RESUMO
BACKGROUND/OBJECTIVE: Heterogeneity and chronicity of Crohn disease (CD) make prediction of outcomes difficult. To date, no longitudinal measure can quantify burden over a patient's disease course, preventing assessment and integration into predictive modeling. Here, we aimed to demonstrate the feasibility of constructing a data driven, longitudinal disease burden score. METHODS: Literature was reviewed for tools used in assessment of CD activity. Themes were identified to construct a pediatric CD morbidity index (PCD-MI). Scores were assigned to variables. Data were extracted automatically from the electronic patient records at Southampton Children's Hospital, diagnosed from 2012 to 2019 (inclusive). PCD-MI scores were calculated, adjusted for duration of follow up and assessed for variation (ANOVA) and distribution (Kolmogorov-Smirnov). RESULTS: Nineteen clinical/biological features across five themes were included in the PCD-MI including blood/fecal/radiological/endoscopic results, medication usage, surgery, growth parameters, and extraintestinal manifestations. Maximal score was 100 after accounting for follow-up duration. PCD-MI was assessed in 66 patients, mean age 12.5 years. Following quality filtering, 9528 blood/fecal test results and 1309 growth measures were included. Mean PCD-MI score was 14.95 (range 2.2-32.5); data were normally distributed ( P = 0.2) with 25% of patients having a PCD-MI < 10. There was no difference in the mean PCD-MI when split by year of diagnosis, F -statistic 1.625, P = 0.147. CONCLUSIONS: PCD-MI is a calculatable measure for a cohort of patients diagnosed over an 8-year period, integrating a wide-range of data with potential to determine high or low disease burden. Future iterations of the PCD-MI require refinement of included features, optimized scores, and validation on external cohorts.
Assuntos
Doença de Crohn , Humanos , Criança , Doença de Crohn/diagnóstico , Doença de Crohn/cirurgia , Progressão da Doença , Efeitos Psicossociais da Doença , MorbidadeRESUMO
Studies of Crohn's disease have consistently implicated NOD2 as the most important gene in disease pathogenesis since first being identified in 2001. Thereafter, genome-wide association, next-generation sequencing and functional analyses have all confirmed a key role for NOD2, but despite this, NOD2 also has significant unresolved complexity. More recent studies have reinvigorated an early hypothesis that NOD2 may be a single-gene cause of disease, and the distinct ileal stricturing phenotype seen with NOD2-related disease presents an opportunity for personalized diagnosis, disease prediction and targeted therapy. The genomics of NOD2 has much that remains unknown, including the role of rare variation, phasing of variants across the haplotype block and the role of variation in the NOD2-regulatory regions. Here, we discuss the evidence and the unmet needs of NOD2 research, based on recently published evidence, and suggest methods that may meet these requirements.
Assuntos
Doença de Crohn , Estudo de Associação Genômica Ampla , Humanos , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Fenótipo , Proteína Adaptadora de Sinalização NOD2/genética , Predisposição Genética para DoençaRESUMO
BACKGROUND: Crohn's disease (CD) is highly heterogenous and may be complicated by stricturing behavior. Personalized prediction of stricturing will inform management. We aimed to create a stricturing risk stratification model using genomic/clinical data. METHODS: Exome sequencing was performed on CD patients, and phenotype data retrieved. Biallelic variants in NOD2 were identified. NOD2 was converted into a per-patient deleteriousness metric ("GenePy"). Using training data, patients were stratified into risk groups for fibrotic stricturing using NOD2. Findings were validated in a testing data set. Models were modified to include disease location at diagnosis. Cox proportional hazards assessed performance. RESULTS: Six hundred forty-five patients were included (373 children and 272 adults); 48 patients fulfilled criteria for monogenic NOD2-related disease (7.4%), 24 of whom had strictures. NOD2 GenePy scores stratified patients in training data into 2 risk groups. Within testing data, 30 of 161 patients (18.6%) were classified as high-risk based on the NOD2 biomarker, with stricturing in 17 of 30 (56.7%). In the low-risk group, 28 of 131 (21.4%) had stricturing behavior. Cox proportional hazards using the NOD2 risk groups demonstrated a hazard ratio (HR) of 2.092 (Pâ =â 2.4â ×â 10-5), between risk groups. Limiting analysis to patients diagnosed agedâ <â 18-years improved performance (HR-3.164, Pâ =â 1â ×â 10-6). Models were modified to include disease location, such as terminal ileal (TI) disease or not. Inclusion of NOD2 risk groups added significant additional utility to prediction models. High-risk group pediatric patients presenting with TI disease had a HR of 4.89 (Pâ =â 2.3â ×â 10-5) compared with the low-risk group patients without TI disease. CONCLUSIONS: A NOD2 genomic biomarker predicts stricturing risk, with prognostic power improved in pediatric-onset CD. Implementation into a clinical setting can help personalize management.
NOD2 is a well-established risk gene for development of Crohn's disease and stricturing behavior. Here we demonstrate NOD2 can be utilized as a genomic biomarker, stratifying patients into 2 stricturing risk groups. Further refinement using disease location at diagnosis improved risk stratification.
Assuntos
Doença de Crohn , Humanos , Doença de Crohn/genética , Doença de Crohn/complicações , Constrição Patológica , Fenótipo , Fatores de Risco , Prognóstico , Proteína Adaptadora de Sinalização NOD2/genéticaRESUMO
Renal Fanconi syndrome (RFS) is a generalised disorder of the proximal convoluted tubule. Many genes have been associated with RFS including those that cause systemic disorders such as cystinosis, as well as isolated RFS. We discuss the case of a 10-year-old female who presented with leg pain and raised creatinine on a screening blood test. Her mother has RFS and required a kidney transplant in her thirties. Further investigations confirmed RFS in the daughter. Exome sequencing was performed on the affected mother, child, and unaffected father. We identified a novel variant in GATM; c.965G>C p.(Arg322Pro) segregating dominantly in the mother and daughter. We validated our finding with molecular dynamics simulations and demonstrated a dynamic signature that differentiates our variant and two previously identified pathogenic variants in GATM from wildtype. Genetic testing has uncovered a novel pathogenic variant that predicts progression to end stage kidney failure and has important implications for family planning and cascade testing. We recommend that GATM is screened for in children presenting with RFS, in addition to adults, particularly with kidney failure, who may have had previous negative gene testing.
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Síndrome de Fanconi , Falência Renal Crônica , Criança , Adulto , Feminino , Humanos , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/genética , Síndrome de Fanconi/complicações , Falência Renal Crônica/genética , Falência Renal Crônica/complicações , Testes Genéticos , CausalidadeRESUMO
Thrombotic microangiopathy is a potentially lethal complication of haematopoietic stem cell (bone marrow) transplantation. The pathophysiology is incompletely understood, although endothelial damage appears to be central. Platelet activation, neutrophil extracellular traps and complement activation appear to play key roles. Diagnosis may be difficult and universally accepted diagnostic criteria are not available. Treatment remains controversial. In some cases, withdrawal of calcineurin inhibitors is adequate. Rituximab and defibrotide also appear to have been used successfully. In severe cases, complement inhibitors such as eculizumab may play a valuable role. Further research is required to define the pathophysiology and determine both robust diagnostic criteria and the optimal treatment.
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Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Rim/patologia , Microvasos/patologia , Microangiopatias Trombóticas/diagnóstico , Proteína ADAMTS13/sangue , Proteína ADAMTS13/metabolismo , Biópsia , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Inativadores do Complemento/uso terapêutico , Células Endoteliais/imunologia , Células Endoteliais/patologia , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Incidência , Rim/irrigação sanguínea , Rim/citologia , Rim/imunologia , Microvasos/citologia , Microvasos/imunologia , Troca Plasmática , Fatores de Risco , Rituximab/uso terapêutico , Microangiopatias Trombóticas/epidemiologia , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/terapia , Resultado do TratamentoRESUMO
We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis.
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Osso e Ossos/fisiologia , Coração/fisiologia , Proteínas/genética , Animais , Western Blotting , Osso e Ossos/metabolismo , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular , Exoma/genética , Feminino , Células HeLa , Humanos , Masculino , Sequenciamento Completo do Genoma , Peixe-ZebraRESUMO
CBL is a tumor suppressor gene on chromosome 11 encoding a multivalent adaptor protein with E3 ubiquitin ligase activity. Germline CBL mutations are dominant. Pathogenic de novo mutations result in a phenotype that overlaps Noonan syndrome (1). Some patients with CBL mutations go on to develop juvenile myelomonocytic leukemia (JMML), an aggressive malignancy that usually necessitates bone marrow transplantation. Using whole exome sequencing methods, we identified a known mutation in CBL in a 4-year-old Caucasian boy with atypical hemolytic uremic syndrome, moyamoya phenomenon, and dysmorphology consistent with a mild Noonan-like phenotype. Exome data revealed loss of heterozygosity across chromosome 11q consistent with JMML but in the absence of clinical leukemia. Our finding challenges conventional clinical diagnostics since we have identified a pathogenic variant in the CBL gene previously only ascertained in children presenting with leukemia. The increasing affordability of expansive sequencing is likely to increase the scope of clinical profiles observed for previously identified pathogenic variants and calls into question the interpretability and indications for clinical management.