ESHG 2014: Copy number variants are a common cause of short stature

Title: S11.3 - Copy number variants are a common cause of short stature Keywords: Short stature; Copy number variation; growth Authors: C. T. Thiel1, A. Reis1, H. Dörr2, A. Rauch3; 1Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, 2Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, 3Institute of Medical Genetics, University of Zurich, Zurich, Switzerland. Abstract: Shortness of stature is one of the most common pediatric concerns and has an incidence of 3 % in the general population. In the majority of patients with idiopathic growth deficit the etiology remains elusive in the absence of morphological details. This unknown etiology prevents a sufficient medical care in most cases. As it has been proposed that the growth fundamentally regulated by genetic factors, GWAS found significant evidence for both single nucleotide and copy number polymorphisms associated with height variation in the general population. However, these associations explain only a small fraction of the overall variability of human height. Based on the early identification of SHOX gene deletions as a common cause of idiopathic and syndromic (Leri-Weil syndrome) short stature as well as copy number variation (CNV) as a common cause of intellectual disability, the hypothesis of a “rare variant - frequent disease” hypothesis seemed to be feasible for short stature. To address this hypothesis we thoroughly build a study group of more than 400 families with idiopathic short stature and conducted SNP array analysis to demonstrate the presence of CNVs as a common underlying cause of short stature. Molecular karyotyping was performed and CNVs of a minimum size of 50kb scored and compared to healthy controls. Based on this technique we found a significant odds ratio for aberrations above 100 kb only. Due to the number of potential disease causing CNVs a gene-centric analysis comparing known CNVs, gene functions, tissue expression and murine knock-out phenotypes was neccessary. We confirmed that 10 % of the patients had de novo and inherited CNVs in agreement to the segregation of the short stature phenotype in the families. These CNV regions include known microdeletion/duplication loci expanding the phenotypical spectrum of these entities. The pathogenicity of novel loci was substantiated by comparison to available information, especially the overlap with loci of genome wide association for short stature. Our data showed a clear connection between the prenatal onset of short stature as well as the severity of the growth deficit with the likelihood of the identification of causal CNVs. Thus, we confirmed CNVs as a main cause of idiopathic short stature. Further improvement of the array technology as well as the application of CNV identification based on next generation sequencing will lead to a more elaborate and detailed view on even smaller CNVs. Application of these methods can help to illuminate the complex heterogeneity of short stature.