ORF08-01 - Clinical and Genetic Evaluation of Osteogenesis Imperfecta with Variable Expressivity

Osteogenesis imperfecta (OI) is an inheritable disorder characterized by bone fragility and wide phenotypic variability. Clinical diagnosis may be challenging, particularly in mild presentations.
This study aimed to perform the clinical and molecular characterization of a family with suspected OI using large-scale parallel sequencing (LPS). A 28-gene panel was analyzed, including COL1A1, COL1A2, IFITM5, FKBP10, P3H1, CRTAP, SERPINF1, SERPINH1, BMP1, PLOD2, PPIB, SP7, SPARC, TMEM38B, WNT1, ALPL, CREB3L1, LRP5, MBTPS2, P4HB, PLS3, SEC24D, SGMS2, and TENT5A.
The index case was a 25-year-old man without consanguinity. Since age 13, he presented multiple femoral fractures (2013–2016) after minimal trauma or spontaneously, requiring internal and external fixation and prolonged immobilization. Clinical features included blue sclerae, short stature (Z-score –1), and nephrolithiasis at age 16.
Laboratory evaluation showed 25-hydroxyvitamin D 31.9 ng/mL (≥30 ng/mL), serum creatinine 0.98 mg/dL (0.6–1.3 mg/dL), intact PTH 20 pg/mL (15–65 pg/mL), total calcium 10.3 mg/dL (8.2–10.2 mg/dL), and alkaline phosphatase 156 U/L (40–129 U/L). In 2017, lumbar spine BMD was 0.702 g/cm² (Z-score –3.5) and total body less head (TBLH) BMD was 0.739 g/cm² (Z-score –3.1). In 2018, a modest improvement was observed (lumbar BMD 0.869 g/cm², Z-score –2.7; TBLH 0.836 g/cm², Z-score –2.4).
Family investigation identified two additional members with OI-compatible features. Among 15 relatives evaluated, 10 presented blue sclerae, two dentinogenesis imperfecta, and two hearing loss.
Molecular analysis identified a heterozygous pathogenic variant in COL1A2 (NM_000089.4:c.2314G>A; p.Gly772Ser) with autosomal dominant inheritance in the index case and 11 affected relatives. The glycine-to-serine substitution occurs within the highly conserved triple-helical region of type I collagen, disrupting molecular stability. This variant is associated with OI types II, III, and IV (OMIM:166210,259420,166220). All carriers had fragility fractures, and 10 showed normal bone metabolism laboratory profiles.
This study underscores the value of molecular diagnosis in OI with variable expressivity, supporting genetic counseling, personalized management, and improved genotype–phenotype correlation. LPS proved to be a robust tool for investigating rare skeletal genetic disorders.