Clinical Protocol: This protocol has as its objective the training of clinical fellows, graduate students and health professionals to afford them a broader understanding of heritable diseases. Additionally by seeing patients with """"""""undiagnosed"""""""" genetic diseases or birth defects it provides clinical cases for the development of new research protocols at NIH. Studies of Pediatric Patients with Metabolic and other Genetic Disorders Under this protocol we provide care for patients with a variety of rare genetic disorders. In addition, we supplement and offer an opportunity for training in clinical genetics, dysmorphology and metabolic genetics in the National Institute of Child Health and Human Development (NICHD) and other Institutes of the National Institutes of Health (NIH), and spearhead the development of new research protocols on particular aspects of diagnosis and care for specific genetic diseases. Evaluations of patients with a broad spectrum of metabolic and genetic conditions are performed, genetic counseling services are offered to patients and their families to assess risk, and give information on preventive measures, and testing options. Disorders that we studied include chromosomal and Mendelian disorders of childhood and/or adult onset, congenital anomalies and/or birth defects, dysmorphic syndromes, familial cancer syndromes, multifactorial disorders, and metabolic abnormalities. If not eligible for another NICHD research protocol (specific for a disease or a treatment), patients with genetic/metabolic-related conditions may be evaluated under the auspices of this protocol to advance the clinical skills of physicians participating in NICHD clinical research and training programs, and to provide stimuli for new clinical research initiatives. The overall purpose of this protocol is to support our Institutes training and research missions by expanding the spectrum of diseases that can be seen in our clinics and wards. We trained IRTAs, undergraduate and graduate students, medical students, residents, and fellows in the care and management of patients with genetic conditions and their families. Autism Research: Autism spectrum disorder, normally exhibits the onset of symptoms before 3 years of age, and is characterized by severe impairment in reciprocal socialization, impairment in communication skills, and repetitive or restrictive behaviors. It is a heterogeneous condition of multiple etiologies;no precise clinical assessment tools currently allow precise definition between the multiple variants, nor are there biological markers to distinguish these variants. A rise in the number of children identified with autism spectrum disorders, from five to 72 cases per 10,000 children in the USA and Europe, and the absence of definitive forms of therapy have resulted in increased public concern (1). Improved strategies for early identification of specific phenotypic characteristics and biological markers (e.g., electrophysiological changes) hopefully might improve the effectiveness of treatment. The invasive nature of collecting primary neuronal tissue from patients might be circumvented through the use of iPSC and their subsequent neuronal differentiation. With the successful reprogramming of human fibroblasts into ES cell‐like state (aka induced pluripotent stem cells, iPSC) by Yamanaka et al in 2007 (2), this methodology has subsequently been successfully employed to derive cultured neural cells from patients with ALS, Parkinson disease, and other disorders (3). These breakthroughs make it possible for us to generate a cell culture model of autism spectrum disorder by application of iPSC reprogramming of human fibroblasts and subsequent neural differentiation. In this study, fibroblast cultures from patients (subject with autism), and non-affected controls have been established;subsequently these cells are reprogrammed into an ES cell-like state (aka induced pluripotent stem cells, iPSC). The reprogrammed cell colonies are cloned, propagated, and induced to differentiate in vitro into neuronal cultures. Based on our underlying assumption that synaptic transmission is aberrant in autism, these patient-specific neuronal cultures will be utilized for neuronal network analysis by using the photoconductive-stimulation system described in Gutierrez et al. Briefly, spontaneous or pulse-stimulated activity of networks is measured by optical techniques, and the structural basis of these patterns will analyzed by fractal dimension analysis. By use of these approaches we have the capacity to characterize the arrangement and complexity of their axonal architecture. This approach has been employed to demonstrate differences in hippocampal cultures of a rat model carrying the neurolignin mutation R471C‐NL3 which has been identified in a subgroup of patients with autism spectrum disorders. This study represents the attempt to evaluate membrane excitation and signal transduction in neural cells derived from patients with autism. The autism spectrum disorders (ASD) have a significant hereditary component, but the implicated genetic loci are heterogeneous and complex. Consequently, there is a gap in understanding how diverse genomic aberrations all result in one clinical ASD phenotype. Gene expression studies from autism brain tissue have demonstrated aberrantly expressed protein-coding genes may converge onto common molecular pathways, potentially reconciling the strong heritability and shared clinical phenotypes with the genomic heterogeneity of the disorder. However, the regulation of gene expression is extremely complex and governed by many mechanisms, including noncoding RNAs. Yet no study in ASD brain tissue has assessed for changes in regulatory long non-coding RNAs (lncRNAs), which represent a large proportion of the human transcriptome, and actively modulate mRNA expression. To assess if aberrant expression of lncRNAs may play a role in the molecular pathogenesis of ASD, we profiled over 33,000 annotated lncRNAs and 30,000 mRNA transcripts from postmortem brain tissue of autistic and control prefrontal cortex and cerebellum by microarray. We detected over 200 differentially expressed lncRNAs in ASD, which were enriched for genomic regions containing genes related to neurodevelopment and psychiatric disease. Additionally, comparison of differences in expression of mRNAs between prefrontal cortex and cerebellum within individual donors showed ASD brains had more transcriptional homogeneity. Moreover, this was also true of the lncRNA transcriptome. Our results suggest that further investigation of lncRNA expression in autistic brain may further elucidate the molecular pathogenesis of this disorder. Premature Aging Syndromes: The diseases of premature aging in human are characterized by the early onset of aging phenotypes that are now known to be caused by mutations of different genes. Werner syndrome (WS) is an adult progeroid syndrome caused by mutations of the RecQ helicase WRN. WRN has been implicated in a variety of biochemical processes including DNA replication, repair, recombination, telomere maintenance and transcription. Loss of the WRN protein results in genomic instability and dysfunctional telomeres. Skin fibroblasts from WS patients demonstrate reduced replication potential and accelerated senescence in culture, possibly due to the dysfunctional telomeres. Previous studies on the pathogenesis of WS were limited to skin fibroblasts or virus-transformed lymphocytes. Secondly, animal models of WRN mutant cannot accurately recapitulate the WS phenotype observed in humans. Reprogramming of WS cells to iPSCs may provide a cell model for the study of the pathogenesis, especially for the differentiation of WS embryonic and adult st

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