Family-based reclassification of COL1A1 NM_000088.4:c.4123G > A (p.Ala1375Thr) in a four-generation pedigree with osteogenesis imperfecta

To identify the genetic basis of osteogenesis imperfecta (OI) in a four-generation Chinese family and provide family-based evidence for variant reinterpretation. Clinical data, prenatal ultrasound findings, postnatal imaging, and genetic. results were collected from a four-generation pedigree with nine affected members. Trio-based whole-exome sequencing was performed in the proband and his parents, followed by Sanger sequencing in additional relatives for segregation analysis. Variant interpretation was conducted according to ACMG/AMP and ClinGen recommendations. Affected individuals showed an OI-compatible phenotype spectrum, including recurrent fractures, blue sclerae, short stature, and dentinogenesis imperfecta-related dental abnormalities, with marked intrafamilial variability. Prenatal ultrasound at 22 weeks and 6 days of gestation revealed fetal long-bone shortening and tricuspid regurgitation, consistent with postnatal skeletal fragility and persistent mild tricuspid regurgitation. The proband carried a maternally inherited heterozygous collagen type I alpha 1 chain (COL1A1) variant, NM_000088.4:c.4123G > A (p.Ala1375Thr), previously classified as a variant of uncertain significance. The variant showed phenotype-consistent cosegregation in the family. Integrated evidence supported reclassification of the variant as likely pathogenic. These findings support COL1A1 c.4123G > A (p.Ala1375Thr) as a likely pathogenic variant underlying autosomal dominant OI in this family and highlight the value of integrating prenatal and postnatal data with pedigree-based molecular analysis. A four-generation Chinese pedigree with osteogenesis imperfecta showed marked intrafamilial phenotypic heterogeneity, ranging from isolated blue sclerae to fractures at birth. Trio-based whole-exome sequencing identified a maternally inherited COL1A1 variant, NM_000088.4:c.4123G > A (p.Ala1375Thr), and family-based Sanger testing demonstrated phenotype-consistent cosegregation. Integrated evidence from pedigree segregation, phenotype specificity, population rarity, in silico prediction, and prior reports supported reclassification of p.Ala1375Thr from VUS to likely pathogenic. Prenatal ultrasound detected long-bone shortening and cardiac clues before birth, highlighting its value in early suspicion and risk stratification in familial osteogenesis imperfecta.