Loeys-Dietz syndrome: genes and variants

Genes linked to Loeys-Dietz 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.

  49 disease-causing and 208 uncertain variants in TGFBR2 are linked to Loeys-Dietz 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.

  23 disease-causing and 107 uncertain variants in TGFBR1 are linked to Loeys-Dietz syndrome.

• TGFB2: Transforming growth factor beta-2 proprotein

  Its secreted signaling regulates extracellular matrix, cell differentiation, proliferation, and cardiovascular development. Haploinsufficiency causes a Loeys-Dietz-spectrum connective-tissue disorder with increased risk of thoracic aortic aneurysm and dissection.

  6 disease-causing and 181 uncertain variants in TGFB2 are linked to Loeys-Dietz syndrome.

• SMAD2: SMAD family member 2

  It carries activated TGF-beta and activin signals from receptors to the nucleus and regulates developmental and extracellular-matrix gene programs. Heterozygous pathogenic variants can cause syndromic thoracic aortic aneurysm and dissection with variable craniofacial and cardiovascular features.

  4 disease-causing and 2 uncertain variants in SMAD2 are linked to Loeys-Dietz syndrome.

• ABCA3: Phospholipid-transporting ATPase ABCA3

  It transports phospholipids into lamellar bodies of alveolar type II cells, supporting pulmonary surfactant assembly and normal gas exchange. Biallelic loss-of-function variants can cause neonatal respiratory failure or childhood interstitial lung disease.

  1 disease-causing and 0 uncertain variants in ABCA3 are linked to Loeys-Dietz syndrome.

• SMAD3: SMAD family member 3

  It carries TGF-beta receptor signals into the nucleus to control extracellular-matrix, differentiation, and growth programs. Heterozygous loss-of-function variants cause Loeys-Dietz syndrome type 3 with arterial aneurysm and dissection risk and often early osteoarthritis.

  0 disease-causing and 1 uncertain variants in SMAD3 are linked to Loeys-Dietz syndrome.

Where Loeys-Dietz syndrome variants cluster

• TGFBR2 Protein kinase (positions 244–544): 49 of 49 disease-causing changes, 1.9× more than its size predicts.
• TGFBR1 Protein kinase (positions 205–495): 21 of 23 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in Loeys-Dietz syndrome

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Uncertain variants in Loeys-Dietz syndrome that look disease-causing

Which prediction tools work for Loeys-Dietz syndrome

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

• PolyPhen-2: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 95 out of 100
• SIFT: 92 out of 100
• phyloP: 91 out of 100
• MetaLR: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Familial thoracic aortic aneurysm and aortic dissection is also caused by TGFBR2 variants; they fall in the same places as the Loeys-Dietz syndrome variants (78 disease-causing).
• Ehlers-Danlos syndrome is also caused by TGFBR2 variants; they fall in the same places as the Loeys-Dietz syndrome variants (4 disease-causing).
• Marfan syndrome is also caused by TGFBR2 variants; they fall mostly in different places as the Loeys-Dietz syndrome variants (3 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by TGFBR1 variants; they fall partly in the same places as the Loeys-Dietz syndrome variants (23 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by TGFB2 variants; they fall mostly in different places as the Loeys-Dietz syndrome variants (5 disease-causing).
• Interstitial lung disease due to ABCA3 deficiency is also caused by ABCA3 variants; they fall mostly in different places as the Loeys-Dietz syndrome variants (30 disease-causing).
• Hereditary pulmonary alveolar proteinosis is also caused by ABCA3 variants; they fall mostly in different places as the Loeys-Dietz syndrome variants (12 disease-causing).

Diseases related to Loeys-Dietz syndrome

• Familial thoracic aortic aneurysm and aortic dissection, also linked to SMAD3, TGFB2, TGFBR1 and TGFBR2
• Ehlers-Danlos syndrome, also linked to SMAD3, TGFB2, TGFBR1 and TGFBR2
• Marfan syndrome, also linked to TGFBR1 and TGFBR2
• Atrial septal defect, also linked to TGFB2
• Interstitial lung disease due to ABCA3 deficiency, also linked to ABCA3
• Connective tissue disorder, also linked to SMAD3
• Hereditary pulmonary alveolar proteinosis, also linked to ABCA3
• Aneurysm-osteoarthritis syndrome, also linked to SMAD3
• Colorectal cancer, hereditary nonpolyposis, type 6, also linked to TGFBR2
• Familial aortopathy, also linked to TGFBR1
• Surfactant metabolism dysfunction, pulmonary, 1, also linked to ABCA3
• Myelodysplastic syndrome, also linked to TGFB2

Frequently asked questions

Which genes are linked to Loeys-Dietz syndrome?

In CATVariant, Loeys-Dietz syndrome is linked to 6 analyzed proteins: TGFBR2 (TGF-beta receptor type-2), TGFBR1 (TGF-beta receptor type-1), TGFB2 (Transforming growth factor beta-2 proprotein), SMAD2 (SMAD family member 2), ABCA3 (Phospholipid-transporting ATPase ABCA3) and SMAD3 (SMAD family member 3).

How many genetic variants are linked to Loeys-Dietz syndrome?

654 variants: 83 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 499 are of uncertain significance or have conflicting reports.

Which uncertain variants in Loeys-Dietz syndrome look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example TGFBR2 R254C and TGFBR2 A531T. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Loeys-Dietz syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 15 disease-causing and 42 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.

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