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PURPOSE: Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive. METHODS: We studied 5 affected individuals from 3 unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We used exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing. RESULTS: We identified biallelic variants in ZFTRAF1, encoding a protein of yet unknown function. Four affected individuals from 2 unrelated families segregated 2 homozygous frameshift variants in ZFTRAF1, whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of 2 affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process. CONCLUSION: Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.
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Mutação com Perda de Função , Microcefalia , Hipotonia Muscular , Transtornos do Neurodesenvolvimento , Linhagem , Humanos , Microcefalia/genética , Microcefalia/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Masculino , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Feminino , Pré-Escolar , Mutação com Perda de Função/genética , Alelos , Criança , Lactente , Sequenciamento do Exoma , Fibroblastos/metabolismo , Fibroblastos/patologia , Autofagia/genéticaRESUMO
BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.
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Anormalidades Múltiplas , Transtorno do Espectro Autista , Doenças do Desenvolvimento Ósseo , Deficiência Intelectual , Anormalidades Dentárias , Masculino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Anormalidades Múltiplas/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Dentárias/genética , Fácies , Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA , Proteínas Repressoras/genética , Deleção Cromossômica , Fenótipo , Fatores de Transcrição/genéticaRESUMO
OBJECTIVE: The aim of this study was to provide a full characterization of a cohort of 11 pediatric patients diagnosed with PTEN hamartoma tumor syndrome (PHTS). PATIENTS AND METHODS: Eleven patients with genetic diagnostic of PHTS were recruited between February 2019 and April 2023. Clinical, imaging, demographic, and genetic data were retrospectively collected from their hospital medical history. RESULTS: Regarding clinical manifestations, macrocephaly was the leading sign, present in all patients. Frontal bossing was the most frequent dysmorphism. Neurological issues were present in most patients. Dental malformations were described for the first time, being present in 27% of the patients. Brain MRI showed anomalies in 57% of the patients. No tumoral lesions were present at the time of the study. Regarding genetics, 72% of the alterations were in the tensin-type C2 domain of PTEN protein. We identified four PTEN genetic alterations for the first time. CONCLUSIONS: PTEN mutations appear with a wide variety of clinical signs and symptoms, sometimes associated with phenotypes which do not fit classical clinical diagnostic criteria for PHTS. We recommend carrying out a genetic study to establish an early diagnosis in children with significant macrocephaly. This facilitates personalized monitoring and enables anticipation of potential PHTS-related complications.
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Síndrome do Hamartoma Múltiplo , PTEN Fosfo-Hidrolase , Humanos , Feminino , Masculino , PTEN Fosfo-Hidrolase/genética , Criança , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/diagnóstico por imagem , Pré-Escolar , Adolescente , Estudos Retrospectivos , Lactente , Mutação/genética , Megalencefalia/genética , Megalencefalia/diagnóstico por imagemRESUMO
RASopathies are a group of related genetic disorders caused by mutations in genes within the RAS/MAPK signaling pathway. This pathway is crucial for cell division, growth, and differentiation, and its disruption can lead to a variety of developmental and health issues. RASopathies present diverse clinical features and pose significant diagnostic and therapeutic challenges. Studying the landscape of biomarkers in RASopathies has the potential to improve both clinical practices and the understanding of these disorders. This review provides an overview of recent discoveries in RASopathy molecular profiling, which extend beyond traditional gene mutation analysis. mRNAs, non-coding RNAs, protein expression patterns, and post-translational modifications characteristic of RASopathy patients within pivotal signaling pathways such as the RAS/MAPK, PI3K/AKT/mTOR, and Rho/ROCK/LIMK2/cofilin pathways are summarized. Additionally, the field of metabolomics holds potential for uncovering metabolic signatures associated with specific RASopathies, which are crucial for developing precision medicine. Beyond molecular markers, we also examine the role of histological characteristics and non-invasive physiological assessments in identifying potential biomarkers, as they provide evidence of the disease's effects on various systems. Here, we synthesize key findings and illuminate promising avenues for future research in RASopathy biomarker discovery, underscoring rigorous validation and clinical translation.
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Biomarcadores , Proteínas ras , Humanos , Biomarcadores/metabolismo , Proteínas ras/metabolismo , Proteínas ras/genética , Transdução de Sinais , Mutação , Mancha Vinho do Porto/genética , Mancha Vinho do Porto/metabolismo , Mancha Vinho do Porto/patologia , Síndrome de Costello/genética , Síndrome de Costello/metabolismo , Síndrome de Costello/patologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/patologia , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/metabolismo , Animais , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , FáciesRESUMO
In recent years, there has been growing interest in understanding the potential role of microbiota dysbiosis or alterations in the composition and function of human microbiota in the development of chronic rhinosinusitis with nasal polyposis (CRSwNP). This systematic review evaluated the literature on CRSwNP and host microbiota for the last ten years, including mainly nasal bacteria, viruses, and fungi, following the PRISMA guidelines and using the major scientific publication databases. Seventy original papers, mainly from Asia and Europe, met the inclusion criteria, providing a comprehensive overview of the microbiota composition in CRSwNP patients and its implications for inflammatory processes in nasal polyps. This review also explores the potential impact of microbiota-modulating therapies for the CRSwNP treatment. Despite variability in study populations and methodologies, findings suggest that fluctuations in specific taxa abundance and reduced bacterial diversity can be accepted as critical factors influencing the onset or severity of CRSwNP. These microbiota alterations appear to be implicated in triggering cell-mediated immune responses, cytokine cascade changes, and defects in the epithelial barrier. Although further human studies are required, microbiota-modulating strategies could become integral to future combined CRSwNP treatments, complementing current therapies that mainly target inflammatory mediators and potentially improving patient outcomes.
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Microbioma Gastrointestinal , Pólipos Nasais , Rinossinusite , Humanos , Doença Crônica , Disbiose/microbiologia , Microbiota , Pólipos Nasais/microbiologia , Rinossinusite/microbiologiaRESUMO
AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
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Cardiomiopatia Hipertrófica , Proteínas Musculares/genética , Proteínas Quinases/genética , Cardiomiopatia Hipertrófica/genética , Heterozigoto , Humanos , Mutação , SarcômerosRESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions. Such reactions can be pharmacologically or immunologically mediated, but in both cases individual susceptibility can be influenced by genetic factors. Polymorphisms in centrosomal protein of 68 kDa (CEP68) have been associated with pharmacologically mediated NSAIDs reactions. Here, we evaluated this gene in immunologically mediated single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) by analyzing 52 single nucleotide polymorphisms in CEP68 in 176 patients and 363 NSAIDs-tolerant controls. Two intronic variants (rs2241160 and rs2241161) were significantly associated with an increased risk of SNIUAA, suggesting CEP68 to be a key player in both types of NSAIDs hypersensitivity. However, we found no overlap with genetic variants previously associated with pharmacologically mediated hypersensitivity, pointing to a complex role for this gene and its potential use in the development of biomarkers of clinical utility to diagnose patients at risk of these reactions and to differentiate entities.
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Anafilaxia/genética , Anti-Inflamatórios não Esteroides/efeitos adversos , Hipersensibilidade a Drogas/genética , Proteínas Associadas aos Microtúbulos/genética , Urticária/genética , Adulto , Anafilaxia/induzido quimicamente , Anafilaxia/patologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Hipersensibilidade a Drogas/patologia , Feminino , Estudos de Associação Genética , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Urticária/induzido quimicamente , Urticária/patologiaRESUMO
INTRODUCTION: Secretory phospholipase A2 regulates surfactant catabolism and inflammatory cascade. This enzyme is correlated with compliance, oxygenation and major outcomes in various forms of acute respiratory failure. Steroids inhibit secretory phospholipase A2 in cell culture and are widely used to boost surfactant production before preterm delivery. No data are available about the effect of antenatal steroids on secretory phospholipase A2 in the offspring: we aimed to study this effect in a rat model of preterm lung. MATERIAL AND METHODS: Fifteen pregnant Wistar rats were randomized to receive betamethasone, dexamethasone or placebo at 20 and 21 days gestation. Newborn rats were supported for 8 h and then sacrificed: lung tissue was analysed for secretory phospholipase A2 expression and activity, inflammatory mediators and protein content. Lipidomics was analysed using liquid chromatography-mass spectrometry. RESULTS: Secretory phospholipase A2 expression was significantly reduced by antenatal steroids (p < 0.001). Secretory phospholipase A2 activity, TNFα and lysophosphatidylethanolamine, a product of phospholipase reaction, were lowest in betamethasone-treated rats (p < 0.001). There was a strong correlation between secretory phospholipase A2 activity and lysophosphatidylethanolamine (r = 0.75; p = 0.001) and this remained significant after adjustment for total proteins or phospholipids. CONCLUSIONS: Antenatal steroids decrease secretory phospholipase A2 in rat model of preterm lung.
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Pulmão/enzimologia , Fosfolipases A2 Secretórias/antagonistas & inibidores , Nascimento Prematuro/patologia , Esteroides/farmacologia , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/farmacologia , Betametasona/farmacologia , Dexametasona/farmacologia , Feminino , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Pulmão/patologia , Lisofosfolipídeos/metabolismo , Gravidez , Surfactantes Pulmonares/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: CYP2D6, a major drug-metabolizing enzyme, is encoded by a highly polymorphic and complex gene locus. We have identified a patient who failed to produce a CYP2D6 genotype with the AmpliChip P450 Test (AmpliChip), whereas his CYP2C19 genotype was readily determined. The aim of this investigation was to fully characterize the patient's CYP2D6 gene locus to resolve the AmpliChip no-call. METHODS: The case, a brother, and son were genotyped with the AmpliChip and subsequently characterized using long-range (XL)-PCR coupled with TaqMan assay technology. Copy number variation was assessed by XL-PCR and quantitative PCR. Selected XL-PCR products were sequenced. RESULTS: The AmpliChip also produced a no-call for the son; the brother produced a result. The two alleles of the case were subsequently found to carry additional gene units that likely caused the AmpliChip no-calls. One was characterized as a CYP2D6*68+*4 tandem (CYP2D6*68 is a hybrid gene composed of 2D6 and 2D7), the other as a rare CYP2D6*13+*2 tandem (CYP2D6*13 is a 2D7/2D6 hybrid formerly known as CYP2D6*77). A novel CYP2D6*2 subvariant was identified in the son; the brother also carried the CYP2D6*68+*4 tandem. CONCLUSIONS: The implementation of pharmacogenetics-guided drug therapy relies on accurate clinical-grade genotype analysis. Although the AmpliChip is deemed to be a reliable platform, numerous more recently discovered allelic variants and gene arrangements are not detected or trigger no-calls. Although such cases may be rare, the clinical/genetic testing community must be aware of the challenges of CYP2D6 testing on the AmpliChip platform and implications regarding accuracy of test results.
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Citocromo P-450 CYP2D6/genética , Análise Mutacional de DNA/métodos , Genótipo , Idoso , Alelos , Simulação por Computador , Variações do Número de Cópias de DNA/genética , Reações Falso-Negativas , Loci Gênicos/genética , Humanos , MasculinoRESUMO
RASopathies, a group of neurodevelopmental congenital disorders stemming from mutations in the RAS/MAPK pathway, present a unique opportunity to delve into the intricacies of complex neurological disorders. Afflicting approximately one in a thousand newborns, RASopathies manifest as abnormalities across multiple organ systems, with a pronounced impact on the central and peripheral nervous system. In the pursuit of understanding RASopathies' neurobiology and establishing phenotype-genotype relationships, in vivo non-mammalian models have emerged as indispensable tools. Species such as Danio rerio, Drosophila melanogaster, Caenorhabditis elegans, Xenopus species and Gallus gallus embryos have proven to be invaluable in shedding light on the intricate pathways implicated in RASopathies. Despite some inherent weaknesses, these genetic models offer distinct advantages over traditional rodent models, providing a holistic perspective on complex genetics, multi-organ involvement, and the interplay among various pathway components, offering insights into the pathophysiological aspects of mutations-driven symptoms. This review underscores the value of investigating the genetic basis of RASopathies for unraveling the underlying mechanisms contributing to broader neurological complexities. It also emphasizes the pivotal role of non-mammalian models in serving as a crucial preliminary step for the development of innovative therapeutic strategies.
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Introduction: Type 2 (T2) asthma is often associated with chronic rhinosinusitis with nasal polyposis (CRSwNP). Additionally, nonsteroidal anti-inflammatory drug (NSAID) intolerance leads to NSAID-exacerbated respiratory disease (N-ERD). Previous transcriptomic data in non-CRSwNP T2 asthma patients showed differentially expressed genes. We focused on ALOX15, CLC, CYSLTR2, HRH4 and SMPD3 to investigate their role in T2 asthma. Methods: The study included 100 healthy controls and 103 T2 asthma patients, divided into patients with asthma (n=54), patients with asthma and CRSwNP (n=29) and patients with N-ERD (n=20). Quantitative PCR analysis was performed on blood-derived RNA samples first to validate the five differentially expressed genes. The data were further analysed to find potential associations and biomarkers. Results: Patients, regardless of stratification, exhibited significantly higher gene expression than healthy controls. The patterns of association revealed that ALOX15 was exclusively present in the non-comorbidity group, SMPD3 and CLC in the comorbidity groups, and HRH4 in all patient groups. ALOX15, CYSLTR2 and SMPD3 expression showed potential as biomarkers to confirm the diagnosis of T2 asthma using peripheral blood eosinophils as the initial criterion. Peripheral blood eosinophils combined with gene expression, especially SMPD3, may improve the diagnosis. CLC and CYSLTR2 expression play a specific role in discriminating N-ERD. Discussion: We validated the transcriptomic data of five differentially expressed genes in T2 asthma. Different patterns of association were identified in patient stratification, suggesting that different molecular mechanisms underlie the spectrum of T2 asthma. Potential biomarkers were also found and used to design an algorithm with practical diagnostic utility for T2 asthma, including risk stratification for N-ERD.
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Background/Objectives: Develop a clinical and genetic characterization, in a group of small-for-gestational-age (SGA) patients who did not experience catch-up growth Methods: In an ambispective cohort study with (SGA) patients. These patients received one treatment with growth hormone (GH) over 14 years. This study analyzes their response to treatment and conducts a genetic analysis in order to identify cases with specific phenotypic and auxological characteristics, defined as presenting two or more dysmorphic traits and/or a stature below -3 SDS (standard deviation score). Whole-exome sequencing (WES) was performed on selected patients. Results: Forty-four SGA patients were examined, with an average age of 6.4 (2.49) years and an initial size of -3.3 SDS. The pubertal growth was 24.1 (5.2) cm in boys and 14.7 (4.3) cm in girls. WES in 11 SGA patients revealed conclusive genetic variants in eight, including two pathogenic ACAN variants, one 15q26.2-q26.3 deletion, and four variants of uncertain significance in other genes. Conclusions: Treatment with GH in SGA patients was shown to be effective, with a similar response in the group with positive genetic results and in the group who did not undergo a genetic study. Genetic testing based on auxological and clinical criteria proved highly cost-effective.
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Allergic asthma is the most common type of asthma. It is characterized by TH2 cell-driven inflammation in which interleukin-13 (IL-13) plays a pivotal role. Cytoplasmic RNAs (Y-RNAs), a variety of non-coding RNAs that are dysregulated in many cancer types, are also differentially expressed in patients with allergic asthma. Their function in the development of the disease is still unknown. We investigated the potential role of RNY3 RNA (hY3) in the TH2 cell inflammatory response using the Jurkat cell line as a model. hY3 expression levels were modulated to mimic the upregulation effect in allergic disease. We evaluated the effect of hY3 over cell stimulation and the expression of the TH2 cytokine IL13. Total RNA was isolated and retrotranscribed, and RNA levels were assessed by qPCR. In Jurkat cells, hY3 levels increased upon stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. When transfecting with high levels of hY3 mimic molecules, cell proliferation rate decreased while IL13 mRNA levels increased upon stimulation compared to stimulated control cells. Our results show the effect of increased hY3 levels on cell proliferation and the levels of IL13 mRNA in Jurkat cells. Also, we showed that hY3 could act over other cells via exosomes. This study opens up new ways to study the potential regulatory function of hY3 over IL-13 production and its implications for asthma development.
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Asma , Interleucina-13 , RNA não Traduzido , Humanos , Proliferação de Células , Epigênese Genética , Interleucina-13/metabolismo , Ativação Linfocitária , RNA Mensageiro , Linfócitos T , Acetato de Tetradecanoilforbol/farmacologia , RNA não Traduzido/metabolismoRESUMO
Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) affects the quality of life of patients suffering from it. The search for a suitable biomarker has been conducted over the last decades. Interleukin 5 receptor subunit alpha (IL-5Rα) involves the activation, maintenance, and survival of eosinophils, which are highly tied to chronic inflammatory processes of the airways, like asthma or CRSwNP. In this study, we evaluate the utility of IL5RA as a genetic biomarker in CRSwNP. IL5RA mRNA expression level was analyzed in different groups of patients by performing qPCR assays. A significant increase in IL5RA expression was observed in CRSwNP patients, especially those with asthma and atopy. We found differences in expression levels when comparing groups with or without polyposis or asthma, as well as some atypical cases related to eosinophil levels. That opens a path to future studies to further characterize groups of patients with common features in the context of pharmacogenetics and in an era towards developing a more precise personalized treatment with IL-5Rα as a therapeutic target for CRSwNP.
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Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.
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Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.
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Cardiotoxicidade , Neoplasias , Feminino , Animais , Camundongos , Cardiotoxicidade/etiologia , Antraciclinas/efeitos adversos , Marcadores Genéticos , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , FenótipoRESUMO
Neurofibromin is engaged in many cellular processes and when the proper protein functioning is impaired, it causes neurofibromatosis type 1 (NF1), one of the most common inherited neurological disorders. Recent advances in sequencing and screening of the NF1 gene have increased the number of detected variants. However, the correlation of these variants with the clinic remains poorly understood. In this study, we analyzed 4610 germinal NF1 variants annotated in ClinVar and determined on exon level the mutational spectrum and potential pathogenic regions. Then, a binomial and sliding windows test using 783 benign and 938 pathogenic NF1 variants were analyzed against functional and structural regions of neurofibromin. The distribution of synonymous, missense, and frameshift variants are statistically significant in certain regions of neurofibromin suggesting that the type of variant and its associated phenotype may depend on protein disorder. Indeed, there is a negative correlation between the pathogenic fraction prediction and the disorder data, suggesting that the higher an intrinsically disordered region is, the lower the pathogenic fraction is and vice versa. Most pathogenic variants are associated to NF1 and our analysis suggests that GRD, CSRD, TBD, and Armadillo1 domains are hotspots in neurofibromin. Knowledge about NF1 genotype-phenotype correlations can provide prognostic guidance and aid in organ-specific surveillance.
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Several biologic therapies that target inflammatory modulators are now used for treating patients with uncontrolled, severe asthma. Knowledge about how this type of treatment modifies the molecular milieu is rapidly increasing. Thus, this systematic review aimed to compile the reported effects of therapeutic antibodies on the transcriptome or proteome of asthma patients. Studies of asthmatic patients under biological treatment describing transcriptomic or proteomic changes upon treatment were included. Preclinical or single gene/protein studies were not considered. PubMed and Scopus search was performed in August and September 2021. Following PRISMA guidelines and GRADE recommendations, we selected 12 studies on gene or protein expression changes in patients treated with the antibodies currently approved by EMA and the FDA. All studies were at low risk of bias as per the RoB2 tool. Different gene clusters have been identified to change upon omalizumab treatment, found a reduction in eosinophil-associated gene signatures after benralizumab treatment, and protein profiles were different in patients treated with mepolizumab and in those treated with benralizumab. The main potential biomarkers proposed by the selected studies are shown. These results may contribute to discovering biomarkers of response and selecting the best therapy for each patient.
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BACKGROUND: The role of genetics in non-steroidal anti-inflammatory drugs (NSAID) exacerbated respiratory disease (NERD) is unclear, with different candidates involved, such as HLA genes, genes related to leukotriene synthesis, and cytokine genes. This study aimed to determine possible associations between 22 polymorphisms in 13 cytokine genes. METHODS: We included 195 patients (85 with NERD and 110 with respiratory disease who tolerate NSAIDs) and 156 controls (non-atopic individuals without a history of asthma, nasal polyposis (NP), or NSAID hypersensitivity). Genotyping was performed by sequence-specific primer polymerase chain reaction (PCR-SSP). Amplicons were analyzed by horizontal gel electrophoresis in 2% agarose. RESULTS: Significant differences in allele and genotype frequency distributions were found in TNF (rs1800629), IL4 (rs2243248 and rs2243250), and IL10 (rs1800896, rs1800871, and rs1800872) genes in patients with NSAID hypersensitivity. In all cases, the minor allele and the heterozygous genotype were more prevalent in NERD. An association of TNF rs1800629 SNP with respiratory disease in NSAID-tolerant patients was also found. CONCLUSIONS: Retrospectively recorded, we found strong associations of NERD with polymorphisms in IL4, IL10, and TNF genes, suggesting that these genes could be involved in the inflammatory mechanisms underlying NERD.