Osteogenesis imperfecta (OI) is a hereditary bone disorder caused by defects of type I collagen. Although up to 90% of patients harbor pathogenic variants in the COL1A1/2 gene, which codes for collagen α1/2 chains, the spectrum of OI genotypes may differ between populations, and there is academic controversy around OI genotype-phenotype correlations. In the current study, 94 Ukrainian OI families were interviewed. Clinical and genealogical information was collected from patients in spoken form, and their phenotypes were described. To identify the spectrum of collagen I pathogenic variants, COL1A1/2 mutational analysis with Sanger sequencing was performed on the youngest affected individual of every family. Of the 143 patients investigated, 67 (46.85%) had type I OI, 24 (16.78%) had type III, 49 (34.27%) had type IV, and III (2.10%) had type V. The mean number of fractures suffered per patient per year was 1.32 ± 2.88 (type I 0.50 ± 0.43; type III 3.51 ± 6.18; type IV 1.44 ± 1.77; and type 5 0.77 ± 0.23). 87.23% of patients had skeletal deformations of different severity. Blue sclera, dentinogenesis imperfecta, and hearing loss were present in 87%, 55%, and 22% of patients, respectively. COL1A1/2 pathogenic variants were harbored by 60 patients (63.83%). 27 pathogenic variants are described herein for the first time. The majority of the pathogenic variants were located in the COL1A1 gene (76.19%). Half (49.21%) of the pathogenic variants were represented by structural variants. OI phenotype severity was highly correlated with type of collagen I defect. The current article presents an analysis of the clinical manifestations and COL1A1/2 mutational spectrum of 94 Ukrainian OI families with 27 novel COL1A1/2 pathogenic variants. It is hoped that this data and its analysis will contribute toward the increased understanding of the phenotype development and genetics of the disorder.

Background Osteogenesis imperfecta (OI) is a rare genetic bone fragility disorder. In the current study, differences between the genotypes and phenotypes of de novo and inherited collagen‐related OI were investigated. Methods A comparative analysis was performed of the genotypes and phenotypes of 146 unrelated inherited and de novo collagen I OI cases from Estonia, Ukraine, and Vietnam. Mutational analysis of the subjects and all available parents were performed with Sanger sequencing. Results Results showed that 56.16% of the OI cases were caused by de novo pathogenic variants. The proportion of OI types OI1, OI4, and OI3 among subjects with inherited OI was 45.31%, 46.88%, and 7.81%, respectively. Among subjects with de novo OI, the proportions of OI types (OI1, OI4, and OI3) were almost equal. Both inherited and de novo OI pathogenic variants occurred more often in the COL1A1 gene than in the COL1A2 . The majority of de novo cases were missense pathogenic variants, whereas inherited OI was mostly caused by loss of function pathogenic variants. Conclusion In summary, there were significant differences between the phenotypes and genotypes of subjects with de novo and inherited OI. These findings may promote the further understanding of OI etiology, and assist with diagnostics procedures, as well as with family planning.

Background Osteogenesis imperfecta (OI) covers a spectrum of bone fragility disorders. OI is classified into five types; however, the genetic causes of OI might hide in pathogenic variants of 20 different genes. Often clinical OI types mimic each other. This sometimes makes it impossible to identify the OI type clinically, which can be a risk for patients. Up to 90% of OI types I–IV are caused by pathogenic variants in the COL1A1/2 genes. OI type V is caused by the c.-14C > T pathogenic variant in the 5′UTR of the IFITM5 gene and is characterized by hyperplastic callus formation and the ossification of interosseous membranes. Results In the current study, we performed IFITM5 5′UTR region mutational analysis using Sanger sequencing on 90 patients who were negative for COL1A1 / 2 pathogenic variants. We also investigated the phenotypes of five patients with genetically confirmed OI type V. The proportion of OI type V patients in our cohort of all OI patients was 1.48%. In one family, there was a history of OI in at least three generations. Phenotype severity differed from mild to extremely severe among patients, but all patients harbored the same typical pathogenic variant. One patient had no visible symptoms of OI type V and was suspected to have had OI type IV previously. We also identified a case of extremely severe hyperplastic callus in a 15-year-old male, who has hearing loss and brittleness of teeth. Conclusions OI type V is underlined with some unique clinical features; however, not all patients develop them. The phenotype spectrum might be even broader than previously suspected, including typical OI features: teeth brittleness, bluish sclera, hearing loss, long bones deformities, and joint laxity. We suggest that all patients negative for COL1A1 / 2 pathogenic variants be tested for the presence of an IFITM5 pathogenic variant, even if they are not expressing typical OI type V symptoms. Further studies on the pathological nature and hyperplastic callus formation mechanisms of OI type V are necessary.

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Актуальність. Лікування деформацій довгих кісток кінцівок — одна з ключових проблем у дітей з порушенням якості кісткової тканини, що пов’язано з комбінованим характером деформацій та їх рецидивами в післяопераційному періоді, нестабільністю фіксаторів, неможливістю самообслуговування пацієнтів. Мета дослідження: визначити в експерименті міцність первинної стабілізації кісткових фрагментів довгих кісток кінцівок при використанні інтрамедулярних фіксаторів різного типу на тлі порушення якості кісткової тканини. Матеріали і методи. Дослідження проведено в лабораторії біомеханіки ДУ «Інститут патології хребта та суглобів ім. проф. М.І. Ситенка НАМН України» на пластикових макетах великогомілкових кісток шляхом моделювання остеотомії в середній їх третині та з’єднання фрагментів за допомогою титанових еластичних стрижнів, ротаційно-нестабільного інтрамедулярного телескопічного фіксатора, а також ротаційно-стабільного інтрамедулярного телескопічного фіксатора шляхом прикладання згинаючого навантаження до середини діафіза моделі в зоні остеотомії. Величину деформації контролювали за величин 50, 100, 150, 200 Н з наступними вимірюваннями навантаження та фіксацією результатів експерименту. Дані оброблялись статистично, для порівняння видів фіксаторів застосовували однофакторний дисперсійний аналіз та апостеріорний тест Дункана, залежність величини деформації від площі перетину моделей досліджували за допомогою парної кореляції Пірсона. Результати. Найкращі результати отримано на моделях з ротаційно-стабільним телескопічним фіксатором, найгірші — при використанні титанових еластичних стрижнів. Висновки. Всі типи фіксаторів забезпечують достатню первинну стабільність фіксації на згинання (величина деформації не перевищує 5 мм), однак найкращі результати отримані на моделях з ротаційно-стабільним телескопічним фіксатором.