RESUMEN
Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear.
Asunto(s)
Enfermedad Crítica/terapia , Medicina de Precisión , Secuenciación Completa del Genoma , California , Estudios de Cohortes , Costo de Enfermedad , Cuidados Críticos , Femenino , Hospitales Pediátricos , Humanos , Lactante , Recién Nacido , Masculino , Medicaid , Estudios Prospectivos , Resultado del Tratamiento , Estados UnidosRESUMEN
We report three unrelated individuals with atypical clinical findings for cardio-facio-cutaneous (CFC) syndrome, all of whom have the same novel, heterozygous de novo p.H119Y (c.355 C>T) transition variant in MAP2K1, identified by exome sequencing. MAP2K1 encodes MEK1, dual specificity mitogen-activated protein kinase kinase 1, and is one of four genes in the canonical RAS/MAPK signal transduction pathway associated with CFC syndrome. The p.H119Y variant is a non-conservative amino acid substitution that is predicted to impact the tertiary protein structure, and it occurs at a position in the protein kinase domain of MAP2K1 that is highly conserved across species. The clinical findings in these three individuals include facial features that are nonclassical for CFC syndrome, extremely poor weight gain, absence of congenital cardiac defects or cardiomyopathy, normal cognition or only mild intellectual disabilities, normal hair, mild skin abnormalities, and consistent behavioral features of anxiety, photophobia, and sensory hypersensitivities. These individuals expand the phenotypic spectrum of MAP2K1-related RASopathy.
RESUMEN
Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.
Asunto(s)
Síndrome de Costello , Displasia Ectodérmica , Cardiopatías Congénitas , Neoplasias , Síndrome de Noonan , Humanos , Proteínas ras/genética , Sistema de Señalización de MAP Quinasas/genética , Síndrome de Costello/genética , Neoplasias/genética , Displasia Ectodérmica/genética , Síndrome de Noonan/genética , Cardiopatías Congénitas/genéticaRESUMEN
We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio-facio-cutaneous (CFC) syndrome. A comprehensive, retrospective medical history survey was distributed to parents of children with confirmed CFC in collaboration with CFC International, Inc. Data were collected on CFC gene variant, maternal characteristics, pregnancy course, delivery, and neonatal outcomes with the support of medical records. We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes. The median age was 8.5 years. Hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia occurred in 5/43 (12%), 4/43 (9%), 3/43 (7%), and 3/43 (7%) of pregnancies, respectively. Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Delivery occurred via spontaneous vaginal, operative vaginal, or cesarean delivery in 15/42 (36%), 7/42 (16%), and 20/42 (48%), respectively. Median gestational age at delivery was 37 weeks and median birth weight was 3501 grams. Germline pathogenic vaiants had mutiple congenital consequences including polyhydramnios, renal and cardiac abnormalities, macrosomia, and macrocephaly on second and third trimester ultrasound. Elevated rates of operative delivery and neonatal complications were also noted. Understanding and defining a prenatal phenotype may improve prenatal prognostic counseling and outcomes.
Asunto(s)
Displasia Ectodérmica , Cardiopatías Congénitas , Megalencefalia , Polihidramnios , Humanos , Embarazo , Femenino , Estudios Retrospectivos , Macrosomía Fetal , Proteínas Proto-Oncogénicas B-raf/genética , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Facies , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patologíaRESUMEN
PURPOSE: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). METHODS: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. RESULTS: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. CONCLUSION: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
Asunto(s)
Metiltransferasas , Trastornos del Neurodesarrollo , Adenosina Difosfato/metabolismo , Animales , Histidina/análogos & derivados , Histidina/metabolismo , Humanos , Metiltransferasas/genética , Ratones , Ratones Endogámicos C57BL , Trastornos del Neurodesarrollo/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , SíndromeRESUMEN
PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.
Asunto(s)
Neurilemoma , Neurofibromatosis , Neurofibromatosis 1 , Neurofibromatosis 2 , Neoplasias Cutáneas , Consenso , Humanos , Neurilemoma/diagnóstico , Neurilemoma/genética , Neurilemoma/patología , Neurofibromatosis/diagnóstico , Neurofibromatosis/genética , Neurofibromatosis 1/genética , Neurofibromatosis 2/diagnóstico , Neurofibromatosis 2/genética , Neoplasias Cutáneas/genéticaRESUMEN
RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.
Asunto(s)
Síndrome de Costello , Síndrome de Noonan , Síndrome de Costello/genética , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Síndrome de Noonan/genética , Transducción de Señal , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
BACKGROUND: Cardio-facio-cutaneous (CFC) syndrome is a human multiple congenital anomaly syndrome that is caused by activating heterozygous mutations in either BRAF, MEK1, or MEK2, three protein kinases of the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC belongs to a group of syndromes known as RASopathies. Skeletal muscle hypotonia is a ubiquitous phenotype of RASopathies, especially in CFC syndrome. To better understand the underlying mechanisms for the skeletal myopathy in CFC, a mouse model with an activating BrafL597V allele was utilized. RESULTS: The activating BrafL597V allele resulted in phenotypic alterations in skeletal muscle characterized by a reduction in fiber size which leads to a reduction in muscle size which are functionally weaker. MAPK pathway activation caused inhibition of myofiber differentiation during embryonic myogenesis and global transcriptional dysregulation of developmental pathways. Inhibition in differentiation can be rescued by MEK inhibition. CONCLUSIONS: A skeletal myopathy was identified in the CFC BrafL597V mouse validating the use of models to study the effect of Ras/MAPK dysregulation on skeletal myogenesis. RASopathies present a novel opportunity to identify new paradigms of myogenesis and further our understanding of Ras in development. Rescue of the phenotype by inhibitors may help advance the development of therapeutic options for RASopathy patients.
Asunto(s)
Displasia Ectodérmica/genética , Insuficiencia de Crecimiento/genética , Cardiopatías Congénitas/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Músculo Esquelético/metabolismo , Enfermedades Musculares/genética , Proteínas Proto-Oncogénicas B-raf/genética , Alelos , Animales , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/metabolismo , Insuficiencia de Crecimiento/patología , Cardiopatías Congénitas/metabolismo , Cardiopatías Congénitas/patología , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Fenotipo , Proteínas Proto-Oncogénicas B-raf/metabolismoRESUMEN
PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
Asunto(s)
Neurofibromatosis 1 , Manchas Café con Leche/genética , Consenso , Pruebas Genéticas , Humanos , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/genéticaRESUMEN
Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies and is caused by germline mutations that activate the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC is due to heterozygous germline mutations in protein kinases BRAF, MEK1, or MEK2 and rarely in KRAS, a small GTPase. CFC is a multiple congenital anomaly disorder in which individuals may have craniofacial dysmorphia, heart issues, skin and hair anomalies, and delayed development. Pathogenic variants for CFC syndrome are usually considered de novo because vertical transmission has only been reported with MEK2 and KRAS. The index case was a 3-year-old male with features consistent with the clinical diagnosis of CFC. Sequencing revealed a previously reported heterozygous likely pathogenic variant BRAF p.G464R. Upon detailed family history, the index case's pregnant mother was noted to have similar features to her son. Targeted familial testing of the BRAF pathogenic variant was performed on the mother, confirming her diagnosis. Prenatal genetic testing for the fetus was declined, but postnatal molecular testing of the index case's sister was positive for the familial BRAF p.G464R variant. Functional analysis of the variant demonstrated increased kinase activity. We report the first identified vertically transmitted functional BRAF pathogenic variant. Our findings emphasize the importance of obtaining a comprehensive evaluation of family members and that activating pathogenic variants within the canonical MAPK cascade mediated by BRAF are compatible with human reproduction.
Asunto(s)
Anomalías Múltiples/genética , Displasia Ectodérmica/genética , Insuficiencia de Crecimiento/genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Anomalías Múltiples/patología , Adulto , Preescolar , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/patología , Femenino , Mutación de Línea Germinal/genética , Cardiopatías Congénitas/patología , Humanos , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 2/genética , Masculino , Embarazo , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Noonan syndrome (NS) is one of the common RASopathies. While the clinical phenotype in NS is variable, it is typically characterized by distinctive craniofacial features, cardiac defects, reduced growth, bleeding disorders, learning issues, and an increased risk of cancer. Several different genes cause NS, all of which are involved in the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. Juvenile xanthogranuloma (JXG) is an uncommon, proliferative, self-limited cutaneous disorder that affects young individuals and may be overlooked or misdiagnosed due to its transient nature. A RASopathy that is known to be associated with JXG is neurofibromatosis type 1 (NF1). JXG in NF1 has also been reported in association with a juvenile myelomonocytic leukemia (JMML). As RASopathies, both NS and NF1 have an increased incidence of JMML. We report a 10-month-old female with NS who has a PTPN11 pathogenic variant resulting in a heterozygous SHP2 p.Y62D missense mutation. She was found to have numerous, small, yellow-pink smooth papules that were histopathologically confirmed to be JXG. In understanding the common underlying pathogenetic dysregulation of the Ras/MAPK pathway in both NS and NF1, this report suggests a possible molecular association for why NS individuals may be predisposed to JXG.
Asunto(s)
Predisposición Genética a la Enfermedad , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Xantogranuloma Juvenil/genética , Femenino , Humanos , Lactante , Leucemia Mielomonocítica Juvenil/complicaciones , Leucemia Mielomonocítica Juvenil/patología , Mutación Missense/genética , Neurofibromina 1/genética , Síndrome de Noonan/complicaciones , Síndrome de Noonan/patología , Fenotipo , Xantogranuloma Juvenil/complicaciones , Xantogranuloma Juvenil/patología , Proteínas ras/genéticaRESUMEN
RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1-related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non-NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.
Asunto(s)
Síndrome de Costello/terapia , Displasia Ectodérmica/terapia , Insuficiencia de Crecimiento/terapia , Cardiopatías Congénitas/terapia , Terapia Molecular Dirigida , Mutación , Neurofibromatosis 1/terapia , Síndrome de Noonan/terapia , Proteínas ras/antagonistas & inhibidores , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Síndrome de Costello/genética , Síndrome de Costello/patología , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Humanos , Colaboración Intersectorial , National Cancer Institute (U.S.) , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Informe de Investigación , Transducción de Señal , Estados Unidos , Proteínas ras/genéticaRESUMEN
The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Proteínas ras/genética , Enfermedades Genéticas Congénitas/patología , Mutación de Línea Germinal/genética , Humanos , Transducción de Señal/genéticaRESUMEN
Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10-16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.
Asunto(s)
Trastorno del Espectro Autista/genética , Epistasis Genética , Sistema de Señalización de MAP Quinasas/genética , Proteínas ras/genética , Línea Celular , Femenino , Genes Modificadores , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Células-Madre Neurales/metabolismo , Polimorfismo de Nucleótido Simple , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
A correction has been published to this Article. The PDF and HTML have been updated accordingly.
RESUMEN
PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
Asunto(s)
Discapacidades para el Aprendizaje/genética , Neurofibroma Plexiforme/genética , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Lactante , Discapacidades para el Aprendizaje/fisiopatología , Masculino , Mutación Missense/genética , Neurofibroma Plexiforme/fisiopatología , Neurofibromatosis 1/patología , Eliminación de Secuencia , Adulto JovenRESUMEN
Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.
Asunto(s)
Anomalías Múltiples/genética , Síndrome de Costello/genética , Corazón/fisiopatología , Proteínas Proto-Oncogénicas p21(ras)/genética , Anomalías Múltiples/fisiopatología , Síndrome de Costello/fisiopatología , Síndrome de Costello/terapia , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Manejo de la Enfermedad , Cara/anomalías , Regulación de la Expresión Génica/genética , Genotipo , Mutación de Línea Germinal/genética , Guías como Asunto , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/fisiopatología , Humanos , FenotipoRESUMEN
The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas Quinasas Activadas por Mitógenos/genética , Neurofibromatosis/etiología , Proteínas ras/genética , Biomarcadores , Manejo de la Enfermedad , Estudios de Asociación Genética/métodos , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida , Neurofibromatosis/diagnóstico , Neurofibromatosis/terapia , Transducción de Señal , Investigación Biomédica Traslacional , Proteínas ras/metabolismoRESUMEN
The RASopathies are a complex group of conditions regarding phenotype and genetic etiology. The ClinGen RASopathy Expert Panel (RAS EP) assessed published and other publicly available evidence supporting the association of 19 genes with RASopathy conditions. Using the semiquantitative literature curation method developed by the ClinGen Gene Curation Working Group, evidence for each gene was curated and scored for Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome, NS with multiple lentigines, and Noonan-like syndrome with loose anagen hair. The curated evidence supporting each gene-disease relationship was then discussed and approved by the ClinGen RASopathy Expert Panel. Each association's strength was classified as definitive, strong, moderate, limited, disputed, or no evidence. Eleven genes were classified as definitively associated with at least one RASopathy condition. Two genes classified as strong for association with at least one RASopathy condition while one gene was moderate and three were limited. The RAS EP also disputed the association of two genes for all RASopathy conditions. Overall, our results provide a greater understanding of the different gene-disease relationships within the RASopathies and can help in guiding and directing clinicians, patients, and researchers who are identifying variants in individuals with a suspected RASopathy.
Asunto(s)
Proteínas ras/metabolismo , Síndrome de Costello/genética , Displasia Ectodérmica/genética , Facies , Insuficiencia de Crecimiento/genética , Cardiopatías Congénitas/genética , Humanos , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/fisiología , Mutación/genética , Síndrome de Noonan/genética , Proteínas ras/genéticaRESUMEN
The RASopathies are defined as a group of medical genetics syndromes that are caused by germ-line mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. Taken together, the RASopathies represent one of the most prevalent groups of malformation syndromes affecting greater than 1 in 1,000 individuals. The Ras/MAPK pathway has been well studied in the context of cancer as it plays essential roles in growth, differentiation, cell cycle, senescence and apoptosis, all of which are also critical to normal development. The consequence of germ-line dysregulation leads to phenotypic alterations of development. RASopathies can be caused by several pathogenetic mechanisms that ultimately impact or alter the normal function and regulation of the MAPK pathway. These pathogenetic mechanisms can include functional alteration of GTPases, Ras GTPase-activating proteins, Ras guanine exchange factors, kinases, scaffolding or adaptor proteins, ubiquitin ligases, phosphatases and pathway inhibitors. Although these mechanisms are diverse, the common underlying biochemical phenotype shared by all the RASopathies is Ras/MAPK pathway activation. This results in the overlapping phenotypic features among these syndromes.