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

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.