Identification and characterization of novel genetic causes of autosomal-dominant short stature

• Applicant: Privatdozent Dr. Christian Thomas Thiel
• Subject Area: Human Genetics
• Term: from 2009 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 143504859

The height of an individual shows a normal distribution in the general population and is a highly heterogeneous trait. Short stature / growth retardation is defined as a height below the 3rd c. or more than 2 standard deviation below the estimated target family height. Although, short stature is a common issue, the unknown etiology prevents a sufficient medical care in most cases.In contrast to the height variability in the population, where common variants have been demonstrated to explain normal variance, we have been able to confirm that monogenic defects indeed explain a significant part of the severe forms of short stature. By systematic recruiting and phenotypically evaluation of more than 400 families with idiopathic short stature we were able to identify copy number variants as the underlying cause in about 10% of the patients. Using positional cloning and functional characterization we further identified the monogenic cause in some families. But, these results underline the genetic heterogeneity for short stature. In recent years, next generation sequencing became feasible to uncover the underlying genetic causes in individuals where positional data is not available.Based on the hypothesis of autosomal recessive inheritance we have been performing whole Exome sequencing in 100 patients with idiopathic short stature and identified mutations in known short stature associated genes in 13 % of the patients and proposed several novel candidate genes. These results underline that NGS followed by functional characterization of the resulting genes is able to confirm novel genetic causes for short stature. Based on these results autosomal recessive inheritance has been recognized to be attributable for only a minor part of the patients with idiopathic short stature. We therefore propose autosomal dominant de novo inherited variants as a main factor in most cases, which can be easily detected by trio analysis and biological and functional characterization of these genes.In this project we now aim to identify novel genetic causes of autosomal dominant inherited short stature. This will help to demonstrate the complex genetic mechanisms involved in both cellular and individual growth. Identifying these underlying defects greatly facilitates counseling about prognosis and possible future management.

• DFG Programme: Research Grants