Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China.
Int J Mol Med. 2018 Sep;42(3):1603-1614. doi: 10.3892/ijmm.2018.3730. Epub 2018 Jun 13.
Hypophosphatemic rickets/osteomalacia is characterized by defective renal phosphate reabsorption and abnormal bone mineralization. Hypophosphatemic rickets/osteomalacia consists of inherited and acquired forms, many of which have unknown aetiology. In the present study, next‑generation sequencing‑based resequencing was used on samples from Chinese subjects with hypophosphatemic rickets/osteomalacia, aiming to detect the spectrum of pathogenic genes in these patients. A total of 86 hypophosphatemic rickets/osteomalacia patients (ranging from 3 to 70 years old) were recruited. Patients with tumour‑induced osteomalacia (TIO), renal tubular acidosis, renal osteodystrophy, and adefovir‑induced Fanconi syndrome were excluded. Targeted massively parallel resequencing of 196 candidate genes for hypophosphatemic rickets/osteomalacia was performed in the 86 affected unrelated individuals (cases) and in 100 unrelated healthy controls to identify new genes and mutations in known genes that cause hypophosphatemic rickets/osteomalacia. The results identified seven phosphate‑regulating gene with homologies to endopeptidases on the X chromosome (PHEX) mutations (of which two were novel) and one novel dentin matrix protein 1 (DMP1) mutation in eight patients. Following targeted exome sequencing data analysis, 14 candidate disease‑related gene loci were selected, two of which were of most concern regarding disease severity. Further validation of the present results is warranted, with additional sequencing projects and functional tests. To our knowledge, the present study is the largest cohort of cases with hypophosphatemic rickets/osteomalacia to undergo targeted resequencing. The diagnosis and understanding of the molecular aetiologies of these disorders will be improved by this fast and efficient approach.
低磷性佝偻病/骨软化症的特征为肾脏磷酸盐重吸收缺陷和骨骼矿物质化异常。低磷性佝偻病/骨软化症包括遗传性和获得性两种形式，其中许多病因不明。本研究对中国低磷性佝偻病/骨软化症患者样本进行基于下一代测序的重测序，旨在检测这些患者的致病基因谱。共纳入 86 例低磷性佝偻病/骨软化症患者（年龄 3~70 岁），排除肿瘤诱导性骨软化症（TIO）、肾小管性酸中毒、肾性骨营养不良和阿德福韦诱导的范可尼综合征患者。对 86 例无亲缘关系的受影响个体（病例）和 100 例无亲缘关系的健康对照者进行 196 个低磷性佝偻病/骨软化症候选基因的靶向大规模平行重测序，以鉴定导致低磷性佝偻病/骨软化症的新基因和已知基因中的突变。结果在 8 例患者中发现了 7 种与 X 染色体上内肽酶同源的磷调节基因（PHEX）突变（其中 2 种为新突变）和 1 种新的牙本质基质蛋白 1（DMP1）突变。在靶向外显子组测序数据分析后，选择了 14 个候选疾病相关基因座，其中 2 个与疾病严重程度最相关。需要进一步验证本研究结果，包括进行额外的测序项目和功能测试。据我们所知，本研究是接受靶向重测序的最大低磷性佝偻病/骨软化症病例队列。这种快速有效的方法将提高这些疾病的诊断和对分子病因的理解。
