RESUMEN
The advent of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated nuclease 9 (Cas9) technology has revolutionized the field of genetic engineering, offering unprecedented potential for the targeted manipulation of DNA sequences. Advances in the mechanism of action of the CRISPR-Cas9 system allowed potential applicability for the treatment of genetic diseases. CRISPR-Cas9's mechanism of action involves the use of an RNA guide molecule to target-specific DNA sequences and the Cas9 enzyme to induce precise DNA cleavage. In the context of the CRISPR-Cas9 system, this review covers nonviral delivery methods for gene editing based on peptide internalization. Here, we describe critical areas of discussion such as immunogenicity, emphasizing the importance of safety, efficiency, and cost-effectiveness, particularly in the context of treating single-mutation genetic diseases using advanced editing techniques genetics as prime editor and base editor. The text discusses the versatility of cell-penetrating peptides (CPPs) in forming complexes for delivering biomolecules, particularly ribonucleoprotein for genome editing with CRISPR-Cas9 in human cells. In addition, it emphasizes the promise of combining CPPs with DNA base editing and prime editing systems. These systems, known for their simplicity and precision, hold great potential for correcting point mutations in human genetic diseases. In summary, the text provides a clear overview of the advantages of using CPPs for genome editing with CRISPR-Cas9, particularly in conjunction with advanced editing systems, highlighting their potential impact on clinical applications in the treatment of single-mutation genetic diseases. [Figure: see text].
Asunto(s)
Sistemas CRISPR-Cas , Péptidos de Penetración Celular , Edición Génica , Enfermedades Genéticas Congénitas , Terapia Genética , Humanos , Edición Génica/métodos , Terapia Genética/métodos , Enfermedades Genéticas Congénitas/terapia , Enfermedades Genéticas Congénitas/genética , Técnicas de Transferencia de Gen , AnimalesRESUMEN
In this pilot study, we aimed to evaluate the feasibility of whole genome sequencing (WGS) as a first-tier diagnostic test for infants hospitalized in neonatal intensive care units in the Brazilian healthcare system. The cohort presented here results from a joint collaboration between private and public hospitals in Brazil considering the initiative of a clinical laboratory to provide timely diagnosis for critically ill infants. We performed trio (proband and parents) WGS in 21 infants suspected of a genetic disease with an urgent need for diagnosis to guide medical care. Overall, the primary indication for genetic testing was dysmorphic syndromes (n = 14, 67%) followed by inborn errors of metabolism (n = 6, 29%) and skeletal dysplasias (n = 1, 5%). The diagnostic yield in our cohort was 57% (12/21) based on cases that received a definitive or likely definitive diagnostic result from WGS analysis. A total of 16 pathogenic/likely pathogenic variants and 10 variants of unknown significance were detected, and in most cases inherited from an unaffected parent. In addition, the reported variants were of different types, but mainly missense (58%) and associated with autosomal diseases (19/26); only three were associated with X-linked diseases, detected in hemizygosity in the proband an inherited from an unaffected mother. Notably, we identified 10 novel variants, absent from public genomic databases, in our cohort. Considering the entire diagnostic process, the average turnaround time from enrollment to medical report in our study was 53 days. Our findings demonstrate the remarkable utility of WGS as a diagnostic tool, elevating the potential of transformative impact since it outperforms conventional genetic tests. Here, we address the main challenges associated with implementing WGS in the medical care system in Brazil, as well as discuss the potential benefits and limitations of WGS as a diagnostic tool in the neonatal care setting.
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Pruebas Genéticas , Unidades de Cuidado Intensivo Neonatal , Secuenciación Completa del Genoma , Humanos , Brasil/epidemiología , Recién Nacido , Masculino , Femenino , Pruebas Genéticas/métodos , Proyectos Piloto , Lactante , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genéticaRESUMEN
Rapid genome sequencing impacted real-time diagnostic and therapeutic management for patients in a nonacademic community hospital. A retrospective chart review of 24 patients identified that more than 60% had a change in medical management as a result of rapid genome sequencing.
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Toma de Decisiones Clínicas/métodos , Anomalías Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/diagnóstico , Hospitales Comunitarios , Planificación de Atención al Paciente , Secuenciación Completa del Genoma/métodos , Anomalías Congénitas/genética , Anomalías Congénitas/terapia , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Marcadores Genéticos , Accesibilidad a los Servicios de Salud , Humanos , Lactante , Recién Nacido , Masculino , Michigan , Pautas de la Práctica en Medicina , Estudios Retrospectivos , Centros de Atención Terciaria , Factores de TiempoAsunto(s)
Oftalmopatías/diagnóstico , Enfermedades Genéticas Congénitas/diagnóstico , Proteínas de Microfilamentos/genética , Adulto , Argentina , Niño , Oftalmopatías/genética , Oftalmopatías/inmunología , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Humanos , Leucopenia/diagnóstico , Leucopenia/genética , Leucopenia/inmunología , Masculino , Hermanos , Adulto JovenRESUMEN
Forkhead box (FOX) proteins are members of a conserved family of transcription factors. Pathogenic variants in FOX genes have been shown to be responsible for several human genetic diseases. Here, we have studied the molecular and structural features of germline pathogenic variants in seven FOX proteins involved in Mendelian disorders and compared them with those of variants present in the general population (gnomAD). Our study shows that the DNA-binding domain of FOX proteins is particularly sensitive to damaging variation, although some family members show greater mutational tolerance than others. Next, we set to demonstrate that this tolerance depends on the inheritance mode of FOX-linked disorders. Accordingly, genes whose variants underlie recessive conditions are supposed to have a greater tolerance to variation. This is what we found. As expected, variants responsible for disorders with a dominant inheritance pattern show a higher degree of pathogenicity compared to those segregating in the general population. Moreover, we show that pathogenic and likely pathogenic variants tend to affect mutually exclusive sites with respect to those reported in gnomAD. The former also tend to affect sites with lower solvent exposure and a higher degree of conservation. Our results show the value of using publicly available databases and bioinformatics to gain insights into the molecular and structural bases of disease-causing genetic variation.
Asunto(s)
Factores de Transcripción Forkhead/genética , Enfermedades Genéticas Congénitas/genética , Mutación Missense/genética , Biología Computacional/métodos , Bases de Datos Genéticas , Predisposición Genética a la Enfermedad/genética , HumanosRESUMEN
The last 10 years have seen an explosion in the amount of data available through next-generation sequencing. These data are advancing quickly, and this pace makes it difficult for most practitioners to easily keep up with all of the new information. Complicating this understanding is sometimes conflicting information about variant pathogenicity or even about the role of some genes in the pathogenesis of disease. The more widespread clinical use of sequencing has expanded phenotypes, including the identification of mild phenotypes associated with previously serious disease, such as with some variants in RUNX1, MYH9, ITG2A, and others. Several organizations have taken up the task of cataloging and systematically evaluating genes and variants using a standardized approach and making the data publicly available so that others can benefit from their gene/variant curation. The efforts in testing for hereditary hemorrhagic, thrombotic, and platelet disorders have been led by the International Society on Thrombosis and Haemostasis Scientific Standardization Committee on Genomics in Thrombosis and Hemostasis, the American Society of Hematology, and the National Institutes of Health National Human Genome Research Institute Clinical Genome Resource. This article outlines current efforts to improve the interpretation of genetic testing and the role of standardizing and disseminating information. By assessing the strength of gene-disease associations, standardizing variant curation guidelines, sharing genomic data among expert members, and incorporating data from existing disease databases, the number of variants of uncertain significance will decrease, thereby improving the value of genetic testing as a diagnostic tool.
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Trastornos de las Plaquetas Sanguíneas , Enfermedades Genéticas Congénitas , Pruebas Genéticas , Hemorragia , Secuenciación de Nucleótidos de Alto Rendimiento , Trombosis , Adolescente , Trastornos de las Plaquetas Sanguíneas/diagnóstico , Trastornos de las Plaquetas Sanguíneas/genética , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Hemorragia/diagnóstico , Hemorragia/genética , Humanos , Trombosis/diagnóstico , Trombosis/genéticaRESUMEN
PURPOSE: To characterize the pediatric population with inborn errors of immunity (IEI) that was treated with hematopoietic stem cell transplantation (HSCT) in three reference centers in Colombia. What have been the characteristics and outcomes of hematopoietic stem cell transplantation in pediatric patients with inborn errors of immunity in three reference care centers in Colombia between 2007 and 2018? METHODS: We conducted an observational, retrospective cohort study in children with a diagnosis of IEI who underwent HSCT between 2007 and 2018. RESULTS: Forty-seven patients were identified, and 5 were re-transplanted. Sixty-eight percent were male. The median age at diagnosis was 0.6 years, and for HSCT was 1.4 years. The most common diseases were chronic granulomatous disease (38%) followed by severe combined immune deficiencies (19%) and hemophagocytic lymphohistiocytosis (15%). Cord blood donors were the most used source of HSCT (44%). T cell-replete grafts from haploidentical donors using post-transplantation cyclophosphamide represent 37% of the cohort. All patients received conditioning, 62% with a non-myeloablative regimen. Calcineurin inhibitors were the main graft-versus-host disease prophylaxis (63.8%). Acute graft-versus-host disease developed in 35% of the total patients. The most frequent post-transplant infections were viral and fungal infections. The 1-year overall survival rates for the patients who received HSCT from identical, haploidentical, and cord sources were 80%, 72%, and 63%, respectively. The 5-year overall survival was 63%. CONCLUSIONS: HSCT is a curative treatment option for some IEI and can be performed with any donor type. Early and timely treatment in referral centers can improve survival.
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Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Predisposición Genética a la Enfermedad , Trasplante de Células Madre Hematopoyéticas , Enfermedades de Inmunodeficiencia Primaria/etiología , Enfermedades de Inmunodeficiencia Primaria/terapia , Preescolar , Colombia , Terapia Combinada , Diagnóstico Diferencial , Femenino , Estudios de Asociación Genética , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Depleción Linfocítica , Masculino , Fenotipo , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/mortalidad , Donantes de Tejidos , Resultado del TratamientoRESUMEN
In the next decades, gene editing technologies are expected to be used in the treatment and prevention of human diseases. Yet, the future uses of gene editing in medicine are still unknown, including its applicability and effectiveness to the treatment and prevention of infectious diseases, cancer, and monogenic and polygenic hereditary diseases. This study aims to address this gap by analyzing the views of over 1,000 gene editing-related researchers from all over the world. Some of our survey results show that, in the next 10 years, DNA double-strand breaks are expected to be the main method for gene editing, and CRISPR-Cas systems to be the mainstream programmable nuclease. In the same period, gene editing is expected to have more applicability and effectiveness to treat and prevent infectious diseases and cancer. Off-targeting mutations, reaching therapeutic levels of editing efficiency, difficulties in targeting specific tissues in vivo, and regulatory and ethical challenges are among the most relevant factors that might hamper the use of gene editing in humans. In conclusion, our results suggest that gene editing might become a reality to the treatment and prevention of a variety of human diseases in the coming 10 years. If the future confirms these researchers' expectations, gene editing could change the way medicine, health systems, and public health deal with the treatment and prevention of human diseases.
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Sistemas CRISPR-Cas , Edición Génica , Enfermedades Genéticas Congénitas/terapia , Terapia Genética , Genoma Humano , Investigadores/estadística & datos numéricos , Enfermedades Genéticas Congénitas/genética , Investigación Genética , Humanos , Investigadores/psicología , Encuestas y CuestionariosRESUMEN
The misuse of sport-related gene transfer methods in elite athletes is a real and growing concern. The success of gene therapy in the treatment of hereditary diseases has been most evident since targets in gene therapy products can be used in healthy individuals to improve sports performance. Performing these practices threatens the sporting character of competitions and may pose potential health hazards. Since the World Anti-Doping Agency pronouncement on the prohibition of such practices in 2003, several researchers have been trying to address the challenge of developing an effective method for the detection of genetic doping. This review presents an overview of the published methods developed for this purpose, the advantages and limitations of technologies and the putative target genes. At last, we present the perspective related to the application of the detection methods in the doping control field.
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Doping en los Deportes , Enfermedades Genéticas Congénitas/terapia , Pruebas Genéticas , Terapia Genética , Atletas , Enfermedades Genéticas Congénitas/genética , HumanosRESUMEN
OBJECTIVES: To evaluate the clinical usefulness of rapid exome sequencing (rES) in critically ill children with likely genetic disease using a standardized process at a single institution. To provide evidence that rES with should become standard of care for this patient population. STUDY DESIGN: We implemented a process to provide clinical-grade rES to eligible children at a single institution. Eligibility included (a) recommendation of rES by a consulting geneticist, (b) monogenic disorder suspected, (c) rapid diagnosis predicted to affect inpatient management, (d) pretest counseling provided by an appropriate provider, and (e) unanimous approval by a committee of 4 geneticists. Trio exome sequencing was sent to a reference laboratory that provided verbal report within 7-10 days. Clinical outcomes related to rES were prospectively collected. Input from geneticists, genetic counselors, pathologists, neonatologists, and critical care pediatricians was collected to identify changes in management related to rES. RESULTS: There were 54 patients who were eligible for rES over a 34-month study period. Of these patients, 46 underwent rES, 24 of whom (52%) had at least 1 change in management related to rES. In 20 patients (43%), a molecular diagnosis was achieved, demonstrating that nondiagnostic exomes could change medical management in some cases. Overall, 84% of patients were under 1 month old at rES request and the mean turnaround time was 9 days. CONCLUSIONS: rES testing has a significant impact on the management of critically ill children with suspected monogenic disease and should be considered standard of care for tertiary institutions who can provide coordinated genetics expertise.
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Secuenciación del Exoma , Enfermedades Genéticas Congénitas/diagnóstico , Pruebas Genéticas , Adolescente , Niño , Preescolar , Cuidados Críticos , Enfermedad Crítica , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Humanos , Lactante , Recién Nacido , Masculino , Selección de Paciente , Estudios RetrospectivosRESUMEN
Abstract There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.
Resumo As doenças renais genéticas raras compreendem mais de 150 desordens. Elas podem ser classificadas segundo achados diagnósticos como (i) distúrbios do crescimento e estrutura, (ii) doenças glomerulares, (iii) tubulares e (iv) metabólicas. Nos últimos anos, houve uma mudança de paradigma nesse campo. Os testes moleculares tornaram-se mais acessíveis, nossa compreensão sobre os mecanismos fisiopatológicos subjacentes a essas doenças evoluiu e novas estratégias terapêuticas foram propostas. Portanto, o papel do nefrologista mudou progressivamente de mero espectador a participante ativo, parte de uma equipe multidisciplinar, no diagnóstico e tratamento desses distúrbios. O presente artigo oferece um panorama geral dos recentes avanços a respeito dos distúrbios renais hereditários raros, discutindo aspectos genéticos, manifestações clínicas e abordagens diagnósticas e terapêuticas de alguns desses distúrbios, mais especificamente a glomeruloesclerose segmentar e focal familiar, complexo da esclerose tuberosa, nefropatia de Fabry e doença relacionada ao MYH9.
Asunto(s)
Humanos , Masculino , Femenino , Lactante , Preescolar , Niño , Adulto , Enfermedades Genéticas Congénitas/genética , Riñón/fisiopatología , Enfermedades Renales/congénito , Enfermedades Renales/diagnóstico , Trombocitopenia/congénito , Trombocitopenia/diagnóstico , Trombocitopenia/terapia , Esclerosis Tuberosa/terapia , Pruebas Genéticas/métodos , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Enfermedad de Fabry/terapia , Comunicación Interdisciplinaria , Tasa de Filtración Glomerular/fisiología , Pérdida Auditiva Sensorineural/diagnóstico , Enfermedades Genéticas Congénitas/diagnóstico , Túbulos Renales/patología , Enfermedades Metabólicas/patología , Nefrología/normasRESUMEN
There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Enfermedades Renales/congénito , Enfermedades Renales/diagnóstico , Riñón/fisiopatología , Adulto , Niño , Preescolar , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Enfermedad de Fabry/terapia , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Pruebas Genéticas/métodos , Tasa de Filtración Glomerular/fisiología , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/terapia , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/terapia , Humanos , Lactante , Comunicación Interdisciplinaria , Enfermedades Renales/fisiopatología , Enfermedades Renales/terapia , Glomérulos Renales/patología , Túbulos Renales/patología , Masculino , Enfermedades Metabólicas/patología , Nefrología/normas , Trombocitopenia/congénito , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/terapia , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/terapiaRESUMEN
OBJECTIVE: Genetic carrier screening has the potential to identify couples at risk of having a child affected with an autosomal recessive or X-linked disorder. However, the current prevalence of carrier status for these conditions in developing countries is not well defined. This study assesses the prevalence of carrier status of selected genetic conditions utilizing an expanded, pan-ethnic genetic carrier screening panel (ECS) in a large population of Mexican patients. METHODS: Retrospective chart review of all patients tested with a single ECS panel at an international infertility center from 2012 to 2018 were included, and the prevalence of positive carrier status in a Mexican population was evaluated. RESULTS: Eight hundred five individuals were analyzed with ECS testing for 283 genetic conditions. Three hundred fifty-two carriers (43.7%) were identified with 503 pathogenic variants in 145 different genes. Seventeen of the 391 participating couples (4.34%) were identified as being at-risk couples. The most prevalent alleles found were associated with alpha thalassemia, cystic fibrosis, GJB2 nonsyndromic hearing loss, biotinidase deficiency, and familial Mediterranean fever. CONCLUSION: Based on the prevalence and severity of Mendelian disorders, we recommend that couples who wish to conceive regardless of their ethnicity background explore carrier screening and genetic counseling prior to reproductive medical treatment.
Asunto(s)
Tamización de Portadores Genéticos , Enfermedades Genéticas Congénitas/epidemiología , Atención Preconceptiva , Adulto , Biotinidasa/genética , Deficiencia de Biotinidasa/epidemiología , Deficiencia de Biotinidasa/genética , Conexina 26/genética , Fibrosis Quística/epidemiología , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fiebre Mediterránea Familiar/epidemiología , Fiebre Mediterránea Familiar/genética , Femenino , Asesoramiento Genético , Enfermedades Genéticas Congénitas/genética , Pérdida Auditiva Sensorineural/epidemiología , Pérdida Auditiva Sensorineural/genética , Hemoglobina A/genética , Heterocigoto , Humanos , Masculino , México/epidemiología , Persona de Mediana Edad , Prevalencia , Pirina/genética , Estudios Retrospectivos , Medición de Riesgo , Talasemia alfa/epidemiología , Talasemia alfa/genéticaRESUMEN
This article examines the origins of the term "genetic disease." In the late 19 and early 20th century, an earlier idea that diseases that occur in families reflect a vague familiar "predisposition" was replaced by the view that such diseases have specific causes, while Mendelian genetics provided then clues to the patterns of their transmission. The genetictisation of inborn pathologies took a decisive turn with the redefinition, in 1959, of Down syndrome as a chromosomal anomaly, then the development of tests for the diagnosis of other hereditary pathologies. At that time, geneticists distinguished "hereditary" diseases that run in families, from "genetic" conditions that are the result of new mutations during the production of egg and sperm cells. In the latter case, the inborn impairment is produced by an anomaly in the genetic material of the cell, but is not hereditary, because it is not transmitted from one or both parents. In the late 20th and early 21st century, new genomic technologies blurred the distinction between hereditary and genetic impairments, extended the concept of genetic disease, and modified the experience of people living with such a disease.
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Enfermedades Genéticas Congénitas/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Enfermedades Genéticas Congénitas/historia , Predisposición Genética a la Enfermedad/historia , Pruebas Genéticas/historia , Genómica/métodos , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
There are currently between six and eight thousand illnesses classified as rare diseases, 80% of which are of genetic origin and among the studies those of a quantitative and biomedical nature stand out. The objective of this study was to identify and describe the characteristics of scientific studies in Brazil and worldwide using a qualitative approach on rare genetic diseases published in indexed databases in the area of health and social sciences. The Scielo, Lilacs, Medline, PubMed, BDENF, Web of Science, Scopus and CINAHL databases were researched between 2013-2018 using the key words "Qualitative Research" and "Rare Disease." A total of 171 articles, classified by year, country, language, rare disease type, data collection strategy, knowledge area and theme were selected. The texts reveal the relevance of qualitative studies on rare genetic diseases in their ability to support organization, decision-making and health training in a way that responds to the social and individual needs of the community. It is important, however, to conduct further studies, especially within Brazil, that address rare genetic conditions, revealing the experiences and how they affect the personal, family, professional and organizational interactions in terms of the proper and effective modes of care.
Atualmente, há entre seis e oito mil adoecimentos catalogados por doenças raras, sendo que 80% são de origem genética e entre os estudos sobressaem os de natureza quantitativa e biomédica. Objetivou-se identificar e descrever as características dos estudos científicos, no Brasil e internacionalmente, com abordagem qualitativa, acerca das doenças genéticas raras publicados em bases indexadas na área da saúde e das ciências sociais. Utilizaram-se as bases de dados Scielo, Lilacs, Medline, PubMed, BDENF, Web of Science, Scopus e CINAHL, com os descritores: "Qualitative Research" e "Rare Disease", entre 2013-2018. Foram selecionados 171 artigos, classificados por ano, país, idioma, tipo de doença rara, estratégia de coleta de dados, área de conhecimento e tema. As produções revelam a pertinência dos estudos qualitativos sobre doença genética rara no seu potencial para subsidiar a organização, a tomada de decisões e a formação em saúde, de maneira que respondam às necessidades sociais e individuais da comunidade. É importante, todavia, desenvolver mais estudos, principalmente brasileiros, que abordem as condições genéticas raras, relevando as vivências e os afetamentos nas interações pessoais, familiares, profissionais e organizacionais perante os modos próprios e efetivos de cuidar.
Asunto(s)
Enfermedades Genéticas Congénitas/epidemiología , Salud Global , Enfermedades Raras/epidemiología , Brasil/epidemiología , Atención a la Salud/organización & administración , Enfermedades Genéticas Congénitas/genética , Humanos , Investigación Cualitativa , Enfermedades Raras/genéticaRESUMEN
Abstract This article examines the origins of the term "genetic disease." In the late 19 and early 20th century, an earlier idea that diseases that occur in families reflect a vague familiar "predisposition" was replaced by the view that such diseases have specific causes, while Mendelian genetics provided then clues to the patterns of their transmission. The genetictisation of inborn pathologies took a decisive turn with the redefinition, in 1959, of Down syndrome as a chromosomal anomaly, then the development of tests for the diagnosis of other hereditary pathologies. At that time, geneticists distinguished "hereditary" diseases that run in families, from "genetic" conditions that are the result of new mutations during the production of egg and sperm cells. In the latter case, the inborn impairment is produced by an anomaly in the genetic material of the cell, but is not hereditary, because it is not transmitted from one or both parents. In the late 20th and early 21st century, new genomic technologies blurred the distinction between hereditary and genetic impairments, extended the concept of genetic disease, and modified the experience of people living with such a disease.
Resumo O presente artigo tem o objetivo de examinar as origens do termo "doença genética. No final do século XIX e início do XX, a vaga ideia que a doença manifesta entre familiares refletia uma "predisposição" familiar, foi substituída pela visão que essas doenças possuem causas específicas, enquanto a genética mendeliana forneceu as pistas para os padrões de transmissão da doença. A genética das patologias congênitas deu uma guinada decisiva, em 1959, com a redefinição da Síndrome de Down como uma anomalia cromossômica e, depois, com o desenvolvimento de testes para o diagnóstico de outras patologias hereditárias. Naquela época, os geneticistas distinguiam doenças "hereditárias" como aquelas que acometiam os elementos de uma família, de condições "genéticas" que são o resultado de novas mutações ocorridas durante a produção dos óvulos e espermatozoides. Neste último caso, a deficiência inata é causada por uma anomalia do material genético da célula, porque não é transmitida por qualquer um ou ambos os pais. No final do século XX e início do XXI, as novas tecnologias genômicas obscureceram a distinção entre deficiências hereditária e a genética, estenderam o conceito da doença genética e modificaram a experiência das pessoas que vivem com esse tipo de doença.
Asunto(s)
Humanos , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Pruebas Genéticas/métodos , Predisposición Genética a la Enfermedad/genética , Enfermedades Genéticas Congénitas/genética , Pruebas Genéticas/historia , Predisposición Genética a la Enfermedad/historia , Genómica/métodos , Enfermedades Genéticas Congénitas/historiaRESUMEN
Resumo Atualmente, há entre seis e oito mil adoecimentos catalogados por doenças raras, sendo que 80% são de origem genética e entre os estudos sobressaem os de natureza quantitativa e biomédica. Objetivou-se identificar e descrever as características dos estudos científicos, no Brasil e internacionalmente, com abordagem qualitativa, acerca das doenças genéticas raras publicados em bases indexadas na área da saúde e das ciências sociais. Utilizaram-se as bases de dados Scielo, Lilacs, Medline, PubMed, BDENF, Web of Science, Scopus e CINAHL, com os descritores: "Qualitative Research" e "Rare Disease", entre 2013-2018. Foram selecionados 171 artigos, classificados por ano, país, idioma, tipo de doença rara, estratégia de coleta de dados, área de conhecimento e tema. As produções revelam a pertinência dos estudos qualitativos sobre doença genética rara no seu potencial para subsidiar a organização, a tomada de decisões e a formação em saúde, de maneira que respondam às necessidades sociais e individuais da comunidade. É importante, todavia, desenvolver mais estudos, principalmente brasileiros, que abordem as condições genéticas raras, relevando as vivências e os afetamentos nas interações pessoais, familiares, profissionais e organizacionais perante os modos próprios e efetivos de cuidar.
Abstract There are currently between six and eight thousand illnesses classified as rare diseases, 80% of which are of genetic origin and among the studies those of a quantitative and biomedical nature stand out. The objective of this study was to identify and describe the characteristics of scientific studies in Brazil and worldwide using a qualitative approach on rare genetic diseases published in indexed databases in the area of health and social sciences. The Scielo, Lilacs, Medline, PubMed, BDENF, Web of Science, Scopus and CINAHL databases were researched between 2013-2018 using the key words "Qualitative Research" and "Rare Disease." A total of 171 articles, classified by year, country, language, rare disease type, data collection strategy, knowledge area and theme were selected. The texts reveal the relevance of qualitative studies on rare genetic diseases in their ability to support organization, decision-making and health training in a way that responds to the social and individual needs of the community. It is important, however, to conduct further studies, especially within Brazil, that address rare genetic conditions, revealing the experiences and how they affect the personal, family, professional and organizational interactions in terms of the proper and effective modes of care.
Asunto(s)
Humanos , Salud Global , Enfermedades Raras/epidemiología , Enfermedades Genéticas Congénitas/epidemiología , Brasil/epidemiología , Atención a la Salud/organización & administración , Enfermedades Raras/genética , Investigación Cualitativa , Enfermedades Genéticas Congénitas/genéticaRESUMEN
OBJECTIVE: To investigate the prevalence of genetic disease and its economic impact in a level IV neonatal intensive care unit (NICU) by identifying and describing diseases diagnosed, genetic testing methodologies used, timing of diagnosis, length of NICU stay, and charges for NICU care. STUDY DESIGN: A retrospective chart review of patients admitted to a level IV NICU from 2013 to 2014 (n = 1327) was undertaken and data collected up to 2 years of age from the electronic medical record. RESULTS: In total, 117 patients (9%) received 120 genetic diagnoses using a variety of methodologies. A significant minority of diagnoses, 36%, were made after NICU discharge and 41% were made after 28 days of age. Patients receiving a genetic diagnosis had significantly longer mean lengths of stay (46 days vs 29.1 days; P < .01) and costlier mean charges ($598 712 vs $352 102; P < .01) for their NICU care. The NICU stay charge difference to care for a newborn with a genetic condition was on average $246â610 in excess of that for a patient without a genetic diagnosis, resulting in more than $28â000â000 in excess charges to care for all patients with genetic conditions in a single NICU over a 2-year period. CONCLUSIONS: Given the high prevalence of genetic disease in this population and the documented higher cost of care, shortening the time to diagnosis and targeting therapeutic interventions for this population could make a significant impact on neonatal care in level IV NICUs.
Asunto(s)
Enfermedades Genéticas Congénitas/economía , Enfermedades Genéticas Congénitas/genética , Pruebas Genéticas/economía , Pruebas Genéticas/métodos , Unidades de Cuidado Intensivo Neonatal , Cuidado Intensivo Neonatal/economía , Metilación de ADN , Registros Electrónicos de Salud , Exoma , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Humanos , Hibridación Fluorescente in Situ , Lactante , Mortalidad Infantil , Recién Nacido , Tiempo de Internación , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Alta del Paciente , Prevalencia , Estudios Retrospectivos , Análisis de Secuencia de ADNRESUMEN
Whole-exome sequencing of samples from affected members of two unrelated families with late-onset non-syndromic hearing loss revealed a novel mutation (c.2090 T > G; NM_017433) in MYO3A. The mutation was confirmed in 36 affected individuals, showing autosomal dominant inheritance. The mutation alters a single residue (L697W or p.Leu697Trp) in the motor domain of the stereocilia protein MYO3A, leading to a reduction in ATPase activity, motility, and an increase in actin affinity. MYO3A-L697W showed reduced filopodial actin protrusion initiation in COS7 cells, and a predominant tipward accumulation at filopodia and stereocilia when coexpressed with wild-type MYO3A and espin-1, an actin-regulatory MYO3A cargo. The combined higher actin affinity and duty ratio of the mutant myosin cause increased retention time at stereocilia tips, resulting in the displacement of the wild-type MYO3A protein, which may impact cargo transport, stereocilia length, and mechanotransduction. The dominant negative effect of the altered myosin function explains the dominant inheritance of deafness.