Role of gene interactions in the pathophysiology of skeletal dysplasias: A case report in Colombia.

BACKGROUND: Genome association studies have shown that gene-gene interactions or epistasis play a crucial role in identifying the etiology, prognosis, and treatment response of many complex diseases beyond their main effects. Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic and gen-gen interaction etiology. The current classification of skeletal dysplasias distinguishes 461 diseases in 42 groups, and the incidence of all skeletal dysplasias is more than 1 in every 5000 newborns. The objective is to present the case of a patient with four variants that generates gen-gen interactions in the skeletal dysplasia.

CASE PRESENTATION: A 1-year-old male patient was diagnosed with skeletal dysplasia based on prenatal ultrasound showing micromelia and pyelocalyceal dilation. Postnatal physical examination revealed body disproportion and involvement of other organs and systems.

MATERIALS AND METHODS: A sequencing study and deletions/duplications analysis were performed for 358 candidate genes associated with skeletal dysplasia. The GeneMANIA interface was used to evaluate the expression network of genes associated with each other for the gen-gen interaction.

RESULTS: Four pathogenic variants were obtained two heterozygous variants with pathogenic significance in SLC26A, one heterozygous pathogenic variant in CLCN7 and another heterozygous pathogenic variant in CEP120. The GeneMANIA interface reveals 77.64% physical interactions, 8.01% co-expression, 5.37% prediction, 3.63% co-localization, 2.87% genetic interactions, 1.88% route of action, and 0.60% shared protein domains.

DISCUSSION AND CONCLUSIONS: These results suggest that the interaction between these genes affects the activity of the inorganic anion exchanger, leading to disorganization of collagen fibers, early mineralization, and decreased assembly of fibronectin in the bone extracellular matrix. Identifying gene-gene interactions is a fundamental step in understanding proper cell function and thus understanding the pathophysiology of many complex human diseases, improving diagnosis, and the possibilities of new personalized therapies.