Rare Genetic Variants as Novel Causes of Idiopathic or Syndromic Short Stature

罕见遗传变异是特发性或综合征性身材矮小的新原因

• 批准号: 8677933
• 负责人: Andrew Nahum Dauber
• 金额: $ 0.87万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677933
• 关键词: Acids; Adult; Affect; Biological; Biological Process; Body Patterning; Candidate Disease Gene; Child; Childhood; Clinical; Clinical Investigator; Clinical Research; Code; Custom; DNA; DNA Sequence; Data; Diabetes Mellitus; Diagnosis; Disease; Endocrinologist; Endocrinology; Enrollment; Etiology; Evaluation; Exons; Family history of; Foundations; Frequencies; Future; Genes; Genetic; Genetic Research; Genetic Variation; Genome; Goals; Grant; Growth; Growth Disorders; Growth Hormone Receptor; Hand; Health; Height; Hormonal; Hybridization Array; Individual; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Investigation; Investigative Techniques; Mentors; Methodology; Mutation; Pathway interactions; Patients; Phenotype; Physiological; Physiology; Recombinants; Regulation; Research; Research Methodology; Research Personnel; Role; Signal Transduction; Signaling Protein; Somatotropin; Surveys; Syndrome; Technology; Testing; Time; Training; Variant; Work; base; career; clinically relevant; cohort; comparative genomic hybridization; exome sequencing; experience; family structure; genetic variant; genome wide association study; insight; mutation carrier; new growth; new therapeutic target; next generation sequencing; novel; public health relevance; rare variant; response; skeletal; skeletal dysplasia; skills; trait

DESCRIPTION (provided by applicant): Dr. Dauber's ultimate career goal is to be a successful and independent clinical investigator applying modern genetic research methods to clinically relevant problems in the field of pediatric endocrinology and specifically growth disorders. During the time period of his K23 grant, Dr. Dauber will acquire the requisite skills in modern genetic research and in-depth phenotyping necessary to achieve this goal through a combination of formal course work, attendance of seminars, mentoring and hands on research experience. Short stature is an extremely common complaint evaluated by pediatric endocrinologists. Despite extensive evaluation, no definitive etiology is found in the vast majorit of children with short stature including those with severe short stature and associated syndromic features. We know that height has a strong genetic component and is influenced by numerous genes. We propose that some children who are referred for evaluation of short stature will have rare genetic variants in genes identified by genome-wide association studies of height, or they will have rare mutations in genes known to underlie syndromes of abnormal growth or in biological pathways known to regulate growth. Furthermore, we believe that carriers of rare coding mutations in these or other genes may have different clinical features and will represent distinct novel syndromes of abnormal growth. To test these hypotheses, we will complete enrollment of a well phenotyped cohort of 500 children with idiopathic short stature. We will then use next generation sequencing technology and a custom comparative genomic hybridization array to search for rare sequence and structural variants in a list of ~1000 candidate genes. We will search for genes with an excess of rare potentially pathogenic variants in subjects compared to controls of normal height. Additionally, we will perform whole exome sequencing in individual subjects with extreme short stature and undefined syndromes of abnormal growth with favorable family structure. We will then correlate these genetic variants with the subjects' clinical features and perform additional detailed physiological investigations to better define these novel syndromes of abnormal growth. Through his prior research and educational experiences, Dr. Dauber has acquired a strong foundation in clinical research. He now seeks further training in the methodologies of genetic studies including the interpretation of next generation sequencing data as well as other modern genetic investigative techniques. He will be mentored by Dr. Joel Hirschhorn, a leading investigator in the genetics of height, and will be advised by a team of experienced genetics researchers. The research proposed in this K23 application has broad implications for understanding growth, a fundamental biological process in childhood. It also has the potential to significantly impact the way we diagnose and treat children with short stature. Dr. Dauber is confident that completion of the work and training plan will prepare him for a successful career as an independent clinical investigator in pediatric endocrinology. PUBLIC HEALTH RELEVANCE: Growth is a fundamental biological process that occurs in childhood, and normal growth is a hallmark of good health. Despite extensive evaluation, many children with poor growth do not have a defined cause for their short stature. This study proposes to search for rare genetic causes of short stature in order to provide insights into this fundamental biological process and to help with the diagnosis and treatment of children with growth disorders.

Dauber博士的最终职业目标是成为一名成功的独立临床研究者，将现代遗传研究方法应用于儿科内分泌学领域的临床相关问题，特别是生长障碍。在他的K23赠款的时间内，Dauber博士将获得必要的技能， 现代遗传学研究和深入的表型分析是通过正式课程、参加研讨会、指导和实际研究经验相结合来实现这一目标所必需的。身材矮小是儿科内分泌学家评估的一种极为常见的主诉。尽管进行了广泛的评估，但在绝大多数身材矮小儿童（包括那些严重身材矮小和相关综合征特征的儿童）中没有发现明确的病因。我们知道，身高有很强的遗传成分，并受到许多基因的影响。我们认为，一些被转诊接受身材矮小评估的儿童将在全基因组身高关联研究中发现的基因中存在罕见的遗传变异，或者他们将在已知为异常生长综合征或已知调节生长的生物学途径的基因中存在罕见的突变。此外，我们相信这些或其他基因中罕见编码突变的携带者可能具有不同的临床特征，并将代表不同的异常生长综合征。为了验证这些假设，我们将完成一个表型良好的队列500名儿童特发性身材矮小。然后，我们将使用下一代测序技术和定制的比较基因组杂交阵列，在约1000个候选基因的列表中搜索罕见的序列和结构变体。我们将在受试者中寻找与正常身高对照相比具有过量罕见潜在致病变异的基因。此外，我们将在具有极端矮小身材和具有有利家族结构的不确定的异常生长综合征的个体受试者中进行全外显子组测序。然后，我们将这些遗传变异与受试者的临床特征相关联，并进行额外的详细生理调查，以更好地定义这些异常生长的新综合征。通过他以前的研究和教育经验，Dauber博士在临床研究方面获得了坚实的基础。他现在寻求遗传研究方法的进一步培训，包括下一代测序数据的解释以及其他现代遗传调查技术。他将由乔尔赫什霍恩博士指导，他是身高遗传学的主要研究者，并将由一组经验丰富的遗传学研究人员提供咨询。K23申请中提出的研究对理解儿童期基本的生物学过程-生长具有广泛的意义。它也有可能显著影响我们诊断和治疗儿童的方式 身材矮小Dauber博士相信，完成工作和培训计划将为他作为儿科内分泌学独立临床研究者的成功职业生涯做好准备。 公共卫生相关性：生长是发生在儿童时期的一个基本生物过程，正常生长是健康的标志。尽管进行了广泛的评估，但许多生长不良的儿童并没有明确的原因导致他们身材矮小。这项研究旨在寻找矮小症的罕见遗传原因，以便深入了解这一基本生物学过程，并帮助诊断和治疗患有生长障碍的儿童。