先证者
成骨不全
桑格测序
医学
基因
牙本质形成不全
遗传学
复合杂合度
基因型-表型区分
突变
基因型
内科学
生物
病理
作者
Yongsong Cao,Hao Zhang,Zhen‐Lin Zhang
摘要
Objective: Osteogenesis imperfecta (OI) is a group of heritable fragile bone diseases, and the majority are caused by pathogenic variants in the COL1A1 and COL1A2 genes. We sought to identify the genetic causes and phenotypes of OI in Chinese patients without COL1A1 or COL1A2 mutations. Methods: Twenty-three patients who were diagnosed with sporadic OI but did not carry COL1A1/2 mutations were recruited, and their genomic DNA was analyzed using targeted next-generation sequencing of rare OI-related genes. The resulting damaging mutations in the probands and their parents were verified using Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment was evaluated in proband 1. Results: Compound heterozygous variants in the WNT1 and TMEM38B genes were identified in proband 1 and proband 2, respectively. A heterozygous mutation in the P4HB gene was identified in proband 3, and a hemizygous mutation in PLS3 was identified in proband 4. The unaffected parents of the probands (except the father of proband 4) with mutations in the WNT1, TMEM38B, and PLS3 genes were heterozygous carriers of each of the variants, respectively. Notably, proband 3 had the characteristic exophthalmos, flat nasal bridge and flat, wide forehead. None of the patients presented with dentinogenesis imperfecta or hearing loss. Furthermore, bisphosphonates exerted beneficial effects on proband 1, who carried the WNT1 mutations, by increasing bone mineral density Z-score, reshaping the compressed vertebrae and decreasing the fracture risk. Conclusion: We identified novel mutations and expanded the spectrum of phenotypes and genotypes of the extremely rare disorder OI. Abbreviations: BMD = bone mineral density; MIM = Mendelian Inheritance in Man; OI = osteogenesis imperfecta; PDI = protein disulfide isomerase
科研通智能强力驱动
Strongly Powered by AbleSci AI