B3992 - Personalizing the assessment of pediatric short stature by utilizing common genetic variation in height and developmental timing - 21/02/2022

B number: 
Principal applicant name: 
Jonathan Mosley | Vanderbilt University Medical Center
John Shelley, Mingjian Shi, Andrew Spieker, Jill Simmons
Title of project: 
Personalizing the assessment of pediatric short stature by utilizing common genetic variation in height and developmental timing
Proposal summary: 

Growth during childhood can be disrupted by a number of diseases. Because of this, the longitudinal assessment of height is an essential aspect of preventive pediatrics. During these assessments, a child's height is measured and compared to the distribution of heights for that patient's age and sex based on population reference standards. Those children with height measurements that are two standard deviations below the mean are classified as having short stature. As short stature can be an indicator of growth failure due to underlying disease, many children are referred for further specialist care. However, the vast majority (75-99%) do not have disease after specialist evaluation and are instead deemed to have genetic/familial or idiopathic short stature [ISS]. These umbrella terms capture the known entities of familial short stature (FSS) and constitutional delay of growth and puberty (CDGP) as well as children whose short stature remains unexplained. The known entities of FSS and CGDP make up a substantial portion of the “benign” diagnosis of ISS. The traits underlying these conditions—height and pubertal timing—are highly heritable and thus, a significant portion of a patient’s genetic baseline can be quantified with the use of polygenic scores (PS), which measure the cumulative contribution of common genetic variants associated with a trait. We propose that using PSs to adjust the existing reference standards for a child's genetic predisposition to height and puberty pubertal onset will improve the value of growth screening.

Impact of research: 
This work will develop a novel approach that integrates common genetic variation into a standard clinical approach to screen for pathologies impacting childhood growth and development. By incorporating genetic variation of both growth and developmental timing, we will acquire a greater understanding of the common genetic variation underpinning longitudinal growth and improve the diagnostic precision of growth assessment.
Date proposal received: 
Monday, 14 February, 2022
Date proposal approved: 
Monday, 21 February, 2022
Genetic epidemiology (including association studies and mendelian randomisation), Pediatric short stature, GWAS, Statistical methods, Genetic epidemiology, Growth, Puberty