A multi-omic approach to study an interesting case of type VI osteogenesis imperfecta

Background: Osteogenesis imperfecta (OI) also known as brittle bone disease, is a genetic pathology in which bones do not form properly and therefore are fragile and break easily. Is a heterogeneous congenital heritable disease that mainly affects connective tissues. Nowadays we number 18 types of OI, distinguished into autosomal dominant, recessive and X-linked inheritance. OI type VI is caused by loss-of-function mutations in SERPINF1, which shows recessive inheritance. Lack of the gene product, PEDF, causes an atypical bone mineralization defect determining a unique clinical phenotype. Aim: the aim of the study is to identify genomic, epigenomic and metabolomic variations that are associated to the disease status in individuals that belong to a nuclear Pakistan family in which is supposed to be segregate type VI osteogenesis imperfecta. Results: exome sequencing confirmed the consanguinity between the parents and shared regions of homozygosity between affected were observed in chr7, chr12 and chr22. In the hypothesis of Autosomal Recessive disease, any compatible mutation was found, and no clear pathogenic variant have been detected. Thus, we explore compound heterozygosis model, identifying and suggesting as potential candidate CERCAM gene, but it is role in bone homeostasis it is still unknown. Epigenetic investigation highlights some interesting genes, known to be involved in bone metabolism, such as RXRA (Retinoid X Receptor Alpha), ELK3 (ETS Transcription Factor) and GLI2 (GLI Family Zinc Finger 2). Metabolomic profiling found 4 modulated pathways: phenylalanine, tyrosine and tryptophan biosynthesis, tryptophan metabolism, pyrimidine metabolism, and Vitamin B6 metabolism. Conclusions: the future investigation will try to enhance and integrate the results from the present omics (transcriptomic analysis is ongoing) into a context of system biology aimed to depict and clarify the defects and biological processes associated to the disease.