Background: Growth hormone is an effective therapy for growth hormone deficiency (GHD) but with a rather variable individual sensitivity. It is unclear whether rare genetic variants may contribute to the differential GH responsiveness.
Methods: The present study aims to investigate the molecular etiology of GHD in Chinese children and adolescents and evaluate the impact of rare variants on therapeutic efficacies of GH.
Results: Twenty-one rare heterozygous variant were classified as promising uncertain significance (n = 14), pathogenic (n = 5) or likely pathogenic (n = 2) for 21 of the 93 GHD patients. After GHD patients harboring these rare variants were excluded, inter-individual variability in the response to GH therapy obviously reduced and the negative correlation between initiation age of treatment and height SDS change became stronger in the group without rare variants. Among rare variants, 7 (likely) pathogenic variants (7.5%, 7/93) involved a total of 6 genes not only associated with GH secretion (PROKR2, LZTR1), but also growth plate chondrocyte signaling (ACAN, FBN1, COL9A1) or genetic syndromes (PTPN11).
Conclusions: Rare genetic variants are an important factor contributing to differential GH responsiveness and genetic testing should be factored into accurate diagnosis and treatment decision making in the future.
Clinical trial registration number: ChiCTR1900026510.
Keywords: Accurate diagnosis; GH treatment; Genetic defects; Growth hormone deficiency; Growth response; Whole-exome sequencing.
Copyright © 2021 Elsevier B.V. All rights reserved.