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.