Distinct genotype-phenotype associations exist among LDS subtypes, with TGFBR1 and TGFBR2 variants associated with greater burden of aggressive vascular disease, SMAD3 variants linked to mitral valve disease, peripheral neuropathy, and osteoarthritis, and a novel association identified between TGFBR1 genotype and migraine.
Renal artery aneurysms were significantly more common in TGFBR1 patients compared to other LDS subtypes.
SMAD3 patients had significantly higher rates of mitral regurgitation compared to other LDS subtypes.
SMAD3 patients had significantly higher rates of peripheral neuropathy compared to other LDS subtypes.
A novel association was identified between TGFBR1 variants and migraine headache.
TGFBR1 and TGFBR2 patients demonstrated trends toward higher rates of ascending aortic aneurysm and aortic dissection compared to SMAD3 patients, though differences were not statistically significant.
Demographics and mortality did not differ significantly between LDS genotype groups.
Patients with pathogenic, likely pathogenic, or suspicious variants in TGFBR1, TGFBR2, or SMAD3 were included in this retrospective cohort study of genetically confirmed LDS.
Loeys-Dietz syndrome (LDS) is a rare inherited disorder affecting connective tissue, caused by mutations in genes involved in a signaling pathway called TGF-β. People with LDS can develop serious problems including aortic aneurysms (dangerous bulging of the main artery from the heart), heart valve disease, and issues affecting other organs. This research suggests that the specific gene mutated in a person with LDS meaningfully influences which health problems they are most likely to develop. In a study of 93 adults across Mayo Clinic sites, patients with mutations in TGFBR1 or TGFBR2 tended to have more aggressive blood vessel disease, while patients with SMAD3 mutations were more likely to experience mitral valve leakage (mitral regurgitation, found in over half of SMAD3 patients), nerve problems in their limbs (peripheral neuropathy), and joint disease (osteoarthritis). The study also identified several statistically significant findings unique to specific gene mutations. Kidney artery aneurysms were notably more common in TGFBR1 patients. Perhaps most strikingly, migraine headaches were found in over 62% of TGFBR1 patients — a connection that has not been previously reported in LDS and that the authors describe as a novel association. Despite these differences in specific complications, rates of major heart and aortic surgeries were similarly high across all three genetic groups, underscoring that all LDS subtypes carry serious cardiovascular risk. This research suggests that knowing which specific gene is mutated in a person with LDS could help doctors tailor their monitoring and management strategies more precisely — for example, watching more carefully for kidney artery aneurysms in TGFBR1 patients or screening more thoroughly for heart valve problems and neurological issues in SMAD3 patients. The findings reinforce the importance of comprehensive genetic testing for people diagnosed with LDS, as the specific mutation type appears to provide meaningful information about what complications to watch for over time.
Nabi H, Dreher L, Hartnett J, Crossley A, El Ghandour H, Osundiji M, et al.. (2026). The Role of Genetic Variation in Phenotypic Variability in Loeys-Dietz Syndrome.. Human mutation. https://doi.org/10.1155/humu/2861205