Monoallelic variants in ACVR1 in a cohort of Egyptian individuals with fibrodysplasia ossificans progressiva.

OBJECTIVES

Fibrodysplasia ossificans progressiva (FOP) is a rare ectopic ossification disorder of connective tissue deposited in the muscles, fascia, tendons, and ligaments. The disease is an autosomal dominant pattern caused by pathogenic variants of ACVR1. Herein, we describe the largest number of affected individuals from the Middle East North Africa region who presented with FOP.

METHODS

DNA extraction and molecular studies using Sanger sequencing was done for the nine affected individuals developing bony swellings of variable severity at different ages.

RESULTS

Sanger sequencing identified the common ACVR1 variant (c.617G>A, p.Arg206His) in 7/9, whereas c.983G>A (p.Gly328Glu) in 2/9 affected individuals. Interestingly, the affected individuals harboring the p.Gly328Glu displayed atypical presentations involving micropenis, partial agenesis of the corpus callosum and dysmorphic brainstem, and reduction defects of fingers/toes. Moreover, they had a severe phenotype compared to affected individuals carrying the p.Arg206His variant.

CONCLUSIONS

Our study highlights the progressive nature of the disease and the importance of early diagnosis to avoid lethal complications such as locked jaw and airway obstructions that affect swallowing and breathing. An early accurate diagnosis gives an opportunity for the affected individuals in the future to be candidates for the agonist Palovarotene drug that prevents the complications arising from ectopic ossification.