charcot-Marie-Tooth , Trastornos del Neurodesarrollo , Animales , Humanos , Ratones , Línea Celular , Enfermedad de Charcot-Marie-Tooth/genética , ARN Helicasas DEAD-box/genética , Diclorodifenil Dicloroetileno , ADN Helicasas , Mamíferos , Proteínas de Neoplasias/genéticaRESUMEN
MOTIVATION: Human epigenomic data has been generated by large consortia for thousands of cell types to be used as a reference map of normal and disease chromatin states. Since epigenetic data contains potentially identifiable information, similarly to genetic data, most raw files generated by these consortia are stored in controlled-access databases. It is important to protect identifiable information, but this should not hinder secure sharing of these valuable datasets. RESULTS: Guided by the Framework for responsible sharing of genomic and health-related data from the Global Alliance for Genomics and Health (GA4GH), we have developed an approach and a tool to facilitate the exploration of epigenomics datasets' aggregate results, while filtering out identifiable information. Specifically, the EpiVar Browser allows a user to navigate an epigenetic dataset from a cohort of individuals and enables direct exploration of genotype-chromatin phenotype relationships. Because individual genotypes and epigenetic signal tracks are not directly accessible, and rather aggregated in the portal output, no identifiable data is released, yet the interface allows for dynamic genotype-epigenome interrogation. This approach has the potential to accelerate analyses that would otherwise require a lengthy multi-step approval process and provides a generalizable strategy to facilitate responsible access to sensitive epigenomics data. AVAILABILITY AND IMPLEMENTATION: Online portal: https://computationalgenomics.ca/tools/epivar; EpiVar Browser source code: https://github.com/c3g/epivar-browser; bw-merge-window tool source code: https://github.com/c3g/bw-merge-window.
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Epigenómica , Programas Informáticos , Humanos , Epigenómica/métodos , Genoma , Genómica , Cromatina/genéticaRESUMEN
Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, microcephaly, nonspecific brain malformations, hypotonia and seizures. Four individuals carry missense variants (three of them detected de novo) and three individuals carry null variants (two of them maternally inherited). Molecular modeling of the heterozygous missense variants suggests that the majority of them affect the globular structure of DOCK4. In vitro functional expression studies in transfected Neuro-2A cells showed that all missense variants impaired neurite outgrowth. Furthermore, Dock4 knockout Neuro-2A cells also exhibited defects in promoting neurite outgrowth. Our results, including clinical, molecular and functional data, suggest that loss-of-function variants in DOCK4 probable cause a variable spectrum of a novel neurodevelopmental disorder with microcephaly.
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Proteínas Activadoras de GTPasa , Heterocigoto , Microcefalia , Mutación Missense , Trastornos del Neurodesarrollo , Humanos , Microcefalia/genética , Femenino , Masculino , Preescolar , Proteínas Activadoras de GTPasa/genética , Niño , Trastornos del Neurodesarrollo/genética , Mutación con Pérdida de Función , Animales , Discapacidades del Desarrollo/genética , Ratones , Lactante , Fenotipo , AdolescenteRESUMEN
BACKGROUND: SINO syndrome (Spastic paraplegia, Intellectual disability, Nystagmus and Obesity) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising eight with SINO and four with an autosomal recessive condition attributed to bi-allelic KIDINS220 variants. METHODS: In our international cohort, we have comprised 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form. We assessed clinical and molecular data of our cohort and previously reported individuals and based on functional experiments reached a better understanding of the pathogenesis behind KIDINS220-related disease. RESULTS: Using fetal tissue and in vitro assays, we demonstrate that the variants generate KIDINS220 truncated forms that mislocalize in punctate intracellular structures, with decreased levels of the full-length protein, suggesting a trans-dominant negative effect. 92% had their diagnosis within three years, with symptoms of developmental delay, spasticity, hypotonia, lack of eye contact and nystagmus. We identified a KIDINS220 variant associated with fetal hydrocephalus and show that 58% of examined individuals present brain ventricular dilatation. We extend the phenotypic spectrum of SINO syndrome to behavioral manifestations not previously highlighted. CONCLUSION: Our study provides further insights into the clinical spectrum, etiology and predicted functional impact of KIDINS220 variants.
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Motivated by a DNA methylation application, this article addresses the problem of fitting and inferring a multivariate binomial regression model for outcomes that are contaminated by errors and exhibit extra-parametric variations, also known as dispersion. While dispersion in univariate binomial regression has been extensively studied, addressing dispersion in the context of multivariate outcomes remains a complex and relatively unexplored task. The complexity arises from a noteworthy data characteristic observed in our motivating dataset: non-constant yet correlated dispersion across outcomes. To address this challenge and account for possible measurement error, we propose a novel hierarchical quasi-binomial varying coefficient mixed model, which enables flexible dispersion patterns through a combination of additive and multiplicative dispersion components. To maximize the Laplace-approximated quasi-likelihood of our model, we further develop a specialized two-stage expectation-maximization (EM) algorithm, where a plug-in estimate for the multiplicative scale parameter enhances the speed and stability of the EM iterations. Simulations demonstrated that our approach yields accurate inference for smooth covariate effects and exhibits excellent power in detecting non-zero effects. Additionally, we applied our proposed method to investigate the association between DNA methylation, measured across the genome through targeted custom capture sequencing of whole blood, and levels of anti-citrullinated protein antibodies (ACPA), a preclinical marker for rheumatoid arthritis (RA) risk. Our analysis revealed 23 significant genes that potentially contribute to ACPA-related differential methylation, highlighting the relevance of cell signaling and collagen metabolism in RA. We implemented our method in the R Bioconductor package called "SOMNiBUS."
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Algoritmos , Simulación por Computador , Metilación de ADN , Modelos Estadísticos , Humanos , Análisis Multivariante , Artritis Reumatoide/genética , Funciones de Verosimilitud , Sulfitos/química , Análisis de Secuencia de ADN/métodosRESUMEN
ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C>T; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases.
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Ataxia Cerebelosa , Discapacidad Intelectual , Humanos , Mutación/genética , Síndrome , Discapacidad Intelectual/genética , Ataxia Cerebelosa/genética , Fenotipo , Espasticidad Muscular/genética , Cationes , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
BACKGROUND: SHROOM4 is thought to play an important role in cytoskeletal modification and development of the early nervous system. Previously, single-nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, but not with congenital anomalies of the urinary tract and the visceral or the cardiovascular system. METHODS: Here, exome sequencing and CNV analyses besides expression studies in zebrafish and mouse and knockdown (KD) experiments using a splice blocking morpholino in zebrafish were performed to study the role of SHROOM4 during embryonic development. RESULTS: In this study, we identified putative disease-causing SNVs and CNVs in SHROOM4 in six individuals from four families with congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems (CNS). Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls. These phenotypes could be rescued by co-injection of human wild-type SHROOM4 mRNA and morpholino. CONCLUSION: The identified SNVs and CNVs in affected individuals with congenital anomalies of the urinary tract, the anorectal, the cardiovascular and the central nervous systems, and subsequent embryonic mouse and zebrafish studies suggest SHROOM4 as a developmental gene for different organ systems.
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Sistema Cardiovascular , Sistema Urinario , Embarazo , Femenino , Humanos , Animales , Ratones , Pez Cebra/genética , Variaciones en el Número de Copia de ADN , Morfolinos , Sistema Urinario/anomalías , Sistema Nervioso CentralRESUMEN
PURPOSE: Persistent inequities in genomic medicine and research contribute to health disparities. This analysis uses a context-specific and equity-focused strategy to evaluate enrollment patterns for Genomic Answers for Kids (GA4K), a large, metropolitan-wide genomic study on children. METHODS: Electronic health records for 2247 GA4K study participants were used to evaluate the distribution of individuals by demographics (race, ethnicity, and payor type) and location (residential address). Addresses were geocoded to produce point density and 3-digit zip code maps showing local and regional enrollment patterns. Health system reports and census data were used to compare participant characteristics with reference populations at different spatial scales. RESULTS: Racial and ethnic minoritized and populations with low-income were underrepresented in the GA4K study cohort. Geographic variation demonstrates inequity in enrollment and participation among children from historically segregated and socially disadvantaged communities. CONCLUSION: Our findings illustrate inequity in enrollment related to both GA4K study design and structural inequalities, which we suspect may exist for similar US-based studies. Our methods provide a scalable framework for continually evaluating and improving study design to ensure equitable participation in and benefits from genomic research and medicine. The use of high-resolution, place-based data represents a novel and practical means of identifying and characterizing inequities and targeting community engagement.
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Etnicidad , Medicina , Niño , Humanos , Genómica , Proyectos de InvestigaciónRESUMEN
PURPOSE: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials. METHODS: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts. RESULTS: Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials). CONCLUSION: Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers' coverage policies.
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Genómica , Cobertura del Seguro , Niño , HumanosRESUMEN
Determining the duration of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is critical for informing the timing of booster immunization. Many genetic and environmental factors could influence both the magnitude and persistence of the antibody response. Here, we showed that SARS-CoV-2 infection before vaccination and age affected the decay of antibody responses to the SARS-CoV-2 messenger RNA vaccine.
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COVID-19 , Vacunas Virales , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , SARS-CoV-2/genética , Vacunación , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
We have identified an underrecognized severe adverse drug reaction (ADR) of trimethoprim-sulfamethoxazole (TMP-SMX) associated respiratory failure in previously healthy children and young adults. We investigated potential genetic risk factors associated with TMP-SMX induced respiratory failure in a cohort of seven patients. We explored whole genome sequence among seven patients representing nearly half of all reported cases worldwide and 63 unrelated control individuals in two stages: (1) human leukocyte antigen (HLA) locus variation as several other ADRs have been associated HLA genetic variants and (2) coding variation to catalog and explore potential rare variants contributing to this devastating reaction. All cases were either heterozygous (carriers) or homozygous for the common HLA-B*07:02-HLA-C*07:02 haplotype. Despite the small sample size, this observation is statistically significant both in conservative comparison to maximum reported population frequencies (binomial P = 0.00017 for HLA-B and P = 0.00028 for HLA-C) and to our control population assessed by same HLA genotyping approach (binomial P = 0.000001 for HLA-B and P = 0.000018 for HLA-C). No gene elsewhere in the genome harnessed shared rare case enriched coding variation. Our results suggests that HLA-B*07:02 and HLA-C*07:02 are necessary for a patient to develop respiratory failure due to TMP-SMX.
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Insuficiencia Respiratoria , Combinación Trimetoprim y Sulfametoxazol , Niño , Antígenos HLA-B/genética , Antígeno HLA-B7 , Antígenos HLA-C/genética , Humanos , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/genética , Combinación Trimetoprim y Sulfametoxazol/efectos adversosRESUMEN
PURPOSE: Efforts have been made to standardize laboratory variant interpretation, but clinicians are ultimately tasked with clinical correlation and application of genetic test results in patient care. This study aimed to explore processes clinicians utilize when reviewing and returning genetic test results, and how they impact patient care. METHODS: Medical geneticists, genetic counselors, and nongenetics clinicians from two Midwestern states completed surveys (n = 98) and in-depth interviews (n = 29) on practices of reviewing and returning genetic test results. Retrospective chart review (n = 130) examined discordant interpretations and the impact on care. RESULTS: Participants reported variable behaviors in both reviewing and returning results based on factors such as confidence, view of role, practice setting, and relationship with the lab. Providers did not report requesting changes to variant classifications from laboratories, but indicated relaying conflicting classifications to patients in some cases. Chart reviews revealed medically impactful differences in interpretation between laboratories and clinicians in 18 (13.8%) records. CONCLUSION: Clinician practices for reviewing and integrating genetic test results into patient care vary within and between specialties and impact patient care. Strategies to better incorporate both laboratory and clinician expertise into interpretation of genetic results could result in improved care across providers and settings.