Abstract：
OBJECTIVE: Osteogenesis imperfecta (OI) is a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. This study aimed to investigate the molecular genetic etiology and to determine the relationship between genotype and phenotype in OI patients with whole exome sequencing (WES).
METHODS: Multiplex-Ligation dependent Probe Amplification (MLPA) analysis of COL1A1 and COL1A2 and WES were performed on cases between the ages of 0 and 18 whose genetic etiology could not be determined before using a targeted next-generation sequencing panel, including 13 genes (COL1A1, COL1A2, IFITM5, SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, SP7, BMP1, MBTPS2, PLOD2) responsible for OI.
RESULTS: Twelve patients (female/male: 4/8) from 10 different families were included in the study. In 6 (50 %) families, consanguineous marriage was noted. The clinical typing based on Sillence classification; 3 (25 %) patients were considered to be type I, 7 (58.3 %) type III, and 2 (16.7 %) type IV. Deletion/duplication wasn\'t detected in the COL1A1 and COL1A2 genes in the MLPA analysis of the patients. Twelve patients were molecularly analyzed by WES, and in 6 (50 %) of them, a disease-causing variant in three different genes (FKBP10, P3H1, and WNT1) was identified. Two (33.3 %) detected variants in all genes have not been previously reported in the literature and were considered deleterious based on prediction tools. In 6 cases, no variants were detected in disease-causing genes.
CONCLUSIONS: This study demonstrates rare OI types\' clinical and molecular features; genetic etiology was determined in 6 (50 %) 12 patients with the WES analysis. In addition, two variants in OI genes have been identified, contributing to the literature.
METHODS: Multiplex-Ligation dependent Probe Amplification (MLPA) analysis of COL1A1 and COL1A2 and WES were performed on cases between the ages of 0 and 18 whose genetic etiology could not be determined before using a targeted next-generation sequencing panel, including 13 genes (COL1A1, COL1A2, IFITM5, SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, SP7, BMP1, MBTPS2, PLOD2) responsible for OI.
RESULTS: Twelve patients (female/male: 4/8) from 10 different families were included in the study. In 6 (50 %) families, consanguineous marriage was noted. The clinical typing based on Sillence classification; 3 (25 %) patients were considered to be type I, 7 (58.3 %) type III, and 2 (16.7 %) type IV. Deletion/duplication wasn\'t detected in the COL1A1 and COL1A2 genes in the MLPA analysis of the patients. Twelve patients were molecularly analyzed by WES, and in 6 (50 %) of them, a disease-causing variant in three different genes (FKBP10, P3H1, and WNT1) was identified. Two (33.3 %) detected variants in all genes have not been previously reported in the literature and were considered deleterious based on prediction tools. In 6 cases, no variants were detected in disease-causing genes.
CONCLUSIONS: This study demonstrates rare OI types\' clinical and molecular features; genetic etiology was determined in 6 (50 %) 12 patients with the WES analysis. In addition, two variants in OI genes have been identified, contributing to the literature.
摘要：
目的：成骨不全症（OI）是一组表型和遗传异质性结缔组织疾病，具有相似的骨骼异常，导致骨骼脆性和变形。本研究旨在通过全外显子组测序（WES）研究OI患者的分子遗传学病因，并确定基因型与表型之间的关系。
方法：对年龄在0至18岁之间的病例进行了COL1A1和COL1A2和WES的多重连接依赖性探针扩增（MLPA）分析，这些病例在使用靶向下一代测序组前无法确定遗传病因，包括13个基因(COL1A1，COL1A2，IFITM5，SERPINF1，CRTAP，P3H1,PPIB,SERPINH1，FKBP10，SP7，BMP1，MBTPS2，PLOD2）负责OI。
结果：本研究包括来自10个不同家庭的12名患者（女/男：4/8）。在6个（50%）家庭中，注意到近亲婚姻。根据Sillence分类进行临床分型;3例(25%)患者被认为是I型,7（58.3%）III型，和2（16.7%）IV型。在患者的MLPA分析中未检测到COL1A1和COL1A2基因的缺失/重复。12例患者通过WES进行分子分析，其中6个（50%），在3种不同基因(FKBP10,P3H1和WNT1)中鉴定出一种致病变异.在所有基因中检测到的两个(33.3%)变体以前在文献中没有报道,并且基于预测工具被认为是有害的。在6个案例中，在致病基因中未检测到变异.
结论：这项研究显示了罕见的OI类型的临床和分子特征；通过WES分析确定了6例（50%）12例患者的遗传病因。此外,OI基因中的两个变异体已经被鉴定,为文学做出贡献。
方法：对年龄在0至18岁之间的病例进行了COL1A1和COL1A2和WES的多重连接依赖性探针扩增（MLPA）分析，这些病例在使用靶向下一代测序组前无法确定遗传病因，包括13个基因(COL1A1，COL1A2，IFITM5，SERPINF1，CRTAP，P3H1,PPIB,SERPINH1，FKBP10，SP7，BMP1，MBTPS2，PLOD2）负责OI。
结果：本研究包括来自10个不同家庭的12名患者（女/男：4/8）。在6个（50%）家庭中，注意到近亲婚姻。根据Sillence分类进行临床分型;3例(25%)患者被认为是I型,7（58.3%）III型，和2（16.7%）IV型。在患者的MLPA分析中未检测到COL1A1和COL1A2基因的缺失/重复。12例患者通过WES进行分子分析，其中6个（50%），在3种不同基因(FKBP10,P3H1和WNT1)中鉴定出一种致病变异.在所有基因中检测到的两个(33.3%)变体以前在文献中没有报道,并且基于预测工具被认为是有害的。在6个案例中，在致病基因中未检测到变异.
结论：这项研究显示了罕见的OI类型的临床和分子特征；通过WES分析确定了6例（50%）12例患者的遗传病因。此外,OI基因中的两个变异体已经被鉴定,为文学做出贡献。
