Preserved bone mineral density in autosomal dominant SP7-related osteogenesis imperfecta: a case report of the p.Glu340Ala variant.

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and variable skeletal deformities. While SP7 variants typically underlie autosomal recessive OI, a single heterozygous SP7 variant has recently been reported to cause autosomal dominant OI. Given the limited family-based genetic studies of OI in Malaysian populations, its inheritance patterns and molecular spectrum remain poorly defined. Here, we investigated a three-generation Malaysian family with three individuals (the 7-year-old proband, her 8-year-old brother, and 34-year-old mother) presenting with lower limb bowing, impaired fracture healing, despite preserved lumbar spine areal bone mineral density. Three affected individuals and seven unaffected relatives were recruited for clinical evaluation and genetic analysis. Targeted sequencing and whole-exome sequencing (WES) revealed a heterozygous SP7 missense variant, NM_001173467.2:c.1019A>C (p.Glu340Ala), initially classified as a variant of uncertain significance, in all affected individuals. Variant evaluation using in silico tools (CADD-Phred, 27.2; REVEL, 0.812; PROVEAN, 0.887), protein stability modeling (ΔΔG