Studies of genetic and metabolic disorders, autism and premature aging

临床方案：该方案的目标是培训临床研究员、研究生和卫生专业人员，使他们对遗传性疾病有更广泛的了解。此外，通过观察患有"未确诊"遗传疾病或出生缺陷的患者，它为NIH制定新的研究方案提供了临床病例。 患有代谢和其他遗传疾病的儿科患者的研究 根据该协议，我们为患有各种罕见遗传疾病的患者提供护理。 此外，我们补充并提供在临床遗传学，畸形学和代谢遗传学在儿童健康和人类发展的国家研究所（NICHD）和美国国立卫生研究院（NIH）的其他研究所的培训机会，并率先在特定遗传疾病的诊断和护理的特定方面的新的研究方案的发展。对患有各种代谢和遗传疾病的患者进行评估，向患者及其家属提供遗传咨询服务，以评估风险，并提供有关预防措施和检测方案的信息。我们研究的疾病包括儿童和/或成人发病的染色体和孟德尔疾病、先天性异常和/或出生缺陷、畸形综合征、家族性癌症综合征、多因素疾病和代谢异常。如果没有资格参加另一项NICHD研究方案（特定于某种疾病或治疗），则可以在本方案的主持下对遗传/代谢相关疾病患者进行评价，以提高参与NICHD临床研究和培训计划的医生的临床技能，并为新的临床研究计划提供刺激。该协议的总体目的是通过扩大我们诊所和病房中可以看到的疾病谱来支持我们研究所的培训和研究任务。我们对IRTA、本科生和研究生、医学生、住院医生和研究员进行了遗传病患者及其家属的护理和管理培训。 自闭症研究： 自闭症谱系障碍，通常在3岁之前表现出症状发作，其特征在于相互社会化严重受损，沟通技能受损，以及重复或限制性行为。这是一种多种病因的异质性疾病;目前没有精确的临床评估工具可以精确定义多种变体，也没有生物标志物可以区分这些变体。在美国和欧洲，自闭症谱系障碍儿童的数量从每10，000名儿童中的5例增加到72例，并且缺乏明确的治疗形式，这导致了公众的关注增加（1）。用于早期鉴定特定表型特征和生物标记物（例如，电生理学变化）有望提高治疗的有效性。通过使用iPSC及其随后的神经元分化，可以避免从患者收集原代神经元组织的侵入性。随着Yamanaka等人在2007年成功地将人成纤维细胞重编程为ES细胞样状态（也称为诱导多能干细胞，iPSC）（2），该方法随后被成功地用于从患有ALS、帕金森病和其他疾病的患者中获得培养的神经细胞（3）。‐这些突破使我们有可能通过应用iPSC重编程人成纤维细胞和随后的神经分化来产生自闭症谱系障碍的细胞培养模型。 自闭症谱系障碍（ASD）具有明显的遗传成分，但涉及的遗传位点是异质性和复杂的。因此，在理解不同的基因组畸变如何导致一种临床ASD表型方面存在差距。来自自闭症脑组织的基因表达研究表明，异常表达的蛋白质编码基因可能会汇聚到共同的分子通路上，从而可能使该疾病的强遗传性和共享的临床表型与基因组异质性相协调。然而，基因表达的调控是非常复杂的，并由许多机制，包括非编码RNA。然而，在ASD脑组织中没有研究评估调节性长非编码RNA（lncRNA）的变化，其代表了人类转录组的大部分，并积极调节mRNA表达。为了评估lncRNA的异常表达是否可能在ASD的分子发病机制中起作用，我们通过微阵列分析了来自自闭症患者和对照组前额叶皮层和小脑的死后脑组织的超过33，000个注释的lncRNA和30，000个mRNA转录本。我们在ASD中检测到超过200种差异表达的lncRNA，这些lncRNA富集了含有神经发育和精神疾病相关基因的基因组区域。此外，比较个体供体中前额叶皮层和小脑之间mRNA表达的差异表明ASD大脑具有更多的转录同质性。此外，lncRNA转录组也是如此。我们的研究结果表明，进一步研究lncRNA在自闭症大脑中的表达可能会进一步阐明这种疾病的分子发病机制。目前，我们正集中精力对McDermid综合征患者进行研究，以建立22q13.3区域缺失基因的表型-基因型关系。

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. 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. Presently we are focusing our efforts on the study of patients with Phelan McDermid syndrome in an effort to establish phenotype-genotype relationships with the constellation of genes deleted in the 22q13.3 region.