RESUMEN
The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.
Asunto(s)
Anemia Aplásica , Enfermedades de la Médula Ósea , Adulto , Humanos , Niño , Anemia Aplásica/genética , Anemia Aplásica/terapia , Anemia Aplásica/patología , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/terapia , Enfermedades de la Médula Ósea/patología , Australia/epidemiología , Trastornos de Fallo de la Médula Ósea , Síndrome , Sistema de RegistrosRESUMEN
Because germ line genetic testing is increasingly integrated into the clinical care of patients with hematologic malignancies, it is important for hematologists to effectively communicate with patients and their families about the genetic testing process and to relay the results in a concise and understandable manner. Effective communication facilitates trust between patients and providers and allows patients to feel empowered to ask questions and actively participate in their health care. Especially for inherited conditions, the patient's understanding of germ line genetic information is critical because it enables them to share this information with relatives who are at risk, thereby promoting cascade testing and providing potentially life-saving information to family members who may be similarly affected. Accordingly, a hematologist's skills in understanding the importance and implications of germ line genetic information and the ability to convey this information in patient-friendly language is a critical first step and can have a far-reaching impact. In this article, we outline a straightforward approach to discussing genetic information and provide the reader with practical tips that can be used when consenting patients to germ line genetic testing and disclosing subsequent test results. We also review special considerations and ethical concerns arising when offering genetic evaluation and germ line testing to patients and related donors for allogeneic hematopoietic stem cell transplantation.
Asunto(s)
Pruebas Genéticas , Neoplasias Hematológicas , Humanos , Familia , Cuidados Paliativos , Células GerminativasAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma Cutáneo de Células T , Linfoma de Células T , Paniculitis , Neoplasias Cutáneas , Humanos , Paniculitis/diagnóstico , Paniculitis/etiología , Paniculitis/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Linfoma de Células T/patología , Neoplasias Cutáneas/patologíaAsunto(s)
ADN Glicosilasas , Neoplasias , Secuencia de Aminoácidos , ADN Glicosilasas/genética , ADN Glicosilasas/metabolismo , Metilación de ADN , Reparación del ADN , Endodesoxirribonucleasas/química , Endodesoxirribonucleasas/genética , Endodesoxirribonucleasas/metabolismo , Humanos , Neoplasias/genética , FenotipoRESUMEN
Telomere biology disorders (TBDs) are a spectrum of multisystem inherited disorders characterized by bone marrow failure, resulting from mutations in the genes encoding telomerase or other proteins involved in maintaining telomere length and integrity. Pathogenicity of variants in these genes can be hard to evaluate, because TBD mutations show highly variable penetrance and genetic anticipation related to inheritance of shorter telomeres with each generation. Thus, detailed functional analysis of newly identified variants is often essential. Herein, we describe a patient with compound heterozygous variants in the TERT gene, which encodes the catalytic subunit of telomerase, hTERT. This patient had the extremely severe Hoyeraal-Hreidarsson form of TBD, although his heterozygous parents were clinically unaffected. Molecular dynamic modeling and detailed biochemical analyses demonstrate that one allele (L557P) affects association of hTERT with its cognate RNA component hTR, whereas the other (K1050E) affects the binding of telomerase to its DNA substrate and enzyme processivity. Unexpectedly, the data demonstrate a functional interaction between the proteins encoded by the two alleles, with wild-type hTERT rescuing the effect of K1050E on processivity, whereas L557P hTERT does not. These data contribute to the mechanistic understanding of telomerase, indicating that RNA binding in one hTERT molecule affects the processivity of telomere addition by the other molecule. This work emphasizes the importance of functional characterization of TERT variants to reach a definitive molecular diagnosis for patients with TBD, and, in particular, it illustrates the importance of analyzing the effects of compound heterozygous variants in combination, to reveal interallelic effects.
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Telomerasa , Biología , Humanos , Mutación , ARN/genética , Telomerasa/genética , Telomerasa/metabolismo , Telómero/genética , Telómero/metabolismoRESUMEN
Zebrafish are an important model for studying phagocyte function, but rigorous experimental systems to distinguish whether phagocyte-dependent effects are neutrophil or macrophage specific have been lacking. We have developed and validated transgenic lines that enable superior demonstration of cell-autonomous neutrophil and macrophage genetic requirements. We coupled well-characterized neutrophil- and macrophage-specific Gal4 driver lines with UAS:Cas9 transgenes for selective expression of Cas9 in either neutrophils or macrophages. Efficient gene editing, confirmed by both Sanger and next-generation sequencing, occurred in both lineages following microinjection of efficacious synthetic guide RNAs into zebrafish embryos. In proof-of-principle experiments, we demonstrated molecular and/or functional evidence of on-target gene editing for several genes (mCherry, lamin B receptor, trim33) in either neutrophils or macrophages as intended. These new UAS:Cas9 tools provide an improved resource for assessing individual contributions of neutrophil- and macrophage-expressed genes to the many physiological processes and diseases modelled in zebrafish. Furthermore, this gene-editing functionality can be exploited in any cell lineage for which a lineage-specific Gal4 driver is available. This article has an associated First Person interview with the first author of the paper.
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Edición Génica , Pez Cebra , Animales , Animales Modificados Genéticamente , Sistemas CRISPR-Cas/genética , Humanos , Macrófagos/metabolismo , Neutrófilos/metabolismo , Factores de Transcripción/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin is demonstrated. Recently, proliferative GN with monoclonal immunoglobulin deposits (PGNMID) has incorporated a light chain variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of C3 is found in addition to monotypic light chain, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year-old man who presented with nephrotic syndrome and was found to have κ light chain multiple myeloma. Immune staining of the glomerulus was positive only for κ light chain and C3, with the striking appearance of nonamyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for light chain and complement and consider local mechanisms whereby monoclonal κ light chain fibrils may have triggered AP activation within the glomerulus.
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Complemento C3/metabolismo , Glomerulonefritis Membranoproliferativa/diagnóstico , Inmunoglobulina G/inmunología , Glomérulos Renales/ultraestructura , Adulto , Biopsia , Fibrosis/diagnóstico , Fibrosis/inmunología , Fibrosis/metabolismo , Glomerulonefritis Membranoproliferativa/inmunología , Glomerulonefritis Membranoproliferativa/metabolismo , Humanos , Inmunoglobulina G/metabolismo , Glomérulos Renales/metabolismo , Masculino , Microscopía ElectrónicaAsunto(s)
Factor de Transcripción GATA2 , Mutación de Línea Germinal , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Proteínas de Neoplasias , Adulto , Femenino , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA2/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismoRESUMEN
Hypocellular bone marrow failure (BMF) has myriad differential diagnoses, most simply considered as acquired and inherited disorders, which are frequently indistinguishable upon morphologic examination of the blood and bone marrow. Accurate diagnosis is critical to optimization of management and begins with a detailed history (including family history) and physical examination. Next-generation sequencing technologies complement traditional testing techniques (such as chromosomal fragility and telomere length assessment) and have a broad application in the diagnosis and prognostication of BMF, with the importance of detection of both germline changes and also somatic variants increasingly well understood and appreciated. There is increasing awareness of germline predisposition to haematological malignancy, which incorporates but is not limited to the traditional inherited BMF syndromes and which raises challenges for counselling, monitoring and treatment of people who harbour a germline lesion. There are many benefits to both patients and their kindred of accurate determination of the precise germline change underlying heritable bone marrow diseases, along with its associated mode of inheritance. While individually, these diseases are rare, collectively they are not so and there are many collaborative efforts underway to document the natural history of these disorders, the associated phenotypes and the ever-increasing list of variants which have sufficient evidence to warrant the ascription of a pathogenic classification. We describe the many diagnostic considerations when evaluating newly presenting patients with hypocellular BMF, with a focus on genomic assessment, which is relevant in both germline and acquired diseases.
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Anemia Aplásica , Predisposición Genética a la Enfermedad , Genómica , Mutación de Línea Germinal , Neoplasias Hematológicas , Secuenciación de Nucleótidos de Alto Rendimiento , Anemia Aplásica/diagnóstico , Anemia Aplásica/genética , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , HumanosAsunto(s)
Leucemia Linfoide , Linfoma no Hodgkin , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Niño , ADN Helicasas , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genéticaAsunto(s)
Anemia Aplásica , Suero Antilinfocítico , Niño , Humanos , Terapia de Inmunosupresión , Estados UnidosRESUMEN
Acquired aplastic anaemia is a rare, serious, immunologically mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and significant pancytopenia. Careful attention and investigation, including molecular testing, is required to confirm the diagnosis and exclude other mimicking conditions, such as inherited bone marrow failure syndromes. In a proportion of patients, the disease evolves to myelodysplasia or acute myeloid leukaemia and in some there is an association with paroxysmal nocturnal haemoglobinuria. The disease has a major impact on patient quality of life. Haemopoietic stem/progenitor cell transplantation for eligible patients with an available donor is the only current curative therapy. Other patients may receive immunosuppression, most commonly with anti-thymocyte globulin and cyclosporin. An initial response to immunosuppression is often encouraging, but relapse is common. Supportive care, including management of transfusion requirements and infections, is central to management. Promising new diagnostic tools and emerging therapies will likely transform approaches to this important, chronic and life-threatening condition.