Genetic Diagnosis of Childhood Growth Disorders

儿童生长障碍的基因诊断

• 批准号: 9260116
• 负责人: Jeffrey Baron
• 金额: $ 16.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260116
• 关键词: Affect; Biochemical; Biochemical Genetics; Biological; Child; Childhood; Chondrogenesis; Clinical; Defect; Diagnostic tests; Disease; Epiphysial cartilage; Etiology; Evaluation; Failure; Family; Family member; Gene Mutation; Genes; Genetic; Genetic study; Genotype; Goals; Growth; Growth Disorders; Hereditary Disease; Human; Human Development; Hydrocortisone; Hypothalamic Diseases; In Vitro; Inheritance Patterns; Insulin-Like Growth Factor I; Laboratories; Magnetic Resonance Imaging; Measurement; Molecular; Molecular Abnormality; Molecular Genetics; Mosaicism; Mutation; Nucleotides; Patients; Phenotype; Physiological; Physiology; Pituitary Diseases; Pituitary Gland; Production; Prolactin; Property; Proteins; Radiology Specialty; Research Personnel; Role; Single Nucleotide Polymorphism; Somatotropin; Tissues; Uniparental Isodisomies; United States National Institutes of Health; Variant; Work; bone imaging; exome; exome sequencing; genetic approach; genetic disorder diagnosis; genetic pedigree; insight; minority children; mutant; novel; outcome forecast; protein function; public health relevance; treatment response

PROJECT SUMMARY Childhood growth failure may be due to abnormalities of growth hormone production caused by pituitary or hypothalamic disease, whereas in other cases the growth failure is due to other systemic abnormalities or to defects intrinsic to the growing tissues. Although growth failure is a common clinical presentation, the etiology often goes undiagnosed and is hence referred to as idiopathic. In most cases, clinical, biochemical and genetic evaluations in current practice are uninformative and the molecular etiology can currently only be identified in a minority of children. Studies from the investigators' laboratories and others have shown that linear growth failure may be due to single gene mutations affecting the GH-IGF-1 axis or directly affecting chondrogenesis in the growth plate. Several studies suggest that the combination of exome sequencing and SNP arrays may effectively identify new molecular causes of short stature. The goals of this proposal, therefore, are to identify new genetic mechanisms that cause childhood growth disorders and to precisely characterize their phenotypic spectrum. We propose to accomplish these goals with the following three aims: Aim 1: To characterize the underlying pathophysiological abnormalities and other phenotypic features of children with growth disorders of unknown etiology. The goal of this aim is to precisely analyze the clinical, biochemical, and radiological features of patients in order to ultimately determine genotype-phenotype relationships. Aim 2: To identify novel molecular genetic abnormalities responsible for growth disorders by complete exome analysis using exome sequencing and single nucleotide polymorphism (SNP) arrays. Both affected and unaffected family members will be studied using exome sequencing and SNP arrays. Aim 3: To determine the molecular and cellular mechanisms by which mutations in identified genes cause growth disorders. The effects of single gene mutations on protein function and the cellular and physiological consequences will be assessed in this specific aim. We anticipate that new genes that are responsible for mammalian growth will be identified. Clinically, identifying the molecular cause can provide clinicians with new genetic diagnostic tests in patients with growth disorders and more precise assessments of prognosis and response to treatment. We are also poised to study the mechanism by which mutations in these genes interfere with growth and function of target tissues. Study of novel gene mutations and their diverse pathophysiological mechanisms will provide important new insights into the fundamental biological roles of those gene in human development and eventually point the way to new treatment approaches.

项目摘要 儿童生长障碍可能是由于垂体或垂体后叶激素分泌异常引起的， 下丘脑疾病，而在其他情况下，生长失败是由于其他全身异常或 生长组织固有的缺陷。虽然生长障碍是一种常见的临床表现， 经常得不到诊断，因此被称为特发性。在大多数情况下，临床，生化和遗传 目前实践中的评估是没有信息的，并且目前只能在一个实验室中鉴定分子病因。 少数儿童。 来自研究者实验室和其他人的研究表明，线性生长失败可能是由于 影响GH-IGF-1轴或直接影响生长板中软骨形成的单基因突变。 一些研究表明，外显子组测序和SNP阵列的组合可以有效地识别 导致身材矮小的新分子原因。因此，这项提案的目标是确定新的遗传学。 研究导致儿童生长障碍的机制，并精确描述其表型谱。 我们建议通过以下三个目标实现这些目标： 目的1：描述潜在的病理生理学异常和其他表型特征 病因不明的生长障碍儿童。这一目标的目标是精确地分析 患者的临床、生化和放射学特征，以最终确定基因型-表型 关系。 目的2：通过完整的基因组测序，鉴定导致生长障碍的新型分子遗传异常。 使用外显子组测序和单核苷酸多态性（SNP）阵列进行外显子组分析。两 将使用外显子组测序和SNP阵列研究受影响和未受影响的家族成员。 目的3：确定已鉴定基因突变的分子和细胞机制 导致生长障碍。单基因突变对蛋白质功能和细胞及 将在这一具体目标中评估生理后果。 我们预计，负责哺乳动物生长的新基因将被确定。在临床上， 确定分子病因可以为临床医生提供新的基因诊断测试， 疾病以及对预后和治疗反应的更精确评估。我们也准备研究 这些基因突变干扰靶组织生长和功能的机制。研究 新的基因突变及其不同的病理生理机制将提供重要的新见解， 这些基因在人类发育中的基本生物学作用，并最终指出了新的 治疗方法。