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.
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.
|de Bruin, Christiaan; Finlayson, Courtney; Funari, Mariana F A et al. (2016) Two Patients with Severe Short Stature due to a FBN1 Mutation (p.Ala1728Val) with a Mild Form of Acromicric Dysplasia. Horm Res Paediatr 86:342-348|
|de Bruin, Christiaan; Orbak, Zerrin; Andrew, Melissa et al. (2016) Severe Short Stature in Two Siblings as the Presenting Sign of ACP5 Deficiency. Horm Res Paediatr 85:358-62|
|Guo, Michael H; Dauber, Andrew; Lippincott, Margaret F et al. (2016) Determinants of Power in Gene-Based Burden Testing for Monogenic Disorders. Am J Hum Genet 99:527-39|
|Dauber, Andrew; MuÃ±oz-Calvo, MarÃa T; Barrios, Vicente et al. (2016) Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med 8:363-74|
|de Bruin, Christiaan; Dauber, Andrew (2016) Genomic insights into growth and its disorders: an update. Curr Opin Endocrinol Diabetes Obes 23:51-6|
|Quintos, Jose Bernardo; Guo, Michael H; Dauber, Andrew (2015) Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene. J Pediatr Endocrinol Metab 28:927-32|
|Wang, Sophie R; Jacobsen, Christina M; Carmichael, Heather et al. (2015) Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Hum Mutat 36:474-81|
|de Bruin, Christiaan; Dauber, Andrew (2015) Insights from exome sequencing for endocrine disorders. Nat Rev Endocrinol 11:455-64|
|de Bruin, Christiaan; Mericq, VerÃ³nica; Andrew, Shayne F et al. (2015) An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome. J Clin Endocrinol Metab 100:E789-98|
|Yu, Yongguo; Yao, RuEn; Wang, Lili et al. (2015) De novo mutations in ARID1B associated with both syndromic and non-syndromic short stature. BMC Genomics 16:701|
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