土耳其全国多中心研究：骨Paget病的遗传谱与基因型-表型关联
Genetic spectrum and genotype-phenotype associations in Paget's disease of bone: A nationwide multicenter study from Türkiye.
文献信息
| PMID | 42887663 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Dilek Gogas Yavuz |
| 作者单位 | Marmara University School of Medicine, Department of Endocrinology and Metabolism, Istanbul, Türkiye. Electronic address: dilekgogas@marmara.edu.tr. |
| 期刊 | Bone |
| SCI 分区 | Q2 |
| IF | 4.3 |
| 研究类型 | 临床研究 · 临床 |
| 所属专科 | 耳科 |
中文摘要
背景： 骨Paget病（PDB）在西北欧血统人群中最为流行，在中东和亚洲人群中相对罕见，其遗传结构和临床表型特征尚不明确。本研究旨在土耳其全国多中心环境下，确定PDB患者中SQSTM1及其他相关基因变异的频率、基因型-表型关系及治疗反应。
方法： 我们研究了105例PDB患者和96例对照。对外周血基因组DNA进行分层测序：先测序SQSTM1，随后对SQSTM1阴性病例进行靶向下一代测序（NGS）panel（包括TNFRSF11A、TNFRSF11B、VCP、PFN1、OPTN、COL1A1/2、SP7、CSF1），使用Illumina MiSeq平台，Sophia DDM分析并经Sanger确认。收集临床、生化、影像学、骨密度和治疗数据。将携带致病性SQSTM1变异的患者与致病性变异阴性患者进行比较。
结果： 平均年龄67.3±10.4岁（52%为女性）；68%有症状，50%为多骨型疾病。在10/105例患者（9.5%）中鉴定出致病性SQSTM1变异；无对照携带SQSTM1变异。在SQSTM1阴性病例中进行panel测序还发现了VCP、TNFRSF11A和TNFRSF11B的罕见意义不明变异，以及一个偶然发现的LRP5变异（高骨量/骨硬化）；这些仅作描述性报告，未合并为单一频率。TNFRSF11B c.1086_1127del改变在已发表的PDB文献中未见，可能为新变异。SQSTM1阳性患者的疾病范围显著更广（多骨型受累90% vs 45%，p=0.008），家族性疾病更常见（30% vs 5%，p=0.023），骨特异性碱性磷酸酶更高（中位数206 vs 58 U/L，p=0.019），总ALP有升高趋势（355 vs 194 U/L，p=0.074）。颅骨受累、听力损失、骨折和畸形无显著差异。97%接受双膦酸盐治疗（主要为唑来膦酸）；95%实现生化缓解，34%复发，按基因型无显著差异。
结论： 在这个土耳其多中心队列中，致病性SQSTM1变异与更广泛且更常见的家族性PDB相关，但与双膦酸盐治疗反应较差无关。这些数据将PDB的基因型-表型图谱扩展到研究不足的人群，并鉴定出一个需要进一步验证的候选新TNFRSF11B变异。
英文摘要
BACKGROUND: Paget's disease of bone (PDB) is most prevalent in populations of North-western European ancestry and relatively rare in Middle-Eastern and Asian populations, where the genetic architecture and clinical phenotype are poorly characterized. The aim of this study was to determine, in patients diagnosed with PDB in Turkey, the frequency of SQSTM1 and other associated gene variants, the genotype-phenotype relationship and treatment response, in a multicenter, nationwide setting.
METHODS: We studied 105 patients with PDB and 96 controls. Genomic DNA from peripheral blood was sequenced in a tiered fashion: SQSTM1 sequencing first, followed by a targeted next-generation sequencing (NGS) panel (including TNFRSF11A, TNFRSF11B, VCP, PFN1, OPTN, COL1A1/2, SP7, CSF1) in SQSTM1-negative cases, on an Illumina MiSeq platform with Sophia DDM analysis and Sanger confirmation. Clinical, biochemical, radiological, bone-mineral-density and treatment data were collected. Patients carrying pathogenic SQSTM1 variants were compared with pathogenic variant-negative patients.
RESULTS: Mean age was 67.3 ± 10.4 years (52% women); 68% were symptomatic and 50% had polyostotic disease. Pathogenic SQSTM1 variants were identified in 10/105 patients (9.5%); no control carried an SQSTM1 variant. Panel sequencing in SQSTM1-negative cases additionally identified rare variants of uncertain significance in VCP, TNFRSF11A and TNFRSF11B, and an incidental LRP5 variant (high bone mass/osteosclerosis); these were reported descriptively rather than aggregated into a single frequency. TNFRSF11B c.1086_1127del change was absent from the published PDB literature and might be novel. SQSTM1-positive patients had significantly more extensive disease (polyostotic involvement 90% vs 45%, p = 0.008) and more frequent familial disease (30% vs 5%, p = 0.023), with higher bone-specific alkaline phosphatase (median 206 vs 58 U/L, p = 0.019) and a trend to higher total ALP (355 vs 194 U/L, p = 0.074). Cranial involvement, hearing loss, fracture and deformity did not differ significantly. Ninety-seven percent received bisphosphonates (predominantly zoledronic acid); biochemical remission occurred in 95% and relapse in 34%, without significant difference by genotype.
CONCLUSIONS: In this Turkish multicenter cohort, pathogenic SQSTM1 variants were associated with more extensive and more frequently familial PDB but not with a poorer response to bisphosphonate therapy. These data extend the genotype-phenotype map of PDB to an understudied population and identify a candidate novel TNFRSF11B variant that require further validation.