评价我国散发性Paget骨病(PDB)的临床特征,进一步探讨其潜在的遗传异常。
临床特征,生化指标,收集患者的骨转换标志物和影像学检查.从外周血中提取基因组DNA并进行全外显子组测序以鉴定潜在的致病基因。此后通过生物信息学分析研究变体的致病性。
共50名患者(57.20±15.52岁,男性/女性:1.63:1)患有PDB,平均发病年龄为48.34岁(48.34±17.24岁)。94.0%的患者表现出描述为骨痛的症状模式(86.0%),病变部位皮肤温度升高(26.0%),骨畸形(22.0%)和局部肿胀(18.0%)。最常见的病变部位是骨盆(52.0%),股骨(42.0%),胫骨(28.0%),头骨(28.0%)和脊柱(18.0%),分别。此外,其中40.0%伴有骨关节炎,14.0%伴病理性骨折,PDB误诊率高达36.0%。血清碱性磷酸酶水平显著升高,平均值为284.00U/L(四分位数,177.00-595.00U/L)。SQSTM1基因的两个杂合错义突变(c.1211T>C,M404T)和HNRNPA2B1基因中的一个新的杂合错义突变(c.989C>T,p.P330L)在我们的研究中鉴定。此外,在神经变性(包括WNT16,RYR3和RYR1基因)和肌萎缩侧索硬化症(ALS,包括NUP205、CAPN2和NUP214基因)。
与西方患者相比,中国患者发病年龄较早,更严重的症状,SQSTM1基因突变频率较低(4.0%)。此外,在1例骨表型分离的男性患者中发现HNRNPA2B1基因的新杂合错义突变.至于其他遗传因素,提示WNT16、RYR3、RYR1、NUP205、CAPN2和NUP214基因可能是潜在的致病基因,神经变性和ALS通路可能在PDB的发病机制中起重要作用。
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.
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.
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 SQSTM1 gene (c.1211T>C, M404T) and one novel heterozygous missense mutation in HNRNPA2B1 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 WNT16, RYR3 and RYR1 genes) and amyotrophic lateral sclerosis (ALS, including NUP205, CAPN2, and NUP214 genes).
In contrast to Western patients, Chinese patients have an earlier onset age, more severe symptoms, and lower frequency of SQSTM1 gene mutation (4.0%). Moreover, a novel heterozygous missense mutation in HNRNPA2B1 gene was identified in one male patient with isolated bone phenotype. As for other genetic factors, it was indicated that WNT16, RYR3, RYR1, NUP205, CAPN2 and NUP214 genes may be potential pathogenic genes, pathways of neurodegeneration and ALS may play a vital role in the pathogenesis of PDB.