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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Mentored Patient-Oriented Research Career Development Award (K23)
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Pediatrics Subcommittee (CHHD)
Program Officer
Winer, Karen
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Children's Hospital Boston
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Swartz, Jonathan M; Akinci, Aysehan; Andrew, Shayne F et al. (2014) A novel ERCC6 splicing variant associated with a mild Cockayne syndrome phenotype. Horm Res Paediatr 82:344-52
Dauber, Andrew; Ercan, Altan; Lee, Jack et al. (2014) Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental delay with minimal adhesion defect. Hum Mol Genet 23:2880-7
Guo, Michael H; Shen, Yiping; Walvoord, Emily C et al. (2014) Whole exome sequencing to identify genetic causes of short stature. Horm Res Paediatr 82:44-52
von Oettingen, Julia E; Tan, Wen-Hann; Dauber, Andrew (2014) Skeletal dysplasia, global developmental delay, and multiple congenital anomalies in a 5-year-old boy-report of the second family with B3GAT3 mutation and expansion of the phenotype. Am J Med Genet A 164A:1580-6
Nilsson, Ola; Guo, Michael H; Dunbar, Nancy et al. (2014) Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. J Clin Endocrinol Metab 99:E1510-8
Kerns, Sarah L; Guevara-Aguirre, Jaime; Andrew, Shayne et al. (2014) A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. J Clin Endocrinol Metab 99:E2117-22
Macedo, Delanie B; Abreu, Ana Paula; Reis, Ana Claudia S et al. (2014) Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab 99:E1097-103
Dauber, Andrew; Rosenfeld, Ron G; Hirschhorn, Joel N (2014) Genetic evaluation of short stature. J Clin Endocrinol Metab 99:3080-92
Salpea, Paraskevi; Horvath, Anelia; London, Edra et al. (2014) Deletions of the PRKAR1A locus at 17q24.2-q24.3 in Carney complex: genotype-phenotype correlations and implications for genetic testing. J Clin Endocrinol Metab 99:E183-8
Batey, Lara; Moon, Jennifer E; Yu, Yongguo et al. (2014) A novel deletion of IGF1 in a patient with idiopathic short stature provides insight Into IGF1 haploinsufficiency. J Clin Endocrinol Metab 99:E153-9

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