Severe cases of osteogenesis imperfecta type VIII due to a homozygous mutation in P3H1 (LEPRE1) and review of the literature.

Background: Osteogenesis imperfecta (OI) is a genetic disorder that causes skeletal fragility, multiple fractures and several extraskeletal disorders. Most cases of OI are caused by mutations in COL1A1/A2. Osteogenesis imperfecta type VIII typically causes a severe and fatal phenotype that presents at birth with severe osteopenia, congenital fractures and other clinical manifestations.

Objectives: We describe the cases of an 11-year-old female and a 9-year-old male with homozygous truncating mutations in P3H1. Both cases were born with intrauterine fractures and suffered multiple fractures shortly after birth, requiring multiple operations to correct both fractures and severe scoliosis. The patients have been treated with pamidronate since the age of 2.

Material And Methods: Whole exome sequencing (WES) was performed by Gene by Gene using Twist Bioscience technology. Initially, ~36.5 Mb of consensus coding sequences (targeting >98% of RefSeq and Gencode v. 28 regions obtained from the human genome) was replicated from fragmented genomic DNA using the Twist Human Core Exome Plus kit. The subsequent library was sequenced on the Illumina Novaseq Next Generation Sequencing platform to achieve at least ×20 reading depth for >98% of the targeted bases. Variant annotations and filtering was performed using Ingenuity Variant Analysis software.

Results: We identified a homozygous mutation in the 3rd exon of P3H1 (c.628C>T/p.Arg210 Ter). Our cases broaden the phenotypic spectrum of OI type VIII as, to the best of our knowledge, these are the first postnatal cases with P3H1 (c.628C>T/p.Arg210 Ter) mutations published in the literature.

Conclusions: We present the first recorded postnatal cases from unrelated families of OI type VIII, broadening our understanding of the severe, but nonfatal spectrum of clinical phenotype of this recessive form of OI.