Molecular and Clinical Landscape of Osteogenesis Imperfecta: Unraveling Autosomal Recessive Forms, Therapeutic Outcomes, and Bone Mineral Density in Carriers.

Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone fragility and marked genetic and phenotypic heterogeneity. This study explores the molecular and clinical spectrum of OI, with a focus on autosomal recessive (AR) forms, therapeutic outcomes, and bone mineral density (BMD) in carriers of AR OI-associated gene variants from the Indian population. A total of 78 clinically suspected OI patients were analyzed, yielding a high diagnostic rate of 92.3%. Exome sequencing was performed in all cases, with whole-genome sequencing in selected exome-negative cases. Autosomal dominant (AD) and AR OI accounted for 66% and 34% of cases, respectively. P3H1 (n = 11) was the most frequently implicated AR gene causing OI, followed by SERPINF1 (n = 5) and WNT1 (n = 4), with 79% of AR variants being novel. Phenotypic evaluation (n = 67) revealed fractures, short stature (87%), and bony deformities (84%) as predominant features. A rare homozygous COL1A1 variant was identified in one patient, while another patient harbored additional variants in AD OI genes, suggesting a potential digenic or modifier effect. Phenotypic severity followed the order from most to least severe: AR genes > COL1A2 (substitution and non-substitution) > COL1A1 (substitution > non-substitution). A self-designed, preliminary clinical severity scoring system ranked CRTAP followed by P3H1, as the AR genes associated with the most severe phenotypes. Therapeutic assessment showed a significant reduction in fracture incidence following zoledronate therapy only in the COL1A1 group, with no notable improvements in the COL1A2 or AR groups. Additionally, BMD evaluation in carrier parents of AR gene causing OI indicated a higher predisposition to low BMD among WNT1 gene carriers. However, these findings are preliminary and limited by small sample size. This study provides an extensive genotypic and phenotypic characterization of OI in the Indian population, with a focus on AR OI. It documents differential therapeutic responses among genetic subgroups and provides preliminary observations on BMD in carrier parents of AR OI-an aspect that has been less explored previously and suggest the need for tailored management strategies. The findings in this study also raise the possibility of genetic modifiers contributing to phenotypic variability, warranting further investigation.