Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome

Background: Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD. Methods: Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation. Results: The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for pathogenicity was found by the predicted damaging effect of this mutation and the co-segregation in the family. Functional analysis with myogenic transdifferentiation of dermal fibroblasts to smooth muscle-like cells, revealed increased myogenic differentiation in patient cells with the TGFBR1 mutation, shown by a higher expression of myogenic markers ACTA2, MYH11 and CNN1 compared to cells from healthy controls. Conclusion: Our findings confirm the pathogenic effect of the TGFBR1 mutation in causing TAAD in Loeys–Dietz syndrome and show increased myogenic differentiation of patient fibroblasts.