Genetic and epidemiological features of fibrodysplasia ossificans progressiva in Venezuela

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease of connective tissue caused by mutations in the ACVR1 gene, producing the formation of heterotopic bone in soft tissues. The hallmark sign of the disease is the congenital malformations of the great toes in the affected individuals. Heterotopic ossification is triggered by mild physical trauma, leading to progressive disability. Its incidence is approximately 1 patient per 1.4 million people worldwide, without gender, ethnic, or geographic localization predisposition. To date, around 25 different mutations have been described, but the substitution of adenine by guanine at nucleotide c.617 replacing an arginine by histidine at residue 206 (p.R206H) accounts for 97 % of cases with classical FOP. Identification of the pathological alterations in ACVR1 has significant diagnostic and therapeutic implications in the clinical management of FOP. Through molecular analysis of the ACVR1 gene in four unrelated Venezuelan patients, the study aimed to confirm the diagnosis, determine whether in-phase haplotypes differentiated between a de novo event or a common remote gene origin in the country, and aid in the nosography of this rare disease. The findings supported a de novo recurring phenomena by demonstrating that all the patients had the p.R206H mutation but did not share an in-phase haplotype.