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.
|Klammt, Jürgen; Neumann, David; Gevers, Evelien F et al. (2018) Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat Commun 9:2105|
|Kim, Ahlee; Fujimoto, Masanobu; Hwa, Vivian et al. (2018) Adrenal Insufficiency, Sex Reversal, and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1. Horm Res Paediatr 89:205-210|
|Cabrera-Salcedo, Catalina; Shah, Amy S; Andrew, Melissa et al. (2017) Isolated growth hormone deficiency due to the R183H mutation in GH1: Clinical analysis of a four-generation family. Clin Endocrinol (Oxf) 87:874-876|
|Dauber, Andrew; Cunha-Silva, Marina; Macedo, Delanie B et al. (2017) Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty. J Clin Endocrinol Metab 102:1557-1567|
|Vairamani, Kanimozhi; Merjaneh, Lina; Casano-Sancho, Paula et al. (2017) Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency. J Endocr Soc 1:345-358|
|Gkourogianni, Alexandra; Andrew, Melissa; Tyzinski, Leah et al. (2017) Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations. J Clin Endocrinol Metab 102:460-469|
|Ocaranza, Paula; Golekoh, Marjorie C; Andrew, Shayne F et al. (2017) Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies. Horm Res Paediatr 87:412-422|
|Nilsson, O; Isoherranen, N; Guo, M H et al. (2016) Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature. Horm Metab Res 48:737-744|
|Boyle, Lia; Wamelink, Mirjam M C; Salomons, Gajja S et al. (2016) Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects. Am J Hum Genet 98:1235-1242|
|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 99:527-539|
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