Severe Osteogenesis Imperfecta Due to Homozygous Glycine Substitutions in COL1A1 and COL1A2

Abstract Background Osteogenesis imperfecta (OI) is a rare monogenic bone fragility disorder most often caused by heterozygous pathogenic variants in COL1A1 and COL1A2, typically showing autosomal dominant inheritance. Biallelic pathogenic variants in these genes are rare and associated with Ehlers-Danlos–like features or severe OI forms. Methods Within a collaborative study on paediatric bone fragility in Egyptian patients, we performed whole-exome sequencing and segregation analysis in families with suspected OI. Furthermore, we systematically analyzed triple-helical-domain glycine substitutions found in unaffected individuals using gnomAD 4.1. Results Two unrelated females with severe OI were identified carrying homozygous glycine substitutions, one patient in COL1A1 (c.1012GA; p.(Gly338Ser)), the other in COL1A2 (c.1730GC; p.(Gly577Ala)). Both presented with features typical for OI type III/IV. The heterozygous parents carrying the COL1A1 variant were asymptomatic, whereas those carrying the COL1A2 variant had OI type I. Analysis of triple-helical-domain glycine substitutions found in unaffected individuals in gnomAD showed that glycine residues in proximity to the N-terminal region of the COL1A1 triple-helix domain exhibit greater tolerance to substitutions which was not found for COL1A2. Discussion We report the second patient with a homozygous glycine substitution within the triple-helical domain of COL1A1 associated with severe OI, and the sixth patient with a homozygous glycine substitution within the triple-helical domain of COL1A2. While glycine substitutions in type I collagen genes are classically dominant and fully penetrant, some can cause severe OI with autosomal recessive or double-dominant inheritance patterns, highlighting the variable expressivity and complexity of type I collagen–related disorders.