Biallelic frameshift variants inPHLDB1cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders characterised by susceptibility to fractures, primarily due to defects in type 1 collagen. The aim of this study is to present a novel OI phenotype and its causative candidate gene.Whole-exome sequencing and clinical evaluation were performed in five patients from two unrelated families.PHLDB1mRNA expression in blood and fibroblasts was investigated by real-time PCR, and western blot analysis was further performed on skin fibroblasts.The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment. We identified biallelic NM_001144758.3:c.2392dup and NM_001144758.3:c.2690_2693del pathogenic variants inPHLDB1in the affected patients, respectively, in the families; parents were heterozygous for these variants.PHLDB1encodes pleckstrin homology-like domain family B member-1 (PHLDB1) protein, which has a role in insulin-dependent Akt phosphorylation. Compared with controls, a decrease in the expression levels ofPHLDB1in the blood and skin fibroblast samples was detected. Western blot analysis of cultured fibroblasts further confirmed the loss of PHLDB1.Two biallelic frameshift variants in the candidate genePHLDB1were identified in independent families with a novel, mild-type, autosomal recessive OI. The demonstration of decreasedPHLDB1mRNA expression levels in blood and fibroblast samples supports the hypothesis thatPHLDB1pathogenic variants are causative for the observed phenotype.