Genetic Causes of Growth Disorders

Children often present to pediatricians and pediatric endocrinologists because of abnormal body growth, including both childhood growth failure and, less commonly, overgrowth. Sometimes the cause is evident, for example, growth hormone deficiency for growth failure and growth hormone excess for overgrowth. In other children, the etiology remains unknown despite extensive evaluation, resulting in the unhelpful diagnosis of severe idiopathic short stature or tall stature. These conditions are quite heterogeneous, including children with isolated growth disorders and others who also have other abnormalities such as developmental delay or a constellation of congenital anomalies (syndromic growth disorders). Some cases of severe growth disorders have a polygenic inheritance while others appear to be inherited as a monogenic trait - recessive, dominant or X-linked. Because of recent advances in DNA sequencing technology, it is now feasible to sequence the exome (portion of the genome that encodes gene exons) in families with monogenic disorders and thereby determine the underlying molecular etiology.

We therefore propose a study to identify novel genetic causes of idiopathic growth disorders using whole-exome sequencing. The primary goal of this study is to identify novel causes of childhood growth disorders in order to improve clinical diagnosis, to provide a more precise characterization of associated medical problems, prognosis, and response to treatment based on etiology, and to gain new insights into the regulation of human growth, which may eventually lead to new therapeutic approaches.

Subjects will include children and adults with a clearly recognizable phenotype that includes either short stature or tall stature and a pedigree that strongly suggests a monogenic inheritance. Both syndromic and non-syndromic growth disorders and both proportionate and disproportionate growth disorders will be included. Affected and unaffected family members (who have informative meiotic inheritance relationships to the proband or index case) will also be studied because of their importance for this genetic approach. The phenotype will be characterized by medical history, physical exam, body measurements, and laboratory evaluation. Blood and saliva samples will be collected for whole-exome sequencing and single nucleotide polymorphism (SNP) array analysis. Candidate sequence variants will typically be verified by Sanger sequencing.