Clinical Characteristics and Pathogenic Gene Identification in Chinese Patients With Paget's Disease of Bone.

Objective: To evaluate the clinical features of sporadic Paget's disease of bone (PDB) in China and further explore the underlying genetic abnormalities of the disease.

Methods: Clinical characteristics, biochemical indices, bone turnover markers and radiographic examinations of the patients were collected. Genomic DNA was extracted from peripheral blood and whole-exome sequencing was carried out to identify the potential pathogenic genes. The pathogenicity of the variants was thereafter investigated by bioinformatics analysis.

Results: A total of 50 patients (57.20 ± 15.52 years, male/female: 1.63: 1) with PDB were included and the mean onset age was 48.34 years (48.34 ± 17.24 years). 94.0% of the patients exhibited symptomatic patterns described as bone pain (86.0%), elevated skin temperature at the lesion site (26.0%), bone deformity (22.0%) and local swelling (18.0%). The most frequently involved lesion sites were pelvis (52.0%), femur (42.0%), tibia (28.0%), skull (28.0%) and spine (18.0%), respectively. Additionally, 40.0% of them accompanied with osteoarthritis, 14.0% with pathological fractures, and the misdiagnosis rate of PDB was as high as 36.0%. Serum level of alkaline phosphatase was significantly increased, with the mean value of 284.00 U/L (quartiles, 177.00-595.00 U/L). Two heterozygous missense mutations of gene (c.1211T>C, M404T) and one novel heterozygous missense mutation in gene (c.989C>T, p. P330L) were identified in our study. Moreover, several potential disease-causing genes were detected and markedly enriched in the pathways of neurodegeneration (including , and genes) and amyotrophic lateral sclerosis (ALS, including , , and genes).

Conclusion: In contrast to Western patients, Chinese patients have an earlier onset age, more severe symptoms, and lower frequency of gene mutation (4.0%). Moreover, a novel heterozygous missense mutation in gene was identified in one male patient with isolated bone phenotype. As for other genetic factors, it was indicated that , , , , and genes may be potential pathogenic genes, pathways of neurodegeneration and ALS may play a vital role in the pathogenesis of PDB.