Background A subset of children with short stature do not have an identified clinical explanation after extensive diagnostic evaluation. We hypothesized that a polygenic score for height (PGSheight) could identify children with non-familial idiopathic short stature (ISS-NF) who carry a polygenic predisposition to shorter height that is not accounted for by existing measures. Methods We studied 534 pediatric participants in an electronic health record (EHR)-linked DNA biobank (BioVU) who had been evaluated for short stature by an endocrinologist. Participants were classified as having one of five short stature subtypes: primary growth disorders, secondary growth disorders, idiopathic short stature (ISS), which was sub-classified into familial (ISS-F) and non-familial (ISS-NF), and constitutional delay of puberty (ISS-DP). Differences in polygenic predisposition between subtypes were analyzed using a validated PGSheight which was standardized to a standard deviation score (SDS). Adult height predictions were generated using the PGSheight and mid-parental height (MPH). Within-child differences in height predictions were compared across subtypes. Logistic regression models and AUC analyses were used to test the ability of the PGSheight to differentiate ISS-NF from growth disorders. The incremental improvement (ΔAUC) of adding the PGSheight to prediction models with MPH was also estimated. Results Among the 534 participants, 29.0% had secondary growth disorders, 24.9% had ISS-F, 20.2% had ISS-NF, 17.2% had ISS-DP, and 8.6% had primary growth disorders. Participants with ISS-NF had similar PGSheight values to those with ISS-F (difference [Δ] in PGSheight SDS [95% CI] = 0.19 [− 0.31 to 0.70], p = 0.75). Predicted heights generated by the PGSheight were lower than the MPH estimate for children with ISS-NF (Δ[PGSheight − MPH] = − 0.37 SDS; p = 3.2 × 10−9) but not for children with ISS-F (Δ = − 0.07; p = 0.56). Children with ISS-NF also had lower PGSheight than children with primary growth disorders (ΔPGSheight = − 0.53 [− 1.03 to − 0.04], p = 0.03) and secondary growth disorders (Δ = − 0.45 [− 0.80 to − 0.10], p = 0.005). The PGSheight improved model discrimination between ISS-NF and children with primary (ΔAUC, + 0.07 [95% CI, 0.02 to 0.17]) and secondary growth disorders (ΔAUC, + 0.03 [95% CI, 0.01 to 0.10]). Conclusions Some children with ISS-NF have an unrecognized polygenic predisposition to shorter height, similar to children with ISS-F and greater than those with growth disorders. A PGSheight could aid clinicians in identifying children with a benign, polygenic predisposition to shorter height.

A polygenic score for height identifies an unmeasured genetic predisposition among pediatric patients with idiopathic short stature

期刊论文
出版模式：

开放获取
发表日期：

2025年3月19日

查看全文

John P. Shelley,
Mingjian Shi,
Josh F. Peterson,
Sara L. Van Driest,
Jill H. Simmons,
Jonathan D. Mosley

摘要

Background

A subset of children with short stature do not have an identified clinical explanation after extensive diagnostic evaluation. We hypothesized that a polygenic score for height (PGS_height) could identify children with non-familial idiopathic short stature (ISS-NF) who carry a polygenic predisposition to shorter height that is not accounted for by existing measures.

Methods

We studied 534 pediatric participants in an electronic health record (EHR)-linked DNA biobank (BioVU) who had been evaluated for short stature by an endocrinologist. Participants were classified as having one of five short stature subtypes: primary growth disorders, secondary growth disorders, idiopathic short stature (ISS), which was sub-classified into familial (ISS-F) and non-familial (ISS-NF), and constitutional delay of puberty (ISS-DP). Differences in polygenic predisposition between subtypes were analyzed using a validated PGS_height which was standardized to a standard deviation score (SDS). Adult height predictions were generated using the PGS_height and mid-parental height (MPH). Within-child differences in height predictions were compared across subtypes. Logistic regression models and AUC analyses were used to test the ability of the PGS_height to differentiate ISS-NF from growth disorders. The incremental improvement (ΔAUC) of adding the PGS_height to prediction models with MPH was also estimated.

Results

Among the 534 participants, 29.0% had secondary growth disorders, 24.9% had ISS-F, 20.2% had ISS-NF, 17.2% had ISS-DP, and 8.6% had primary growth disorders. Participants with ISS-NF had similar PGS_height values to those with ISS-F (difference [Δ] in PGS_height SDS [95% CI] = 0.19 [− 0.31 to 0.70], p = 0.75). Predicted heights generated by the PGS_height were lower than the MPH estimate for children with ISS-NF (Δ[PGS_height − MPH] = − 0.37 SDS; p = 3.2 × 10⁻⁹) but not for children with ISS-F (Δ = − 0.07; p = 0.56). Children with ISS-NF also had lower PGS_height than children with primary growth disorders (ΔPGS_height = − 0.53 [− 1.03 to − 0.04], p = 0.03) and secondary growth disorders (Δ = − 0.45 [− 0.80 to − 0.10], p = 0.005). The PGS_height improved model discrimination between ISS-NF and children with primary (ΔAUC, + 0.07 [95% CI, 0.02 to 0.17]) and secondary growth disorders (ΔAUC, + 0.03 [95% CI, 0.01 to 0.10]).

Conclusions

Some children with ISS-NF have an unrecognized polygenic predisposition to shorter height, similar to children with ISS-F and greater than those with growth disorders. A PGS_height could aid clinicians in identifying children with a benign, polygenic predisposition to shorter height.