Özen Samim, Gökşen Damla, Evin Ferda, Işık Esra, Onay Hüseyin, Akgün Bilçağ, Ata Aysun, Atik Tahir, Düzcan Füsun, Özkınay Ferda, Darcan Şükran, Çoğulu Özgür
Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, İzmir, Turkey
Bakırçay University, Çiğli Training and Research Hospital, Clinic of Pediatric Endocrinology, İzmir, Turkey
J Clin Res Pediatr Endocrinol. 2024 Dec 4;16(4):431-442. doi: 10.4274/jcrpe.galenos.2024.2022-12-8. Epub 2024 Jun 3.
Osteogenesis imperfecta (OI) consists of a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. The aim was to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype in OI patients using targeted next-generation sequencing (NGS).
A targeted NGS analysis panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform in patients with a confirmed diagnosis of OI.
Fifty-six patients (female/male: 25/31) from 46 different families were included. Consanguinity was noted in 15 (32.6%) families. Based on Sillence classification 18 (33.1%) were type 1 OI, 1 (1.7%) type 2, 26 (46.4%) type 3 and 11 (19.6%) type 4. Median body weight was -1.1 (-6.8, - 2.5) standard deviation scores (SDS), and height was -2.3 (-7.6, - 1.2) SDS. Bone deformity affected 30 (53.5%), while 31 (55.4%) were evaluated as mobile. Thirty-six (60.7%) had blue sclera, 13 (23.2%) had scoliosis, 12 (21.4%) had dentinogenesis imperfecta (DI), and 2 (3.6%) had hearing loss. Disease-causing variants in and were found in 24 (52.1%) and 6 (13%) families, respectively. In 8 (17.3%) of the remaining 16 (34.7%) families, the NGS panel revealed disease-causing variants in three different genes (, and ). Nine (23.6%) of the variants detected by NGS panel had not previously been reported and were also classified as pathogenic based on American College of Medical Genetics guidelines pathogenity scores. In ten (21.7%) families, a disease-related variant was not found in any of the 13 OI genes on the panel.
Genetic etiology was found in 38 (82.6%) of 46 families by targeted NGS analysis. Furthermore, nine new variants were identified in known OI genes which were classified as pathogenic by standard guidelines.
成骨不全症（OI）是一组表型和遗传异质性的结缔组织疾病，具有相似的骨骼异常，可导致骨骼脆弱和变形。本研究旨在通过靶向二代测序（NGS）探究OI患者的分子遗传病因，并确定基因型与表型之间的关系。
对确诊为OI的患者，在Illumina Nextseq550平台上使用包含参与胶原蛋白/骨合成相关基因的靶向NGS分析面板（Illumina TruSight One）进行检测。
纳入了来自46个不同家庭的56例患者（女性/男性：25/31）。15个（32.6%）家庭存在近亲结婚情况。根据Sillence分类，18例（33.1%）为1型OI，1例（1.7%）为2型，26例（46.4%）为3型，11例（19.6%）为4型。体重中位数为-1.1（-6.8，-2.5）标准差评分（SDS），身高为-2.3（-7.6，-1.2）SDS。30例（53.5%）存在骨骼畸形，31例（55.4%）被评估为活动型。36例（60.7%）有蓝色巩膜症，13例（23.2%）有脊柱侧弯，12例（21.4%）有牙本质发育不全（DI），2例（3.6%）有听力损失。分别在24个（52.1%）和6个（13%）家庭中发现了 和 基因的致病变异。在其余16个（34.7%）家庭中的8个（17.3%）家庭，NGS面板显示在三个不同基因（ 、 和 ）中存在致病变异。NGS面板检测到的变异中有9个（23.6%）此前未被报道，根据美国医学遗传学学会的致病性评分指南也被归类为致病性变异。在10个（21.7%）家庭中，在该面板的13个OI相关基因中均未发现疾病相关变异。
通过靶向NGS分析，在46个家庭中的38个（82.6%）家庭发现了遗传病因。此外，在已知的OI基因中鉴定出9个新变异，根据标准指南被归类为致病性变异。
