Very recently, heterozygous mutations in the genes encoding
transforming growth factor beta receptors I (
TGFBR1) and II (
TGFBR2) have been reported in
Loeys-Dietz aortic aneurysm syndrome (LDS). In addition, dominant
TGFBR2 mutations have been identified in
Marfan syndrome type 2 (MFS2) and familial
thoracic aortic aneurysms and dissections (
TAAD). In the past, mutations of these genes were associated with
atherosclerosis and several human
cancers. Here, we report a total of nine novel and one known heterozygous sequence variants in the
TGFBR1 and
TGFBR2 genes in nine of 70 unrelated individuals with MFS-like phenotypes who previously tested negative for mutations in the gene encoding the
extracellular matrix protein fibrillin-1 (FBN1). To assess the pathogenic impact of these sequence variants, in silico analyses were performed by the PolyPhen, SIFT, and Fold-X algorithms and by means of a 3D homology model of the
TGFBR2 kinase domain. Our results showed that in all but one of the patients the pathogenic effect of at least one sequence variant is highly probable (c.722C > T, c.799A > C, and c.1460G > A in
TGFBR1 and c.773T > G, c.1106G > T, c.1159G > A, c.1181G > A, and c.1561T > C in
TGFBR2). These deleterious alleles occurred de novo or segregated with the disease in the families, indicating a causative association between the sequence variants and clinical phenotypes. Since
TGFBR2 mutations found in patients with MFS-related disorders cannot be distinguished from heterozygous
TGFBR2 mutations reported in
tumor samples, we emphasize the importance of segregation analysis in affected families. In order to be able to find the mutation that is indeed responsible for a MFS-related phenotype, we also propose that genetic testing for sequence alterations in
TGFBR1 and
TGFBR2 should be complemented by mutation screening of the FBN1 gene.