Faculty

Yong Guo Yu

The study of Phenotype Standardization and Genotype-phenotype Associations in short stature

Idiopathic short stature (ISS), which is considered when height is more than two standard deviations below the mean height for a given age, sex, and population without evidence of a systemic disorder, nutritional, psychological or chromosomal disorder, or over hormonal abnormalities, is a common medical concern in the world. Nowadays, it is generally accepted that patients with idiopathic short stature, are more likely to be caused by the pathogenic effect of rare mutations in a single major gene, and thus genetic testing is often used to explore the cause of idiopathic short stature.

As for the detection methods, next-generation sequencing, especially whole-exome sequencing, has been rapidly adopted in the clinical diagnosis of idiopathic short stature due to its ability to simultaneously analyze several genes or gene regions. However, our previous research had indicated that the positive rate of next-generation sequencing was low for simple short stature while the patients with specific facial features or skeletal abnormalities were more likely to find genetic causes through high-throughput molecular detection technology. With our in-depth survey, we concluded several reasons that may lead to this dilemma, including no standardized describing system for short stature as well as no accurate correspondence between phenotype and genotype.

So how to figure out these limitations is an urgent problem needed to be solved. To this end, we conduct the study of Phenotype Standardization and Genotype-phenotype Associations in short stature. We first complemented detailed phenotypic information linked to variants by case analysis and then integrated known relationships from public databases. After completing these basic works, we collected more than 600 cases from over 50 units around China, trying to discover new relationships by GWAS. In addition, to discover solid phenotypic-genotypic relationships and further develop special auto-interpretation tools for short stature, we need standardized terms of idiopathic short stature (what we call short stature ontology). In this process, domain experts, users, and ontology/knowledge engineers primarily design the ontology, and then we establish a control board and revise ontology according to the users’
feedback. In view of the fact that phenotype and genotype are too much to be included at once, users can update ontology at any time. As the ultimate aim of this research is to establish a special autointerpretation model in short stature, we have researched and evaluated previous auto-interpretation tools and are combining them with integrating related resources based on short stature ontology in our study. All in all, we hope our study could help the etiologic diagnosis of the short stature.

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