Genetic spectrum and genotype-phenotype associations in Paget's disease of bone: A nationwide multicenter study from Türkiye.

Abstract

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.