Rare SERPINH1 and SERPINF1 Variants in Autosomal Recessive Osteogenesis Imperfecta Type X and Type VI

Osteogenesis imperfecta (OI) is a group of connective tissue disorders characterized by bone fragility and low bone mineral density (BMD). Two severe autosomal recessive forms, OI type X and VI, can be caused by variants in the SERPINH1 and SERPINF1 genes, respectively. In this study, we reported two children from two unrelated families exhibiting low BMD (z-score <-2.2) and multiple fractures. Whole-genome sequencing revealed a homozygous variant in each family. In family 1, a novel 5' untranslated region (UTR) variant in SERPINH1 (c.-35G>C) was identified at a highly conserved site, predicted to be deleterious by multiple in silico tools. In family 2, a deletion of the whole exon 5 of SERPINF1 was detected. This variant leads to an in-frame loss of amino acids 147 to 215 within the pigment epithelium derived factor like domain and has already been reported in two patients with OI. Both patients have a mild OI phenotype compared with previously reported patients and showed a marked improvement with bisphosphonate treatment. These identified variants expand the mutational spectrum in SERPINH1 and SERPINF1-related OI. Our findings underscore the utility of whole-genome sequencing for comprehensive genetic analysis, particularly for detecting non-coding and structural variants.