TRANSFER: 5U01HD086838-03 Genetic Diagnosis of Childhood Growth Disorders

Project Details


PROJECT SUMMARY Childhood growth failure may be due to abnormalities of growth hormone production caused by pituitary or hypothalamic disease, whereas in other cases the growth failure is due to other systemic abnormalities or to defects intrinsic to the growing tissues. Although growth failure is a common clinical presentation, the etiology often goes undiagnosed and is hence referred to as idiopathic. In most cases, clinical, biochemical and genetic evaluations in current practice are uninformative and the molecular etiology can currently only be identified in a minority of children. Studies from the investigators' laboratories and others have shown that linear growth failure may be due to single gene mutations affecting the GH-IGF-1 axis or directly affecting chondrogenesis in the growth plate. Several studies suggest that the combination of exome sequencing and SNP arrays may effectively identify new molecular causes of short stature. The goals of this proposal, therefore, are to identify new genetic mechanisms that cause childhood growth disorders and to precisely characterize their phenotypic spectrum. We propose to accomplish these goals with the following three aims: Aim 1: To characterize the underlying pathophysiological abnormalities and other phenotypic features of children with growth disorders of unknown etiology. The goal of this aim is to precisely analyze the clinical, biochemical, and radiological features of patients in order to ultimately determine genotype-phenotype relationships. Aim 2: To identify novel molecular genetic abnormalities responsible for growth disorders by complete exome analysis using exome sequencing and single nucleotide polymorphism (SNP) arrays. Both affected and unaffected family members will be studied using exome sequencing and SNP arrays. Aim 3: To determine the molecular and cellular mechanisms by which mutations in identified genes cause growth disorders. The effects of single gene mutations on protein function and the cellular and physiological consequences will be assessed in this specific aim. We anticipate that new genes that are responsible for mammalian growth will be identified. Clinically, identifying the molecular cause can provide clinicians with new genetic diagnostic tests in patients with growth disorders and more precise assessments of prognosis and response to treatment. We are also poised to study the mechanism by which mutations in these genes interfere with growth and function of target tissues. Study of novel gene mutations and their diverse pathophysiological mechanisms will provide important new insights into the fundamental biological roles of those gene in human development and eventually point the way to new treatment approaches.
Effective start/end date8/1/176/30/20


  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $185,297.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $168,712.00


  • Genetics(clinical)
  • Genetics


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