He Dongye, Li Yanying, Yang Wanling, Chen Shuxiong, Sun Hailing, Li Ping, Zhang Mei, Ban Bo
Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, PR China; Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China; Chinese Research Center for Behavior Medicine in Growth and Development, Jining, PR China.
Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, PR China; Chinese Research Center for Behavior Medicine in Growth and Development, Jining, PR China.
Clin Chim Acta. 2022 Jan 1;524:1-10. doi: 10.1016/j.cca.2021.11.021. Epub 2021 Nov 23.
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.
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.
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).
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.
ChiCTR1900026510.
生长激素是治疗生长激素缺乏症（GHD）的有效疗法，但个体敏感性差异较大。目前尚不清楚罕见基因变异是否会导致生长激素反应性的差异。
本研究旨在探讨中国儿童和青少年GHD的分子病因，并评估罕见变异对生长激素治疗效果的影响。
在93例GHD患者中，有21例患者检测到21种罕见的杂合变异，其中14种被分类为意义未明的变异，5种为致病变异，2种为可能致病变异。排除携带这些罕见变异的GHD患者后，生长激素治疗反应的个体间变异性明显降低，且在无罕见变异的组中，治疗起始年龄与身高标准差评分变化之间的负相关性更强。在罕见变异中，7种（可能）致病变异（7.5%，7/93）涉及6个基因，这些基因不仅与生长激素分泌（PROKR2、LZTR1）有关，还与生长板软骨细胞信号传导（ACAN、FBN1、COL9A1）或遗传综合征（PTPN11）有关。
罕见基因变异是导致生长激素反应性差异的重要因素，未来在准确诊断和治疗决策中应考虑基因检测。
ChiCTR1900026510。
