Clinical impact and genomic profile in patients with nonsyndromic FBN1-related thoracic aortic aneurysm and dissection
H Yagi, H Setoguchi-Aono, N Takeda, N Akiyama, M Ando, H Yamauchi, H Akazawa, N TakedaAbstract
Background
Marfan syndrome (MFS) is characterized by annulo-aortic ectasia (AAE) and multisystem disorders of the skeleton, eyes, and lungs (syndromic). In the recent era, with the widespread use of gene panel testing for hereditary thoracic aortic aneurysm and dissection (TAAD), FBN1 pathogenic or likely pathogenic (P/LP) variants have also been identified in some patients with nonsyndromic TAAD (FBN1-related TAAD)1)2). However, the clinical profile and natural history in patients with FBN1-related TAAD were still unknown.
Methods
We retrospectively analyzed 319 cases that underwent panel analysis of candidate genes for hereditary TAAD at our center between January 2018 and September 2025. Cases diagnosed with MFS were those that met the revised Ghent criteria. FBN1-related TAAD was defined as cases without the typical physical features of MFS (systemic score of 4 or less, no ectopia lentis, and no family history of MFS) in which FBN1 P/LP variants were identified through genetic testing. Severe aortic events (SAEs) were defined as type A or B aortic dissection (AD), prophylactic surgery for AAE, or aneurysm of the descending to abdominal aorta. The pathogenicity of the FBN1 gene was evaluated according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology classification guidelines.
Results
FBN1 P/LP variants were identified in 126 out of 319 cases. Among these, 104 cases (82.5%) were diagnosed with MFS, and 29 cases (27.9%) involved concomitant SAEs at the time of diagnosis. Meanwhile, 22 cases (17.5%) were classified as FBN1-related TAAD, with numerous patients (77.3%) already exhibiting SAEs at the time of diagnosis. Comparing the clinical profile of the FBN1-related TAAD group (n=22) and the syndromic MFS group (n=104), we found a similar family history of AD or AAE in both groups, but a higher number of dominant-negative variants in the FBN1-related TAAD group and a significantly later age at start of follow-up (33.9 ± 11.3 vs 16.2 ± 14.7 years), which was associated with a lower systemic score (1.9 ± 1.5 vs 6.9 ± 4.3 points) (respectively, p<0.05). In contrast, the majority of FBN1-related TAAD group (81.8%) began outpatient care following AD, and there were no significant differences in the timing of SAEs [FBN1-related TAAD vs. MFS: Adjusted HR 0.73 (0.4-1.4); p=0.370] (Figure).
Conclusion
FBN1-related TAAD represents a severe spectrum of MFS that is challenging to diagnose and manage early. Diagnosis before major vascular complications is rare; therefore, proactive genetic testing in TAAD cases with a family history of dissection is crucial for early diagnosis, and further case accumulation is warranted.For image description, please refer to the figure legend and surrounding text.