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

BackgroundA 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.MethodsWe 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 (Delta AUC) of adding the PGSheight to prediction models with MPH was also estimated.ResultsAmong 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 [Delta] 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 (Delta[PGSheight - MPH] = - 0.37 SDS; p = 3.2 x 10-9) but not for children with ISS-F (Delta = - 0.07; p = 0.56). Children with ISS-NF also had lower PGSheight than children with primary growth disorders (Delta PGSheight = - 0.53 [- 1.03 to - 0.04], p = 0.03) and secondary growth disorders (Delta = - 0.45 [- 0.80 to - 0.10], p = 0.005). The PGSheight improved model discrimination between ISS-NF and children with primary (Delta AUC, + 0.07 [95% CI, 0.02 to 0.17]) and secondary growth disorders (Delta AUC, + 0.03 [95% CI, 0.01 to 0.10]).ConclusionsSome 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.