骨帕盖特病（PDB）是一种常见的晚发性骨疾病，其特点是骨转换的局部增加，可能导致骨病变。Sequestosome 1（SQSTM1）基因中的杂合致病变异被发现是PDB的主要遗传致病原因。最近，PFN1和ZNF687被确定为早期的、多骨骨骼系统严重型PDB和发展成巨细胞肿瘤的患者中的致病基因。在我们的研究中，我们对比利时的PDB队列（n = 188）进行了PFN1和ZNF687的编码区域筛查。在PFN1基因中未找到任何变异，支持了该基因在PDB中极为罕见的观察结果。然而，在ZNF687中我们发现了3个非同义编码变异。有趣的是，这两个罕见变异（p.Pro937His和p.Arg939Cys）在编码的ZNF687蛋白的核定位信号中集中出现，并且还携带了先前报告的致病变异p.Pro937Arg。总之，我们的发现支持了ZNF687基因的遗传变异与经典PDB的发病机制的相关性，并扩大了其突变谱。© 2023. 作者已独家授权给施普林格科教传媒股份有限公司，属于施普林格自然出版集团。

Paget's disease of bone (PDB) is a common, late-onset bone disorder, characterized by focal increases of bone turnover that can result in bone lesions. Heterozygous pathogenic variants in the Sequestosome 1 (SQSTM1) gene are found to be the main genetic cause of PDB. More recently, PFN1 and ZNF687 have been identified as causal genes in patients with a severe, early-onset, polyostotic form of PDB, and an increased likelihood to develop giant cell tumors. In our study, we screened the coding regions of PFN1 and ZNF687 in a Belgian PDB cohort (n = 188). In the PFN1 gene, no variants could be identified, supporting the observation that variants in this gene are extremely rare in PDB. However, we identified 3 non-synonymous coding variants in ZNF687. Interestingly, two of these rare variants (p.Pro937His and p.Arg939Cys) were clustering in the nuclear localization signal of the encoded ZNF687 protein, also harboring the p.Pro937Arg variant, a previously reported disease-causing variant. In conclusion, our findings support the involvement of genetic variation in ZNF687 in the pathogenesis of classical PDB, thereby expanding its mutational spectrum.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.