Aggrecan, encoded by ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated.We sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone (GH) therapies.Over 1000 unrelated short stature patients ascertained across China were genetically evaluated by Next-generation sequencing (NGS)-based test.We identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort, it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, five out of eleven ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SDS improvement.Our data suggested that ACAN mutation is one of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.
Li Lin, Mengting Li, Jingsi Luo, Pin Li, Shasha Zhou, Yu Yang, Ka Chen, Ying Weng, Xiuying Ge, Maimaiti Mireguli, Haiyan Wei, Haihua Yang, Guimei Li, Yan Sun, Lanwei Cui, Shulin Zhang, Jing Chen, Guozhang Zeng, Lijun Xu, Xiaoping Luo, Yiping Shen