Short stature is a common problem in pediatric endocrinology. With the exception of chronic disease and overt hormonal deficiencies, patients with short stature often go without a definitive diagnosis, and are therefore classified as having idiopathic short stature. Treatment with growth hormone therapy is of limited effect in many of these individuals, highlighting the multiple pathways involved in human growth. Height has been shown to be more than 90% heritable, and a large portion of the genetic variation in height can be explained by the additive effects of many common variants; however, there is a substantial contribution of rare variants with larger effect size, particularly at the extremes of height. The chapters of this thesis describe the use of both whole exome sequencing as well as large-scale targeted sequencing in patients with extreme short stature as strategies to discover novel or rare pathogenic variants that lead to short stature phenotypes. A number of pathogenic variants were identified including novel mutations in the insulin-like growth factor 1 receptor (IGF1R) and natriuretic peptide receptor-B (NPR2). These studies also highlight the potential for the detection of a large number of candidate genes, complicating interpretation of results in both the research and clinical settings.
