RESUMEN
We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
Asunto(s)
Trastorno Autístico/genética , Corteza Cerebral/crecimiento & desarrollo , Secuenciación del Exoma/métodos , Regulación del Desarrollo de la Expresión Génica , Neurobiología/métodos , Estudios de Casos y Controles , Linaje de la Célula , Estudios de Cohortes , Exoma , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Mutación Missense , Neuronas/metabolismo , Fenotipo , Factores Sexuales , Análisis de la Célula Individual/métodosRESUMEN
Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.
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Trastorno del Espectro Autista/genética , Medicina Basada en la Evidencia/métodos , Estudios de Asociación Genética/métodos , Encéfalo/crecimiento & desarrollo , Cognición/fisiología , Humanos , Discapacidad Intelectual/genéticaRESUMEN
Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive and behavioral abnormalities. Previous literature has begun to elucidate genotype-phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype-phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions) or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype-phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories and comorbidities as a function of specific genetic alteration.
Asunto(s)
Trastorno del Espectro Autista , Trastornos de los Cromosomas , Trastorno del Espectro Autista/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 22/genética , Estudios de Asociación Genética , HumanosRESUMEN
The cornea transplant is considered the most frequently performed type of transplant in the world, with a demand that has been increasing in recent years. An observational descriptive study was conducted, focusing on the ocular tissue extracted from cadaveric donors from January 2019 to December 2021 at the Red Cross Eye Bank in Medellin, Colombia. This is the first epidemiological characterization of corneal donor tissues within the eye banks of our city, where high rates of violence-related deaths explain that tissue donors are mostly young individuals. This, in turn, results in excellent counts of endothelial cells and tissue viability in their microscopic studies. Additionally, there are lower rates of discarded tissues compared to similar studies.
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Córnea , Trasplante de Córnea , Bancos de Ojos , Donantes de Tejidos , Colombia , Humanos , Adulto , Femenino , Persona de Mediana Edad , Masculino , Bancos de Ojos/estadística & datos numéricos , Anciano , Adulto Joven , Adolescente , Anciano de 80 o más Años , CiudadesRESUMEN
Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.
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Trastornos de los Cromosomas , Humanos , Fenotipo , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/epidemiología , Trastornos de los Cromosomas/genética , Deleción Cromosómica , Proteínas del Tejido Nervioso/genética , Cromosomas Humanos Par 22/genéticaRESUMEN
PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.
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Trastorno del Espectro Autista , Trastorno Autístico , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Trastorno Autístico/diagnóstico , Trastorno Autístico/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genéticaRESUMEN
Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced nonverbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities.
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Factor de Transcripción COUP I/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Atrofia Óptica/genética , Adulto , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Codón sin Sentido/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Atrofia Óptica/fisiopatología , Fenotipo , Secuenciación del Exoma , Adulto JovenRESUMEN
Cre/loxP recombination is a widely used approach to study gene function in vivo, using mice models expressing the Cre recombinase under the control of specific promoters or through viral delivery of Cre-expressing constructs. A profuse literature on transgenic mouse lines points out the deleterious effects of Cre expression in various cell types and tissues, presumably by acting on illegitimate loxP-like sites present in the genome. However, most studies reporting the consequences of Cre-lox gene invalidation often omit adequate controls to exclude the potential toxic effects of Cre, compromising the interpretation of data. In this study, we report the anatomical, neurochemical, and behavioral consequences in mice of adeno-associated virus (AAV)-mediated Cre expression in the dopaminergic nuclei substantia nigra, at commonly used viral titers (3 × 109 genome copies/0.3 µL or 2 × 109 genome copies/0.6 µL). We found that injecting AAV-eGFP-Cre into the SN engendered drastic and reproducible modifications of behavior, with increased basal locomotor activity as well as impaired locomotor response to cocaine compared to AAV-eGFP-injected controls. Cre expression in the SN induced a massive decrease in neuronal populations of both pars compacta and pars reticulata and dopamine depletion in the nigrostriatal pathway. This anatomical injury was associated with typical features of programmed cell death, including an increase in DNA break markers, evidence of apoptosis, and disrupted macroautophagy. These observations underscore the need for careful control of Cre toxicity in the brain and the reassessment of previous studies. In addition, our findings suggest that Cre-mediated ablation may constitute an efficient tool to explore the function of specific cell populations and areas in the brain, and the impact of neurodegeneration in these populations.
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Integrasas , Neuronas/patología , Sustancia Negra/metabolismo , Sustancia Negra/patología , Animales , Apoptosis/efectos de los fármacos , Dependovirus , Dopamina/metabolismo , Vectores Genéticos , Integrasas/administración & dosificación , Integrasas/genética , Integrasas/toxicidad , Locomoción/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
Asunto(s)
Trastorno Autístico/genética , Proteínas de Unión al ADN/genética , Exones/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Factores de Transcripción/genética , Estudios de Casos y Controles , Exoma/genética , Salud de la Familia , Humanos , Modelos Genéticos , Herencia Multifactorial/genética , Fenotipo , Distribución de Poisson , Mapas de Interacción de ProteínasRESUMEN
Autism Spectrum Disorders (ASD) are highly heritable and characterised by impairments in social interaction and communication, and restricted and repetitive behaviours. Considering four sets of de novo copy number variants (CNVs) identified in 181 individuals with autism and exploiting mouse functional genomics and known protein-protein interactions, we identified a large and significantly interconnected interaction network. This network contains 187 genes affected by CNVs drawn from 45% of the patients we considered and 22 genes previously implicated in ASD, of which 192 form a single interconnected cluster. On average, those patients with copy number changed genes from this network possess changes in 3 network genes, suggesting that epistasis mediated through the network is extensive. Correspondingly, genes that are highly connected within the network, and thus whose copy number change is predicted by the network to be more phenotypically consequential, are significantly enriched among patients that possess only a single ASD-associated network copy number changed gene (pâ=â0.002). Strikingly, deleted or disrupted genes from the network are significantly enriched in GO-annotated positive regulators (2.3-fold enrichment, corrected pâ=â2×10(-5)), whereas duplicated genes are significantly enriched in GO-annotated negative regulators (2.2-fold enrichment, corrected pâ=â0.005). The direction of copy change is highly informative in the context of the network, providing the means through which perturbations arising from distinct deletions or duplications can yield a common outcome. These findings reveal an extensive ASD-associated molecular network, whose topology indicates ASD-relevant mutational deleteriousness and that mechanistically details how convergent aetiologies can result extensively from CNVs affecting pathways causally implicated in ASD.
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Trastornos Generalizados del Desarrollo Infantil/genética , Dosificación de Gen , Redes Reguladoras de Genes , Mapas de Interacción de Proteínas/genética , Animales , Niño , Eliminación de Gen , Duplicación de Gen , Predisposición Genética a la Enfermedad , Genoma Humano , Humanos , RatonesRESUMEN
SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.
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Trastorno Autístico/genética , Proteínas Portadoras/genética , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Humanos , Hibridación Fluorescente in Situ , Masculino , Datos de Secuencia Molecular , Mutación , Proteínas del Tejido Nervioso , LinajeRESUMEN
Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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Trastorno Autístico/genética , Aberraciones Cromosómicas , Mapeo Cromosómico , Ligamiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Trastorno Autístico/diagnóstico , Familia , Femenino , Variación Genética , Humanos , Escala de Lod , Masculino , Factores de RiesgoRESUMEN
The proline dehydrogenase (PRODH) gene maps to 22q11.2 in the region deleted in the velo-cardio-facial syndrome (VCFS). A moderate to severe reduction (>50%) in PRODH activity resulting from recessive deletions and/or missense mutations has been shown to cause type 1 hyperprolinemia (HPI). Autistic features have been reported as a common clinical manifestation of HPI. Here we studied the frequency of a recurrent small 22q11.2 deletion encompassing PRODH and the neighboring DGCR6 gene in three case-control studies, one comprising HPI patients (n = 83), and the other two comprising autism spectrum disorder (ASD) patients (total of n = 2800), analyzed with high-resolution microarrays. We found that the PRODH deletion is a strong risk factor for HPI (OR = 50.7; 95%CI = 7.5-2147) but not for ASD (P = 0.4, OR = 0.6-3.3). This result indicates either that the suggested association between ASD and HPI is spurious and results from a bias leading to the preferential inclusion of patients with autistic features in HPI series, or that HPI is present in only a very small subset of ASD patients. In this latter case, a very large sample size would be required to detect an association between the PRODH deletion and ASD in a case-control study.
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Errores Innatos del Metabolismo de los Aminoácidos/genética , Trastorno del Espectro Autista/genética , Cromosomas Humanos Par 22/genética , Proteínas de la Matriz Extracelular/genética , Eliminación de Gen , Predisposición Genética a la Enfermedad , Prolina Oxidasa/genética , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Proteínas Nucleares , Factores de RiesgoRESUMEN
We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.
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Trastorno Autístico , Carnitina/deficiencia , Cromosomas Humanos X/genética , Genes Ligados a X/genética , Errores Innatos del Metabolismo , Oxigenasas de Función Mixta/genética , Trastorno Autístico/epidemiología , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Carnitina/biosíntesis , Cognición/fisiología , Exones/genética , Eliminación de Gen , Humanos , Masculino , Errores Innatos del Metabolismo/epidemiología , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Oxigenasas de Función Mixta/sangre , Oxigenasas de Función Mixta/orina , Penetrancia , Factores de Riesgo , HermanosRESUMEN
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (nâ=â396 patients and nâ=â659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (Pâ=â0.004, ORâ=â2.37, 95% CIâ=â1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (Pâ=â0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
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Trastornos Generalizados del Desarrollo Infantil/genética , Proteínas del Tejido Nervioso/genética , Eliminación de Secuencia/genética , Sinapsis/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Empalme Alternativo/genética , Línea Celular , Niño , Preescolar , Femenino , Dosificación de Gen/genética , Regulación de la Expresión Génica , Humanos , Masculino , Neuronas/citología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Sitios de Empalme de ARN/genética , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Sinapsis/patología , Distribución Tisular , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
BACKGROUND: Little is known about the incidence of delirium and its subtypes in patients admitted to different departments of university hospitals in Latin America. OBJECTIVE: To determine the incidence of delirium and the frequency of its subtypes, as well as its associated factors, in patients admitted to different departments of a university hospital in Bogotá, Colombia. METHODS: A cohort of patients over 18 years of age admitted to the internal medicine (IM), geriatrics (GU), general surgery (GSU), orthopaedics (OU) and intensive care unit (ICU) services of a university hospital was followed up between January and June 2018. To detect the presence of delirium, we used the CAM (Confusion Assessment Method) and the CAM-ICU if the patient had decreased communication skills. The delirium subtype was characterised using the RASS (Richmond Agitation and Sedation Scale). Patients were assessed on their admission date and then every two days until discharged from the hospital. Those in whom delirium was identified were referred for specialised intra-institutional interdisciplinary management. RESULTS: A total of 531 patients admitted during the period were assessed. The overall incidence of delirium was 12% (95% CI, 0.3-14.8). They represented 31.8% of patients in the GU, 15.6% in the ICU, 8.7% in IM, 5.1% in the OU, and 3.9% in the GSU. The most frequent clinical display was the mixed subtype, at 60.9%, followed by the normoactive subtype (34.4%) and the hypoactive subtype (4.7%). The factors most associated with delirium were age (adjusted RRâ¯=â¯1.07; 95% CI, 1.05-1.09), the presence of four or more comorbidities (adjusted RRâ¯=â¯2.04; 95% CI, 1.31-3.20), and being a patient in the ICU (adjusted RRâ¯=â¯2.02; 95% CI, 1.22-3.35). CONCLUSIONS: The incidence of delirium is heterogeneous in the different departments of the university hospital. The highest incidence occurred in patients that were admitted to the GU. The mixed subtype was the most frequent one, and the main associated factors were age, the presence of four or more comorbidities, and being an ICU patient.
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Delirio , Hospitales Universitarios , Humanos , Delirio/epidemiología , Delirio/diagnóstico , Incidencia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Colombia/epidemiología , Anciano de 80 o más Años , Adulto , Unidades de Cuidados Intensivos/estadística & datos numéricos , Estudios de Cohortes , Hospitalización/estadística & datos numéricos , Factores de RiesgoRESUMEN
BACKGROUND: Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD. METHODS: We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells. RESULTS: One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells. CONCLUSIONS: While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.
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Trastornos Generalizados del Desarrollo Infantil/genética , Oxigenasas de Función Mixta/genética , Adolescente , Secuencia de Aminoácidos , Animales , Encéfalo/diagnóstico por imagen , Células COS , Trastornos Generalizados del Desarrollo Infantil/patología , Preescolar , Chlorocebus aethiops , Estudios de Cohortes , Eliminación de Gen , Genotipo , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Oxigenasas de Función Mixta/metabolismo , Datos de Secuencia Molecular , Linaje , Polimorfismo de Nucleótido Simple , Radiografía , Factores de Riesgo , Análisis de Secuencia de ADNRESUMEN
Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.
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Trastorno Autístico/genética , Proteínas Portadoras/genética , Cromosomas Humanos X/genética , Proteínas de la Membrana/genética , Mutación , Proteínas del Tejido Nervioso/genética , Secuencia de Aminoácidos , Trastorno Autístico/metabolismo , Secuencia de Bases , Encéfalo/metabolismo , Moléculas de Adhesión Celular Neuronal , ADN Complementario/genética , Femenino , Perfilación de la Expresión Génica , Ligamiento Genético , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , ARN Mensajero/genética , ARN Mensajero/metabolismo , Homología de Secuencia de AminoácidoRESUMEN
Selective serotonin reuptake inhibitors (SSRI) are common first-line treatments for major depression. However, a significant number of depressed patients do not respond adequately to these pharmacological treatments. In the present preclinical study, we demonstrate that organic cation transporter 2 (OCT2), an atypical monoamine transporter, contributes to the effects of SSRI by regulating the routing of the essential amino acid tryptophan to the brain. Contrarily to wild-type mice, OCT2-invalidated mice failed to respond to prolonged fluoxetine treatment in a chronic depression model induced by corticosterone exposure recapitulating core symptoms of depression, i.e., anhedonia, social withdrawal, anxiety, and memory impairment. After corticosterone and fluoxetine treatment, the levels of tryptophan and its metabolites serotonin and kynurenine were decreased in the brain of OCT2 mutant mice compared to wild-type mice and reciprocally tryptophan and kynurenine levels were increased in mutants' plasma. OCT2 was detected by immunofluorescence in several structures at the blood-cerebrospinal fluid (CSF) or brain-CSF interface. Tryptophan supplementation during fluoxetine treatment increased brain concentrations of tryptophan and, more discreetly, of 5-HT in wild-type and OCT2 mutant mice. Importantly, tryptophan supplementation improved the sensitivity to fluoxetine treatment of OCT2 mutant mice, impacting chiefly anhedonia and short-term memory. Western blot analysis showed that glycogen synthase kinase-3ß (GSK3ß) and mammalian/mechanistic target of rapamycin (mTOR) intracellular signaling was impaired in OCT2 mutant mice brain after corticosterone and fluoxetine treatment and, conversely, tryptophan supplementation recruited selectively the mTOR protein complex 2. This study provides the first evidence of the physiological relevance of OCT2-mediated tryptophan transport, and its biological consequences on serotonin homeostasis in the brain and SSRI efficacy.
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Trastorno Depresivo Mayor , Transportador 2 de Cátion Orgánico , Inhibidores Selectivos de la Recaptación de Serotonina , Animales , Ratones , Anhedonia , Antidepresivos/uso terapéutico , Encéfalo/metabolismo , Corticosterona/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Fluoxetina/farmacología , Quinurenina/metabolismo , Transportador 2 de Cátion Orgánico/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , Triptófano/metabolismoRESUMEN
Autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders with significant combined prevalence (â¼1%) and high heritability. Dozens of individually rare genes and loci associated with high-risk for ASD have been identified, which overlap extensively with genes for intellectual disability (ID). However, studies indicate that there may be hundreds of genes that remain to be identified. The advent of inexpensive massively parallel nucleotide sequencing can reveal the genetic underpinnings of heritable complex diseases, including ASD and ID. However, whole exome sequencing (WES) and whole genome sequencing (WGS) provides an embarrassment of riches, where many candidate variants emerge. It has been argued that genetic variation for ASD and ID will cluster in genes involved in distinct pathways and protein complexes. For this reason, computational methods that prioritize candidate genes based on additional functional information such as protein-protein interactions or association with specific canonical or empirical pathways, or other attributes, can be useful. In this study we applied several supervised learning approaches to prioritize ASD or ID disease gene candidates based on curated lists of known ASD and ID disease genes. We implemented two network-based classifiers and one attribute-based classifier to show that we can rank and classify known, and predict new, genes for these neurodevelopmental disorders. We also show that ID and ASD share common pathways that perturb an overlapping synaptic regulatory subnetwork. We also show that features relating to neuronal phenotypes in mouse knockouts can help in classifying neurodevelopmental genes. Our methods can be applied broadly to other diseases helping in prioritizing newly identified genetic variation that emerge from disease gene discovery based on WES and WGS.