FBN1 – Familial Thoracic Aortic Aneurysm and Aortic Dissection

FBN1 encodes the extracellular matrix protein fibrillin-1, a key component of connective tissue microfibrils. Heterozygous mutations in FBN1 are a well-established cause of Marfan syndrome and related thoracic aortic disease, including familial thoracic aortic aneurysm and aortic dissection (FTAAD). Recent large-scale genome sequencing has focused on under-recognized noncanonical splice site variants in FBN1 that lie beyond the ±8 intronic boundary and are not captured by standard exon-centric diagnostic assays.

A cohort analysis of 78,195 individuals from the 100,000 Genomes Project identified 21 ultrarare FBN1 variants with SpliceAI scores >0.5. These were significantly enriched in FTAAD cases (9/703) versus non-FTAAD participants (12/77,492; odds ratio = 84, P = 9.7×10⁻¹⁴) (PMID:40476350). Subsequent targeted analysis uncovered an additional 14 families harboring 11 distinct noncanonical FBN1 splice variants, bringing the total to 20 candidate splice variants in 23 families.

Experimental validation—including RNA sequencing, reverse transcriptase–PCR, and minigene assays—confirmed aberrant splicing for 16 of the 20 variants, with pseudoexon inclusion demonstrated in nine cases. Replication in UK Biobank further supported the association. These noncanonical splice variants account for approximately 3% of FTAAD families previously undiagnosed by conventional FBN1 testing.

Inheritance of FTAAD due to FBN1 splice variants is autosomal dominant, consistent with fibrillin-1 haploinsufficiency or dominant-negative effects. The variant spectrum broadly encompasses deep-intronic mutations that disrupt normal splicing and microfibril assembly, expanding the known allelic heterogeneity of fibrillinopathies.

Integration of intronic sequence analysis and confirmatory RNA studies into genetic testing pipelines enhances diagnostic yield for FBN1-related aortopathy. Early identification of affected individuals facilitates surveillance and prophylactic intervention for life-threatening aortic complications.

Key Take-home: Noncanonical FBN1 splice variants are a clinically actionable cause of familial thoracic aortic aneurysm and dissection and should be included in comprehensive diagnostic workflows.

References

• Genetics in medicine • 2025 • Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome. PMID:40476350
• FBN1
• Familial Thoracic Aortic Aneurysm and Aortic Dissection

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