Marfan syndrome: genes and variants

Genes linked to Marfan syndrome

• FBN1: Fibrillin-1

  Its fibrillin-1 microfibrils provide mechanical support to elastic tissues and regulate local availability of growth factors such as TGF-beta. Pathogenic variants cause Marfan syndrome and related fibrillinopathies affecting the aorta, skeleton, eyes, skin, and lungs.

  434 disease-causing and 1,113 uncertain variants in FBN1 are linked to Marfan syndrome.

• TGFBR2: TGF-beta receptor type-2

  It binds TGF-beta ligands and activates TGFBR1 to initiate canonical and noncanonical signaling. Germline pathogenic variants cause Loeys-Dietz syndrome type 2, while somatic loss can remove growth-suppressive TGF-beta responses in cancer.

  3 disease-causing and 0 uncertain variants in TGFBR2 are linked to Marfan syndrome.

• TGFBR1: TGF-beta receptor type-1

  After activation by the ligand-bound receptor complex, it phosphorylates SMAD2 and SMAD3 to propagate TGF-beta signals. Germline pathogenic variants cause Loeys-Dietz syndrome type 1 with arterial aneurysm and dissection and variable craniofacial or skeletal features.

  2 disease-causing and 1 uncertain variants in TGFBR1 are linked to Marfan syndrome.

Weakly linked (only a few uncertain records): COL5A1, COL5A2, FBN2 and NOTCH1.

Where Marfan syndrome variants cluster

• FBN1 EGF-like 32 (positions 1891–1929): 13 of 434 disease-causing changes, 2.2× more than its size predicts.
• FBN1 EGF-like 26 (positions 1487–1527): 13 of 434 disease-causing changes, 2.1× more than its size predicts.
• FBN1 EGF-like 8 (positions 530–571): 13 of 434 disease-causing changes, 2.0× more than its size predicts.
• FBN1 EGF-like 10 (positions 613–653): 12 of 434 disease-causing changes, 1.9× more than its size predicts.
• FBN1 Hybrid domain 2 (positions 862–887): 8 of 434 disease-causing changes, 2.0× more than its size predicts.

Known disease-causing variants in Marfan syndrome

Showing 60 of 439.

Uncertain variants in Marfan syndrome that look disease-causing

Which prediction tools work for Marfan syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 99 out of 100
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 90 out of 100
• SIFT: 88 out of 100
• PolyPhen-2: 80 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 74 out of 100

Same protein, different disease

• Isolated thoracic aortic aneurysm is also caused by FBN1 variants; they fall in the same places as the Marfan syndrome variants (12 disease-causing).
• Marfan syndrome/loeys-dietz syndrome/familial thoracic aortic aneurysms and dissections is also caused by FBN1 variants; they fall mostly in different places as the Marfan syndrome variants (10 disease-causing).
• Acromicric dysplasia is also caused by FBN1 variants; they fall partly in the same places as the Marfan syndrome variants (6 disease-causing).
• Ectopia lentis 1, isolated, autosomal dominant is also caused by FBN1 variants; they fall partly in the same places as the Marfan syndrome variants (6 disease-causing).
• Geleophysic dysplasia is also caused by FBN1 variants; they fall in the same places as the Marfan syndrome variants (6 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by TGFBR2 variants; they fall mostly in different places as the Marfan syndrome variants (78 disease-causing).
• Loeys-Dietz syndrome is also caused by TGFBR2 variants; they fall mostly in different places as the Marfan syndrome variants (49 disease-causing).
• Ehlers-Danlos syndrome is also caused by TGFBR2 variants; they fall mostly in different places as the Marfan syndrome variants (4 disease-causing).
• Loeys-Dietz syndrome is also caused by TGFBR1 variants; they fall mostly in different places as the Marfan syndrome variants (23 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by TGFBR1 variants; they fall mostly in different places as the Marfan syndrome variants (23 disease-causing).

Diseases related to Marfan syndrome

• Familial thoracic aortic aneurysm and aortic dissection, also linked to FBN1, TGFBR1 and TGFBR2
• Ehlers-Danlos syndrome, also linked to TGFBR1 and TGFBR2
• Loeys-Dietz syndrome, also linked to TGFBR1 and TGFBR2
• Familial aortopathy, also linked to FBN1 and TGFBR1
• Perrault syndrome, also linked to FBN1
• Connective tissue disorder, also linked to FBN1
• Colorectal cancer, hereditary nonpolyposis, type 6, also linked to TGFBR2
• Isolated thoracic aortic aneurysm, also linked to FBN1
• Marfan syndrome/loeys-dietz syndrome/familial thoracic aortic aneurysms and dissections, also linked to FBN1
• Ectopia lentis 1, isolated, autosomal dominant, also linked to FBN1
• Acromicric dysplasia, also linked to FBN1
• Geleophysic dysplasia, also linked to FBN1

Frequently asked questions

Which genes are linked to Marfan syndrome?

In CATVariant, Marfan syndrome is linked to 3 analyzed proteins: FBN1 (Fibrillin-1), TGFBR2 (TGF-beta receptor type-2) and TGFBR1 (TGF-beta receptor type-1).

How many genetic variants are linked to Marfan syndrome?

1,782 variants: 439 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,117 are of uncertain significance or have conflicting reports.

Which uncertain variants in Marfan syndrome look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example FBN1 L879R, FBN1 D1363V and FBN1 R2220L. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Marfan syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 324 disease-causing and 24 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

Download every variant as CSV · Browse all diseases · Methods · About the Center