Expanding the Genotypic and Phenotypic Spectrum of P3H1 Related Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) is a genetically heterogeneous disorder with a clinical spectrum ranging from mild to severe. Biallelic P3H1 (OMIM*610339) variants are generally associated with a severe recessive phenotype. This study reports six individuals from three families with phenotypic variability and two novel variants, aiming to expand the phenotypic and genotypic spectrum of P3H1-related OI. The six patients from three unrelated families exhibited varying severity of P3H1-related OI. In Family 1, three siblings, all homozygous for the recurrent c.446 T > G (p.Leu149Arg) variant, showed marked phenotypic differences. One presented with a deforming phenotype, while the other two had milder forms with fewer fractures and little to no skeletal deformity. In Family 2, the affected individual had neonatal fractures and was compound heterozygous for a novel splice-site variant (c.1171-2_1171-1delinsC) and a missense change previously classified as variant of uncertain significance (VUS) (c.1224G > C; p.Lys408Asn). The variants were segregated confirming compound heterozygosity. In Family 3, two siblings with neonatal fractures were homozygous for a novel 58 bp deletion in exon 15 (c.2112_2169del; p.Glu708AlafsTer21), with both parents identified as carriers. This study expands the P3H1 genotypic spectrum with two novel variants and provides evidence supporting reclassification of c.1224G > C as likely pathogenic based on the updated PM3 criterion. It highlights phenotypic variability in patients with the same variant and suggests mild phenotypes may be seen in patients with certain P3H1 variants.