Cardio-facio-cutaneous syndrome: genes and variants

Genes linked to Cardio-facio-cutaneous syndrome

• BRAF: Serine/threonine-protein kinase B-raf

  It relays activated RAS signals through MEK and ERK to control proliferation, differentiation, and survival. Activating variants, especially V600E, drive melanoma and several other cancers and create sensitivity to pathway-directed therapies.

  26 disease-causing and 1 uncertain variants in BRAF are linked to Cardio-facio-cutaneous syndrome.

• MAP2K1: Dual specificity mitogen-activated protein kinase kinase 1

  It phosphorylates ERK1 and ERK2 downstream of RAF and thereby propagates RAS-MAPK growth and developmental signals. Activating somatic variants occur in several cancers, while germline activating variants can cause cardio-facio-cutaneous syndrome and related RASopathies.

  6 disease-causing and 0 uncertain variants in MAP2K1 are linked to Cardio-facio-cutaneous syndrome.

• KRAS: GTPase KRas

  A small GTPase that acts as a molecular switch in the RAS-MAPK signaling pathway. By cycling between GDP- and GTP-bound states, it relays growth and survival signals, and activating KRAS variants are common drivers of cancer.

  4 disease-causing and 0 uncertain variants in KRAS are linked to Cardio-facio-cutaneous syndrome.

• MAP2K2: Dual specificity mitogen-activated protein kinase kinase 2

  It works with MEK1 to activate ERK signaling downstream of RAS and RAF. Germline activating variants can cause cardio-facio-cutaneous syndrome, while acquired activation can support oncogenic MAPK signaling and drug resistance.

  2 disease-causing and 0 uncertain variants in MAP2K2 are linked to Cardio-facio-cutaneous syndrome.

Weakly linked (only a few uncertain records): PTPN11.

Where Cardio-facio-cutaneous syndrome variants cluster

• BRAF Protein kinase (positions 457–717): 19 of 26 disease-causing changes, 2.1× more than its size predicts.
• BRAF Phorbol-ester/DAG-type (positions 234–280): 7 of 26 disease-causing changes, 4.4× more than its size predicts.

Known disease-causing variants in Cardio-facio-cutaneous syndrome

Which prediction tools work for Cardio-facio-cutaneous syndrome

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

• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 88 out of 100
• AlphaMissense: 85 out of 100
• CATVariant: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 80 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 75 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• DMS / MaveDB: 67 out of 100

Same protein, different disease

• RASopathy is also caused by BRAF variants; they fall in the same places as the Cardio-facio-cutaneous syndrome variants (36 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by BRAF variants; they fall partly in the same places as the Cardio-facio-cutaneous syndrome variants (17 disease-causing).
• Noonan syndrome is also caused by BRAF variants; they fall partly in the same places as the Cardio-facio-cutaneous syndrome variants (11 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by BRAF variants; they fall in the same places as the Cardio-facio-cutaneous syndrome variants (10 disease-causing).
• Non-small cell lung carcinoma is also caused by BRAF variants; they fall in the same places as the Cardio-facio-cutaneous syndrome variants (9 disease-causing).
• RASopathy is also caused by MAP2K1 variants; they fall mostly in different places as the Cardio-facio-cutaneous syndrome variants (14 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by MAP2K1 variants; they fall partly in the same places as the Cardio-facio-cutaneous syndrome variants (14 disease-causing).
• RASopathy is also caused by KRAS variants; they fall partly in the same places as the Cardio-facio-cutaneous syndrome variants (23 disease-causing).
• Noonan syndrome is also caused by KRAS variants; they fall partly in the same places as the Cardio-facio-cutaneous syndrome variants (16 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by KRAS variants; they fall partly in the same places as the Cardio-facio-cutaneous syndrome variants (9 disease-causing).
• Autoimmune lymphoproliferative syndrome is also caused by KRAS variants; they fall mostly in different places as the Cardio-facio-cutaneous syndrome variants (5 disease-causing).
• Non-small cell lung carcinoma is also caused by KRAS variants; they fall mostly in different places as the Cardio-facio-cutaneous syndrome variants (5 disease-causing).
• RASopathy is also caused by MAP2K2 variants; they fall mostly in different places as the Cardio-facio-cutaneous syndrome variants (9 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by MAP2K2 variants; they fall partly in the same places as the Cardio-facio-cutaneous syndrome variants (9 disease-causing).

Diseases related to Cardio-facio-cutaneous syndrome

• RASopathy, also linked to BRAF, KRAS, MAP2K1 and MAP2K2
• Noonan syndrome, also linked to BRAF, KRAS, MAP2K1 and MAP2K2
• Noonan syndrome and Noonan-related syndrome, also linked to BRAF, KRAS, MAP2K1 and MAP2K2
• Cardiofaciocutaneous syndrome, also linked to BRAF, KRAS, MAP2K1 and MAP2K2
• Hypertrophic cardiomyopathy, also linked to BRAF, MAP2K1 and MAP2K2
• Non-small cell lung carcinoma, also linked to BRAF, KRAS and MAP2K1
• Costello syndrome, also linked to BRAF, MAP2K1 and MAP2K2
• Vascular malformation, also linked to BRAF, KRAS and MAP2K1
• Melanoma, also linked to BRAF, MAP2K1 and MAP2K2
• Neurofibromatosis, also linked to MAP2K1 and MAP2K2
• Colorectal cancer, also linked to BRAF and KRAS
• Lung adenocarcinoma, also linked to BRAF and KRAS

Frequently asked questions

Which genes are linked to Cardio-facio-cutaneous syndrome?

In CATVariant, Cardio-facio-cutaneous syndrome is linked to 4 analyzed proteins: BRAF (Serine/threonine-protein kinase B-raf), MAP2K1 (Dual specificity mitogen-activated protein kinase kinase 1), KRAS (GTPase KRas) and MAP2K2 (Dual specificity mitogen-activated protein kinase kinase 2).

How many genetic variants are linked to Cardio-facio-cutaneous syndrome?

41 variants: 38 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2 are of uncertain significance or have conflicting reports.

Which uncertain variants in Cardio-facio-cutaneous syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Cardio-facio-cutaneous syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 20 disease-causing and 40 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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