Mei Yazhao, Zhang Hao, Zhang Zhenlin
Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Front Endocrinol (Lausanne). 2022 Jul 14;13:935905. doi: 10.3389/fendo.2022.935905. eCollection 2022.
Nearly 85%-90% of osteogenesis imperfecta (OI) cases are caused by autosome dominant mutations of and genes, of which mutations cover a large proportion, whereas their characteristics remain to be elucidated. This study aims to compare the differences in clinical and genetic characteristics of and inherited mutations of OI, assess the average paternal and maternal age at conception in mutations, and research the rate of nonpenetrance in inherited mutations.
A retrospective comparison between and inherited mutations was performed among 135 OI probands with mutations. Mutational analyses of all probands and their family members were completed by Sanger sequencing. A new clinical scoring system was developed to assess the clinical severity of OI quantitatively.
A total of 51 probands (37.78%) with mutations and 84 probands (62.22%) with inherited mutations were grouped by the results of the parental gene verification. The proportion of clinical type III (<0.001) and clinical scores (<0.001) were significantly higher in mutations. Missense mutations covered a slightly higher proportion of mutations (46.34%) compared with inherited mutations (33.33%), however, lacking a significant difference (=0.1923). The mean BMD Z/T-score at the lumbar spine in mutations was -2.3 ± 1.5, lower than inherited mutations (-1.7 ± 1.8), but lacking statistical significance (=0.0742). There was no significant difference between the two groups in OI-related phenotypes (like fracture frequency, blue sclera, and hearing loss) and biochemical indexes. In mutations, the average paternal and maternal age at conception was 29.2 (<0.05) and 26.8 (<0.0001), respectively, which were significantly younger than the average gestational age of the population. Additionally, 98.04% of pedigrees (50/51) with mutations were spontaneous conception. The rate of nonpenetrance of parents with pathogenic variants in the inherited mutation group was 25.64% (20/78).
Our data revealed that the proportion of clinical type III and clinical scores were significantly higher in mutations than in inherited mutations, demonstrating that mutations are more damaging because they have not undergone purifying selection.
近85%-90%的成骨不全（OI）病例由 和 基因的常染色体显性突变引起，其中 突变占很大比例，但其特征仍有待阐明。本研究旨在比较OI的 和 遗传突变在临床和遗传特征上的差异，评估 突变中受孕时的平均父龄和母龄，并研究遗传突变中的非外显率。
对135例有 突变的OI先证者进行了 和 遗传突变的回顾性比较。通过桑格测序完成了所有先证者及其家庭成员的突变分析。开发了一种新的临床评分系统来定量评估OI的临床严重程度。
根据亲代基因验证结果，将51例（37.78%）有 突变的先证者和84例（62.22%）有 遗传突变的先证者进行分组。 突变中临床III型比例（<0.001）和临床评分（<0.001）显著更高。与 遗传突变（33.33%）相比，错义突变在 突变中所占比例略高（46.34%），但差异无统计学意义（ =0.1923）。 突变中腰椎的平均骨密度Z/T评分是-2.3±1.5，低于 遗传突变（-1.7±1.8），但无统计学意义（ =0.0742）。两组在OI相关表型（如骨折频率、蓝巩膜和听力损失）和生化指标方面无显著差异。在 突变中，受孕时的平均父龄和母龄分别为29.2（<0.05）和26.8（<0.0001），显著低于人群平均妊娠年龄。此外，98.04%（50/51）有 突变的家系为自然受孕。遗传突变组中携带致病变异的父母的非外显率为25.64%（20/78）。
我们的数据显示， 突变中临床III型比例和临床评分显著高于 遗传突变，表明 突变更具危害性，因为它们未经历纯化选择。
