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Over the past several decades, molecular genetic testing volumes have grown and testing has expanded from single-gene assays to multigene panels, exome sequencing, and genome sequencing. The number of molecular genetic variants that require manual interpretation has grown simultaneously, resulting in an increased demand for education on molecular variant evaluation (MVE). To meet this growing need, a team of genetic counselors and educational experts undertook a quality improvement (QI) initiative with the objectives of assessing, standardizing, and scaling access to MVE education, without increasing instructor time to deliver the education. Using the Six Sigma define-measure-analyze-improve-control (DMAIC) framework, a flipped learning course with a series of standardized online modules was developed to deliver MVE education in an enduring and accessible format for a diverse group of learners. Outcome measures included the number of online modules developed, the number of individual learners and unique learner groups accessing MVE education, and direct instruction time required to deliver MVE education. Countermeasures to ensure maintenance of educational quality included post-course learner satisfaction scores and performance on competency assessments. Both the total number of learners and the number of unique learner groups accessing MVE education increased, while instructor time required to deliver content per learner decreased. Learner satisfaction scores remained constant and performance on competency assessments improved. The QI initiative successfully scaled MVE education to a diverse group of learners without decreasing learner outcomes or satisfaction. The flipped learning format provides a scalable and flexible educational model for instructors and learners in a rapidly changing environment that often includes remote work and education.
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Consejeros , Mejoramiento de la Calidad , Humanos , Escolaridad , AprendizajeRESUMEN
Black women in the USA experience some of the poorest health outcomes and this is especially true for those involved in the carceral system who are at elevated risks for HIV/STIs, reproductive health, and chronic diseases. This study aimed to investigate Black women's experience accessing healthcare services. We conducted semi-structured interviews with 43 women from Project EWORTH under community supervision in New York City. We analysed responses focusing on barriers to healthcare engagement. All interviews were recorded, and data analysis was conducted using NVivo. Themes influencing Black women's ability to engage with healthcare providers and systems included: 1) disclosed provider mistrust/judgement; 2) feeling disrespected by providers and the medical system; 3) mistrust of medical providers/system/hospital/government; 4) lack of health communication; 5) low health literacy; 6) provider gender preference. Findings highlight the need to improve trust and collaboration between healthcare providers and Black women. This study addresses the critical gap in understanding perceptions of discrimination, stigma, and barriers to attaining health care. Funders and accreditation agencies must hold providers and organisations accountable for acquiring and making available diversity, equity and inclusion training for providers, demonstrating increasingly equitable medical relationships through responsiveness to patient feedback, and increasing the number of Black providers.
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This study examined retention and its relationship to mental health, substance use, and social determinants of health in a randomized clinical trial of a behavioral HIV/sexually transmitted infection prevention intervention with drug-involved Black women (N = 348) under community supervision programs in New York City. Using secondary analysis, we used logistic models to test the association between factors related to mental health, substance use, and social determinants of health and follow-up assessment completion (three, six, and 12 months). Participants who were diagnosed with schizophrenia had lower odds of retention. Participants who misused prescription opiates during their lifetime or food insecure in the past 90 days had higher odds of retention throughout the intervention.
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Infecciones por VIH , Enfermedades de Transmisión Sexual , Trastornos Relacionados con Sustancias , Humanos , Femenino , Infecciones por VIH/diagnóstico , Enfermedades de Transmisión Sexual/prevención & control , Trastornos Relacionados con Sustancias/diagnóstico , Salud Mental , Atención a la SaludRESUMEN
BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.
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Enfermedades Raras , Enfermedades no Diagnosticadas , Estados Unidos , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Enfermedades Raras/terapia , Atención Terciaria de Salud , Medicina Genómica , Pruebas Genéticas , Asesoramiento GenéticoRESUMEN
The intrinsically disordered N-terminal region of the E7 protein from high-risk human papillomavirus (HPV) strains is responsible for oncogenic transformation of host cells through its interaction with a number of cellular factors, including the TAZ2 domain of the transcriptional coactivator CREB-binding protein. Using a variety of spectroscopic and biochemical tools, we find that despite its nanomolar affinity, the HPV16 E7 complex with TAZ2 is disordered and highly dynamic. The disordered domain of HPV16 E7 protein does not adopt a single conformation on the surface of TAZ2 but engages promiscuously with its target through multiple interactions involving two conserved motifs, termed CR1 and CR2, that occupy an extensive binding surface on TAZ2. The fuzzy nature of the complex is a reflection of the promiscuous binding repertoire of viral proteins, which must efficiently dysregulate host cell processes by binding to a variety of host factors in the cellular environment.
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Proteína de Unión a CREB/química , Proteínas E7 de Papillomavirus/química , Secuencia de Aminoácidos , Animales , Proteína de Unión a CREB/genética , Transformación Celular Neoplásica , Secuencia Conservada , Interacciones Microbiota-Huesped , Humanos , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/genética , Ratones , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Proteínas E7 de Papillomavirus/genética , Unión Proteica , Conformación Proteica , Dominios y Motivos de Interacción de ProteínasRESUMEN
OBJECTIVE: To describe the impact of a novel communication and triage pathway called fast track dialysis (FTD) on the length of stay (LOS), resource utilization, and charges for unscheduled hemodialysis for end stage renal disease (ESRD) patients presenting to the emergency department (ED). METHODS: Prospective and retrospective cohorts of ESRD patients meeting requirements of routine or urgent hemodialysis at a tertiary academic hospital from September 25th, 2016 to September 25th, 2018 in 1 year cohorts. Two sample t-tests were used to compare most outcomes of the cohorts with a Mann-Whitney U test used for skewed data. Nephrology group outcomes were analyzed by two-way ANOVA and Kruskal-Wallis and chi-square tests. RESULTS: There were 98 encounters in the historical cohort and 143 encounters in the fast track dialysis cohort. FTD had significantly lowered median ED LOS (4.05 h, vs 5.3 h, p < 0.001), median hospital LOS (12.8 h vs 27 h, p < 0.001), time to hemodialysis (4.78 h vs 7.29 h, p < 0.001), and median hospital charges ($26,040 vs $30,747, p < 0.016). The FTD cohort had increased 30 day ED return for each encounter compared to the historical cohort (1.85 visits vs 0.73 visits, p < 0.001), however no significant increase in 1 year ED visits (6.52 visits vs 5.80, p = 0.4589) or 1 year readmissions (5.89 readmissions vs 4.81 readmissions, p = 0.3584). Most nephrology groups had significantly lower time to hemodialysis order placement and time to start hemodialysis. CONCLUSION: A multidisciplinary approach with key stakeholders using a standard pathway can lead to improved efficiency in throughput, reduced charges, and hospital resource utilization for patients needing urgent or routine hemodialysis. A study with a dedicated geographic observation unit for protocolized short stay patients including conditions ranging from low risk chest pain to transient ischemic events that incorporates FTD patients under this protocol should be considered.
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Servicio de Urgencia en Hospital/normas , Fallo Renal Crónico/terapia , Diálisis Renal , Tiempo de Tratamiento , Femenino , Precios de Hospital/estadística & datos numéricos , Humanos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Mejoramiento de la Calidad , Estudios Retrospectivos , TriajeRESUMEN
AIMS: Rhabdomyosarcomas of bone are extremely rare, with fewer than 10 reported cases. A very rare subtype of spindle cell/sclerosing rhabdomyosarcoma harbouring a FUS-TFCP2 fusion and involving both soft tissue and bone locations has been reported very recently. We report only the fourth case of this unusual, clinically aggressive rhabdomyosarcoma. MATERIAL AND RESULTS: A previously well 72-year-old male presented with a destructive lesion of the mandible. Morphological and immunohistochemical study of a needle biopsy and the subsequent resection showed a spindle cell rhabdomyosarcoma. RNA-seq, RT-PCR and FISH confirmed the presence of the FUS-TFCP2 fusion. CONCLUSIONS: Spindle cell rhabdomyosarcomas carrying the FUS-TFCP2 fusion are very rare rhabdomyosarcoma variants with osseous predilection. The classification and differential diagnosis of this unusual molecular variant of spindle cell/sclerosing rhabdomyosarcoma are discussed.
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Proteínas de Unión al ADN/genética , Neoplasias Mandibulares/genética , Proteínas de Fusión Oncogénica/genética , Proteína FUS de Unión a ARN/genética , Rabdomiosarcoma/genética , Factores de Transcripción/genética , Anciano , Humanos , Masculino , Neoplasias Mandibulares/patología , Rabdomiosarcoma/patologíaRESUMEN
OBJECTIVE: To increase genetic counseling referrals for patients with newly diagnosed epithelial ovarian cancer (EOC). METHODS: A practice-gap analysis was performed after measuring baseline genetic counseling referral rates to identify barriers to referral from the multidisciplinary single institution EOC care group. A Genetics Referral Toolkit consisting of a referral template, a genetic risk checklist, family history worksheet and provider and patient awareness was developed to address identified gaps with the goal of increasing referral rates. Clinical characteristics, referral placement, completion of genetic counseling/testing were abstracted for a historic cohort and intervention cohort. Data for the two cohorts were compared using chi-square, Fisher's exact test, or t-test. Association with referral was determined by univariate logistic regression. RESULTS: Eighty one patients from July through December 2013 (historic cohort) and 62 patients from July through December 2015 (intervention cohort) were identified as having a new diagnosis of EOC. Among these women, genetic counseling referral rates increased from 48.1% (39/81) in 2013 to 74.2% (46/62) in 2015 (p=0.002) after implementation of the toolkit. In a subset of patients without a previous genetic counseling referral, 87.9% (29/33) completed counseling and 79.3% (23/29) pursued testing from the historic cohort. In the intervention cohort, 60% (24/40) were seen for counseling and 100% (24/24) had testing. CONCLUSION: Application of a quality improvement process to create a Genetics Referral Toolkit increased the genetic counseling referral rate in patients with a new diagnosis of EOC. The majority of patients who were referred completed genetics consultation and elected genetic testing.
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Asesoramiento Genético/métodos , Neoplasias Glandulares y Epiteliales/diagnóstico , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Carcinoma Epitelial de Ovario , Estudios de Cohortes , Femenino , Asesoramiento Genético/estadística & datos numéricos , Humanos , Persona de Mediana Edad , Pautas de la Práctica en Medicina , Derivación y Consulta/estadística & datos numéricosRESUMEN
BACKGROUND: In rural Bangladesh, India and elsewhere, pour-flush pit latrines are the most common sanitation system. When a single pit latrine becomes full, users must empty it themselves and risk exposure to fresh feces, pay an emptying service to remove pit contents or build a new latrine. Double pit pour-flush latrines may serve as a long-term sanitation option including high water table areas because the pits do not need to be emptied immediately and the excreta decomposes into reusable soil. METHODS: Double pit pour-flush latrines were implemented in rural Bangladesh for 'hardcore poor' households by a national NGO, BRAC. We conducted interviews, focus groups, and spot checks in two low-income, rural areas of Bangladesh to explore the advantages and limitations of using double pit latrines compared to single pit latrines. RESULTS: The rural households accepted the double pit pour-flush latrine model and considered it feasible to use and maintain. This latrine design increased accessibility of a sanitation facility for these low-income residents and provided privacy, convenience and comfort, compared to open defecation. Although a double pit latrine is more costly and requires more space than a single pit latrine the households perceived this sanitation system to save resources, because households did not need to hire service workers to empty pits or remove decomposed contents themselves. In addition, the excreta decomposition process produced a reusable soil product that some households used in homestead gardening. The durability of the latrine superstructures was a problem, as most of the bamboo-pole superstructure broke after 6-18 months of use. CONCLUSIONS: Double pit pour-flush latrines are a long-term improved sanitation option that offers users several important advantages over single pit pour-flush latrines like in rural Bangladesh which can also be used in areas with high water table. Further research can provide an understanding of the comparative health impacts and effectiveness of the model in preventing human excreta from entering the environment.
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Población Rural , Cuartos de Baño , Adulto , Bangladesh , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pobreza , Investigación Cualitativa , Población Rural/estadística & datos numéricosRESUMEN
Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors' research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.Genet Med 18 1, 13-19.
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Adenosina Trifosfatasas/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Detección Precoz del Cáncer/métodos , Mutación de Línea Germinal , Heterocigoto , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , PenetranciaRESUMEN
Ethical dilemmas are encountered commonly in the setting of the clinical genetic testing laboratory due to the complexity of genetic testing and the number of relevant stakeholders involved in the genetic testing process. Based on their clinical training and role within the laboratory, genetic counselors are uniquely equipped to identify and facilitate management of ethical dilemmas. This paper reviews the historical context of ethical theory and its application to the field of genetic counseling. Theoretical and applied ethics are explored in the context of dilemmas arising in the laboratory setting, with a focus on the role of the laboratory genetic counselor in managing ethical dilemmas. Two illustrative case examples are provided.
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Ética Profesional , Asesoramiento Genético/ética , Pruebas Genéticas/ética , Consejeros , HumanosRESUMEN
The number of available genetic testing options and the nuances associated with these options continue to expand. In addition, the scope of genetic testing has broadened to areas and specialties beyond Medical Genetics. In response to these changes, diagnostic laboratories have employed genetic counselors to help navigate the increasing complexity of genetic testing, given their expertise and training in human genetics. However a largely unrecognized aspect of this role involves the use of counseling skills. Counseling skills are used by laboratory genetic counselors in a variety of situations to convey information and facilitate understanding among clinicians and medical staff. This helps to reduce test ordering errors, promote optimal test utilization, and ensure best patient care practices. The specific counseling skills used by laboratory counselors will be explored using three fictional case vignettes, followed by a discussion of the applicability of these skills in other contexts. Exploration of the unique ways in which laboratory genetic counselors apply their counseling skills can be useful for professional development and instructive for graduate training programs.
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Consejo/estadística & datos numéricos , Asesoramiento Genético/estadística & datos numéricos , Pruebas Genéticas/estadística & datos numéricos , Comunicación Interdisciplinaria , Personal de Laboratorio Clínico/estadística & datos numéricos , Predisposición Genética a la Enfermedad , Humanos , Atención al Paciente/estadística & datos numéricosRESUMEN
PURPOSE: The Muir-Torre syndrome variant of Lynch syndrome is characterized by the presence of sebaceous neoplasms (adenoma, epithelioma/sebaceoma, carcinoma) and Lynch syndrome-associated cancers (colon, endometrial, and others). Several clinical scoring systems have been developed to identify patients with colon cancer at high risk of Lynch syndrome. However, no such system has been described for patients presenting with sebaceous neoplasms. METHODS: Based on logistic regression analysis, a scoring system was developed for patients with sebaceous neoplasm to identify those with the highest likelihood of having Muir-Torre syndrome. The final version of the scoring system included variables such as age at presentation of initial sebaceous neoplasm, total number of sebaceous neoplasms, personal history of a Lynch-related cancer, and family history of Lynch-related cancers. RESULTS: Patients with a score of 3 or more were more likely to have Muir-Torre syndrome (28 of 29 patients), those with a score of 2 had intermediate likelihood (12 of 20 patients), and no patient with a score of 0 or 1 was diagnosed with Muir-Torre syndrome. CONCLUSION: The Mayo Muir-Torre syndrome risk scoring system appears to identify whether patients who present with sebaceous neoplasms are in need of further Lynch syndrome evaluation using easily ascertained clinical information. Abnormal mismatch repair gene immunohistochemistry of a sebaceous neoplasm is a poor predictor in regard to diagnosing Lynch syndrome.
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Síndrome de Muir-Torre/epidemiología , Síndrome de Muir-Torre/etiología , Riesgo , Neoplasias de las Glándulas Sebáceas/complicaciones , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Estudios de Asociación Genética , Sitios Genéticos , Mutación de Línea Germinal , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Mutación , Factores de Riesgo , Neoplasias de las Glándulas Sebáceas/diagnósticoRESUMEN
The dual visuomotor channel theory proposes that prehension consists of a Reach that transports the hand in relation to an object's extrinsic properties (e.g., location) and a Grasp that shapes the hand to an object's intrinsic properties (e.g., size and shape). In central vision, the Reach and the Grasp are integrated but when an object cannot be seen, the movements can decompose with the Reach first used to locate the object and the Grasp postponed until it is assisted by touch. Reaching for an object in a peripheral visual field is an everyday act, and although it is reported that there are changes in Grasp aperture with target eccentricity, it is not known whether the configuration of the Reach and the Grasp also changes. The present study examined this question by asking participants to reach for food items at 0° or 22.5° and 45° from central gaze. Participants made 15 reaches for a larger round donut ball and a smaller blueberry, and hand movements were analyzed using frame-by-frame video inspection and linear kinematics. Perception of targets was degraded as participants could not identify objects in peripheral vision but did recognize their differential size. The Reach to peripheral targets featured a more dorsal trajectory, a more open hand, and less accurate digit placement. The Grasp featured hand adjustments or target manipulations after contact, which were associated with a prolonged Grasp duration. Thus, Grasps to peripheral vision did not consist only of a simple modification of visually guided reaching but included the addition of somatosensory assistance. The kinematic and behavioral changes argue that proprioception assists the Reach and touch assists the Grasp in peripheral vision, supporting the idea that Reach and Grasp movements are used flexibly in relation to sensory guidance depending upon the salience of target properties.
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Fuerza de la Mano/fisiología , Movimiento/fisiología , Propiocepción/fisiología , Desempeño Psicomotor/fisiología , Tacto , Campos Visuales/fisiología , Fenómenos Biomecánicos , Femenino , Humanos , Masculino , Percepción Visual , Adulto JovenRESUMEN
OBJECTIVE: Pain's impact on executive function is understood and specific cognitive abilities may contribute to coping with pain, though past work is confounded by chronic pain populations. This study aims to understand how executive functioning may predict the experience of pain among healthy adults. It was hypothesized that poorer executive functioning would predict more intense pain perception. METHOD: A total of 172 young adults were recruited for participation. Three aspects of executive functioning (i.e., impulsivity, cognitive flexibility, working memory) were assessed before randomizing participants to varying types and levels of stimulated pain. RESULTS: Results supported the hypothesis that poorer performance on tasks of working memory predicts more intense pain perception. CONCLUSIONS: Findings are counter to past work that has found inhibition may be important for coping, and future research is needed to understand the impact of specific cognitive abilities as well as how this may differ for chronic pain.
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Beta-arrestins (ßarrs) are key regulators and transducers of G-protein coupled receptor signaling; however, little is known of how ßarrs communicate with their downstream effectors. Here, we use cryo-electron microscopy to elucidate how ßarr1 recruits and activates non-receptor tyrosine kinase Src. ßarr1 binds Src SH3 domain via two distinct sites: a polyproline site in the N-domain and a non-proline site in the central crest region. At both sites ßarr1 interacts with the aromatic surface of SH3 which is critical for Src autoinhibition, suggesting that ßarr1 activates Src by SH3 domain displacement. Binding of SH3 to the central crest region induces structural rearrangements in the ß-strand V, finger, and middle loops of ßarr1 and interferes with ßarr1 coupling to the receptor core potentially impacting receptor desensitization and downstream signaling.
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BACKGROUND: Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics. RESULTS: We analyzed complete ES/GS raw sequencing data from Mayo Clinic's Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A). CONCLUSION: ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP's limitations in detecting new disease-associated genes underscore the necessity for periodic updates.
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Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Adulto , Femenino , Masculino , Persona de Mediana Edad , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación del Exoma/métodos , Exoma/genética , Adulto Joven , Enfermedades Raras/genética , Enfermedades Raras/diagnóstico , Anciano , Adolescente , Secuenciación Completa del Genoma/métodosRESUMEN
Monokines (i.e., interleukin [IL]-12, -18, and -15) induce natural killer (NK) cells to produce interferon-gamma (IFN-gamma), which is a critical factor for immune surveillance of cancer and monocyte clearance of infection. We show that SET, which is a potent inhibitor of protein phosphatase type 2A (PP2A) activity, is highly expressed in human CD56bright NK cells, which produce more IFN-gamma than CD56dim NK cells. SET was up-regulated upon monokine stimulation of primary human NK cells. Furthermore, ectopic overexpression of SET significantly enhanced IFN-gamma gene expression in monokine-stimulated NK cells. In contrast, RNAi-mediated suppression of SET expression renders NK cells inefficient in producing high levels of IFN-gamma in response to monokine costimulation. Mechanistically, suppression of PP2A activity by SET is important for IFN-gamma gene expression in NK cells. In fact, treatment of primary human NK cells with the PP2A activator 1,9-dideoxy-forskolin, as well as administration of the drug to C57BL/6 mice, significantly reduced NK-dependent IFN-gamma production in response to monokine treatment. Further, SET knockdown or pharmacologic activation of PP2A diminished extracellular signal-regulated kinase 1/2, p65RelA, signal transducer and activator of transduction 4 (STAT4), and STAT5 activity in monokine-stimulated NK cells, potentially contributing to the reduction in IFN-gamma gene expression. Thus, SET expression is essential for suppressing PP2A phosphatase activity that would otherwise limit NK cell antitumoral and/or antiinflammatory functions by impairing NK cell production of IFN-gamma.