Bone Abstracts

Background: Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder characterized by increased bone fragility and low bone mass. The different types of OI may be distinguished by their clinical features and the causative genes, with COL1A1 and COL1A2 genes as the most frequent. The guidelines for OI genetic diagnosis first recommends the screening of COL1A1 and COL1A2 genes using Sanger sequencing. However, this method has limitations to detect somatic mutations with low allele frequency, which could be overcome with the use of next generation sequencing (NGS) technologies.

Presenting problem: We describe an infant born from a bichorionic twin gestation at 33 weeks. At 8 days of life, she presented displaced right femur fracture. The skeletal series also revealed ribs fractures and thoracic vertebral compression. Bone metabolism screening was normal. Despite no familial history of OI was registered and no other features of OI were detected, a genetic study was performed.

Clinical management: COL1A1 and COL1A2 genes were screened using Sanger sequencing. The analysis of COL1A1 detected the c.1129G>A transition, which generates the already known p.Gly377Ser mutation. However, analyses of chromatograms revealed a marked disbalanced fluorescence intensities among wild-type and mutated alleles, suggesting a potential somatic COL1A1 mosaicism. To address this issue, we performed targeted deep sequencing using genomic DNA extracted from blood and mucosal swabs. This analysis revealed the c.1129G>A mutation in both samples at a similar allele frequency (25%). The mutation was not detected in patient’s parents, supporting its de novo nature. The patient started treatment with pamidronate, calcium and vitamin D, and no fractures occurred during 20 months of follow-up.

Discussion: We describe the first case of somatic COL1A1 mosaicism causing OI. Due to the relatively high frequency of the mutated allele, Sanger sequencing was able to detect it and NGS technologies finally confirmed and quantified the degree of mosaicism. This approach enabled us to definitively diagnose this patient, and support NGS as the recommended technology to evaluate gene mosaicism.

Disclosure: The authors declared no competing interests.