Introduction: The aim of this study was to investigate the molecular genetic etiology and to determine the relationship between genotype and phenotype with targeted next-generation sequence (NGS)analysis.
Method: Patients with a clinical diagnosis of OI were included in the study. Initially, mutations in COL1A1 and COL1A2 genes which are known to be most responsible for OI were investigated. In the second step, a targeted NGS panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform in cases without mutations of COL1A1 and COL1A2. Pathogenicity of determined variants was determined according to ACMG criteria.
Results: Of the 42 patients (F/M:17/25), 13(31%) of the parents had consanguineous marriage and 21(50%) had a family history of affected individuals. The mean age at admission was 4.5±3.8 years, and the median body weight and height SDS was -1.3 (-6.8-1.2) and -2 (-7.6-0.8)SD. 18 of the patients (42.9%) were evaluated as type 1, 3(7.1%) as type 2, 15(35.7%) as type 3, and 6(14.3%) as type 4 clinically. While bone deformity was detected in 23(54.8%) of the cases, 22(52.4%) was independently mobile. Blue sclera was found in 27(64.3%) of the patients, scoliosis in 11(26.2%), dentinogenesis imperfecta in 6(14.3%) and hearing loss in 2(4.8%).Mutation in COL1A1 and COL1A2 gene was found in 20(47.6%), and in 3 patients (7.1%) respectively. One (2.3%) patient had a mutation in both genes. In 16 (38%) of the remaining 25 patients, 3 different gene (SERPINF1, FKBP10, and P3H1) mutations were found with targeted sequence analysis. 13 (39.3%) of the mutations detected in all investigated genes were not previously reported in the literature and were considered to be disease-specific according to in-silico analysis programs. In nine (21.4%) of the patients, a disease-related mutation was not found in a total of 15 genes, which were known to be associated with OI and were included in the panel list. Advanced genetic analyzes are ongoing in cases whom no mutation is found.
Conclusion: This study is a comprehensive research that shows the clinical and molecular characteristics of OI disease. Genetic etiology was found in 33 (78.5%) of 42 cases by targeted sequence analysis. In addition, 13 new mutations were assessed in OI genes which can be defined as significant contribution to the literature.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology