A Deep Intronic Splice Variant in COL1A1 Causing Osteogenesis Imperfecta Type II

Osteogenesis imperfecta (OI) is a rare disease, hallmarked by bone fragility, multiple fractures, and deformities, and is commonly caused by pathogenic variants in the genes encoding type I collagen. Type II OI is the most severe form and is lethal in the perinatal period. Here, we report recurrence of perinatal lethal OI in two fetuses due to parental mosaicism for a deep intronic pathogenic variant at c.2451 + 77C > T in intron 35 of COL1A1, which resulted in aberrant splicing and the in-frame addition of 75 nucleotides into the mRNA. These patients highlight the importance of considering deep intronic variants in type 1 collagen genes in patients with high suspicion of OI, which may be missed with conventional genetic analysis.