Rare Genetic Variants as Novel Causes of Idopathic 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: 8916932
• 负责人: Andrew Nahum Dauber
• 金额: $ 12.6万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916932
• 关键词: Rare; Genetic; Variants; Novel; Causes

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.

描述（由申请人提供）：Dr. Dauber的最终职业目标是成为一名成功和独立的临床研究者，将现代基因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基金期间，道伯博士将获得必要的技能