Mäkitie R E, Mäkitie S, Mäyränpää M K, Pekkinen M
Folkhälsan Research Center, Institute of Genetics, Helsinki, Finland.
Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Bone Rep. 2022 Mar 26;16:101525. doi: 10.1016/j.bonr.2022.101525. eCollection 2022 Jun.
Several genome-wide association studies (GWAS), GWAS meta-analyses, and mouse studies have demonstrated that wingless-related integration site 16 (WNT16) gene is associated with bone mineral density (BMD), cortical bone thickness, bone strength and fracture risk. Practically no data exist regarding the significance of WNT16 in childhood-onset osteoporosis and related fractures. We hypothesized that pathogenic variants and genetic variations in could explain skeletal fragility in affected children. We screened the gene by Sanger sequencing in three pediatric cohorts: 35 with primary osteoporosis, 59 with multiple fractures, and in 95 healthy controls. Altogether, we identified 12 variants in . Of them one was a rare 5'UTR variant rs1386898215 in genome aggregate and medical trans-omic databases (GnomAD, TOPMED; minor allele frequency (MAF) 0.00 and 0.000008, respectively). One variant rs1554366753, overrepresented in children with osteoporosis (MAF = 0.06 healthy controls MAF = 0.01), was significantly associated with lower BMD. This variant was found associated with increased gene expression at mRNA level in fibroblast cultures. None of the other identified variants were rare (MAF < 0.001) or deemed pathogenic by predictor programs. WNT16 may play a role in childhood osteoporosis but genetic variation is not a common cause of skeletal fragility in childhood.
多项全基因组关联研究（GWAS）、GWAS荟萃分析及小鼠研究表明，无翅相关整合位点16（WNT16）基因与骨密度（BMD）、皮质骨厚度、骨强度及骨折风险相关。关于WNT16在儿童期骨质疏松症及相关骨折中的意义，几乎没有相关数据。我们推测，[此处原文缺失相关基因名称]中的致病变异和基因变异可解释患病儿童的骨骼脆弱性。我们通过桑格测序法在三个儿科队列中筛查了[此处原文缺失相关基因名称]基因：35例原发性骨质疏松症患儿、59例多发骨折患儿以及95例健康对照儿童。我们总共在[此处原文缺失相关基因名称]中鉴定出12个变异。其中一个是基因组聚合和医学跨组学数据库（GnomAD、TOPMED；次要等位基因频率（MAF）分别为0.00和0.000008）中一种罕见的5'非翻译区变异rs1386898215。一种变异rs1554366753在骨质疏松症患儿中过度表达（MAF = 0.06，健康对照儿童MAF = 0.01），与较低的骨密度显著相关。在成纤维细胞培养中，发现该变异与mRNA水平上[此处原文缺失相关基因名称]基因表达增加有关。其他鉴定出的变异均不罕见（MAF < 0.001），也未被预测程序判定为致病。WNT16可能在儿童期骨质疏松症中起作用，但基因变异并非儿童骨骼脆弱的常见原因。
