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“未诊断的”遗传病或出生缺陷的患者，它为NIH开发新的研究方案提供了临床案例。 儿童代谢性及其他遗传性疾病的研究 根据这一方案，我们为患有各种罕见遗传病的患者提供护理。此外，我们还在国家儿童健康与人类发展研究所(NICHD)和美国国立卫生研究院(NIH)的其他研究所补充和提供临床遗传学、畸形学和代谢遗传学方面的培训，并带头开发关于特定遗传病诊断和护理的特定方面的新研究方案。对具有广泛代谢和遗传条件的患者进行评估，向患者及其家人提供遗传咨询服务，以评估风险，并提供关于预防措施和检测选择的信息。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、多因素障碍和代谢异常。如果不符合另一项NICHD研究方案(针对某种疾病或治疗)，可在本方案的支持下对有遗传/代谢相关疾病的患者进行评估，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。该议定书的总体目的是通过扩大在我们的诊所和病房可以看到的疾病的范围来支持我们的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有关遗传疾病患者及其家人的护理和管理方面的培训。 自闭症研究： 自闭症谱系障碍，通常在3岁前出现症状，特征是相互社交严重障碍，沟通技能障碍，以及重复或限制性行为。它是一种多种病因的异质性疾病；目前还没有精确的临床评估工具允许在多种变种之间进行准确的定义，也没有生物标记来区分这些变种。在美国和欧洲，被确认患有自闭症谱系障碍的儿童数量从每10,000名儿童中有5例上升到72例，而且缺乏明确的治疗形式，这导致了公众越来越关注[1]。改进早期识别特定表型特征和生物标记(例如，电生理变化)的策略有望提高治疗效果。从患者身上收集原代神经元组织的侵袭性可以通过使用IPSC及其随后的神经元分化来规避。随着Yamanaka等人在2007年成功地将人成纤维细胞重新编程为类似ES细胞的状态(又名诱导多能干细胞，IPSC)(2)，这种方法随后被成功地用于从ALS、帕金森病和其他疾病患者的培养神经细胞中提取细胞(3)。这些突破使我们有可能通过应用IPSC对人成纤维细胞进行重编程和随后的神经分化来生成自闭症谱系障碍的细胞培养模型。 自闭症谱系障碍(ASD)具有显著的遗传成分，但所涉及的遗传位点是异质性和复杂性的。因此，在理解不同的基因组异常如何导致一种临床ASD表型方面存在差距。自闭症脑组织的基因表达研究表明，异常表达的蛋白编码基因可能聚集到共同的分子通路上，潜在地调和了强大的遗传性和共享的临床表型与该疾病的基因组异质性。然而，基因表达的调控是极其复杂的，受许多机制的支配，包括非编码RNA。然而，在ASD脑组织中还没有研究评估调节性长非编码RNAs(LncRNAs)的变化，LncRNAs在人类转录组中占很大比例，并积极调节mRNA的表达。为了评估lncRNAs的异常表达是否可能在ASD的分子发病机制中发挥作用，我们用基因芯片从自闭症患者和对照组的前额叶皮质和小脑的死后脑组织中提取了33,000多个注释的lncRNA和30,000个mRNA转录本。我们检测到200多个在ASD中差异表达的LncRNAs，这些LncRNAs富含包含与神经发育和精神疾病相关的基因的基因组区域。此外，对个体捐赠者的前额叶皮质和小脑的mRNAs表达差异的比较表明，ASD大脑的转录同质性更高。此外，lncRNA转录组也是如此。我们的结果提示，进一步研究孤独症患者脑内LncRNA的表达可能进一步阐明该疾病的分子发病机制。目前，我们正致力于费兰-麦克德米德综合征患者的研究，以期与22q13.3区域缺失的基因群建立表型-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.