To Örebro University

BACKGROUND: Fibrillinopathies comprise allelic disorders with opposing phenotypes. Pathogenic variants in fibrillin-2, encoded by FBN2, have mainly been associated with congenital contractural arachnodactyly but in a few cases also with brachydactyly.

METHODS AND RESULTS: We recruited two families with index patients presenting with short stature (heights ≤3 SD scores), brachydactyly, joint contractures and facial dysmorphism as major features. In Family 2, the proband and father also had carpal tunnel syndrome. Radiographs showed signs of mild skeletal dysplasia with short long bones, brachydactyly and mild metaphyseal and vertebral irregularity. Whole genome sequencing revealed novel variants in the FBN2 gene that segregated with the phenotype: in Family 1, a novel heterozygous missense variant c.4862G>A, p.(Cys1621Tyr) and in Family 2, a novel heterozygous deletion of exons 9-11. The missense variant affects a highly conserved residue and is predicted to be deleterious by most in silico tools. The FBN2 deletion affects a well-conserved region and leads to loss of the transforming growth factor β binding-like 2 domain and part of the calcium-binding epidermal growth factor-like domain.

CONCLUSION: Our findings suggest that short stature and mild skeletal dysplasia might be part of the spectrum of FBN2-related phenotypes. The study supports the role of FBN2 variants in growth failure and expands the molecular spectrum of FBN2 variants.