Validation and functional characterization of novel genetic factors of idiopathic short stature

• Applicant: Privatdozent Dr. Christian Thomas Thiel
• Subject Area: Human Genetics
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440849937

The height of an individual is a highly heterogeneous trait. It follows a normal distribution in the general population. Short stature, defined as a height two standard deviations below the mean height in the population, affects about 3% of the individuals and is a common medical concern. In contrast to GWAS studies where rare and common height associated variants together explain about 27.4% of the height variability, in previous studies we were able to demonstrate that rare variants are the main underlying cause in extreme forms of short stature. The identification of novel genes for short stature is hampered by the locus heterogenicity as demonstrated by the systematic clinical characterization of 735 families with idiopathic short stature. Even though we demonstrated that about 10 % of the patients with idiopathic short stature have a copy number variant, by conventional diagnostic evaluation the underlying cause was identified in only 13.6%. WES in 200 patients showed that in additional 16.5% of the patients a genetic diagnosis can be established. In previous work we now identified additional 63 potential candidate genes for idiopathic short stature in 254 families. These results confirmed WES to identify potential candidate genes for short stature but highlighted that the identification of mutations in further patients is necessary to establish new genes for idiopathic short stature. The aim of this project is to identify further variants in the 63 potential candidate genes using smMIPs. Further functional characterization of selected candidate gene using CRISPR/Cas9 following RNASeq will pe performed to further evaluate the functional networks of growth defects.

• DFG Programme: Research Grants