Cardiofaciocutaneous syndrome: genes and variants

Genes linked to Cardiofaciocutaneous 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.

  17 disease-causing and 27 uncertain variants in BRAF are linked to Cardiofaciocutaneous 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.

  14 disease-causing and 21 uncertain variants in MAP2K1 are linked to Cardiofaciocutaneous 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.

  9 disease-causing and 55 uncertain variants in MAP2K2 are linked to Cardiofaciocutaneous 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.

  9 disease-causing and 2 uncertain variants in KRAS are linked to Cardiofaciocutaneous syndrome.

• NRAS: GTPase NRas

  Its active GTP-bound state drives RAF-MEK-ERK and PI3K signaling downstream of growth-factor receptors. Somatic activating variants are common drivers of melanoma, leukemia, and other cancers, while germline activating variants can cause Noonan syndrome.

  0 disease-causing and 0 uncertain variants in NRAS are linked to Cardiofaciocutaneous syndrome.

Where Cardiofaciocutaneous syndrome variants cluster

• BRAF Protein kinase (positions 457–717): 16 of 17 disease-causing changes, 2.8× more than its size predicts.

Known disease-causing variants in Cardiofaciocutaneous syndrome

Which prediction tools work for Cardiofaciocutaneous syndrome

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

• PolyPhen-2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 79 out of 100
• MetaLR: 77 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 76 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• DMS / MaveDB: 71 out of 100

Same protein, different disease

• RASopathy is also caused by BRAF variants; they fall partly in the same places as the Cardiofaciocutaneous syndrome variants (36 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by BRAF variants; they fall mostly in different places as the Cardiofaciocutaneous syndrome variants (26 disease-causing).
• Noonan syndrome is also caused by BRAF variants; they fall partly in the same places as the Cardiofaciocutaneous syndrome variants (11 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by BRAF variants; they fall partly in the same places as the Cardiofaciocutaneous syndrome variants (10 disease-causing).
• Non-small cell lung carcinoma is also caused by BRAF variants; they fall partly in the same places as the Cardiofaciocutaneous syndrome variants (9 disease-causing).
• RASopathy is also caused by MAP2K1 variants; they fall partly in the same places as the Cardiofaciocutaneous syndrome variants (14 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by MAP2K1 variants; they fall mostly in different places as the Cardiofaciocutaneous syndrome variants (6 disease-causing).
• RASopathy is also caused by MAP2K2 variants; they fall in the same places as the Cardiofaciocutaneous syndrome variants (9 disease-causing).
• RASopathy is also caused by KRAS variants; they fall partly in the same places as the Cardiofaciocutaneous syndrome variants (23 disease-causing).
• Noonan syndrome is also caused by KRAS variants; they fall partly in the same places as the Cardiofaciocutaneous syndrome variants (16 disease-causing).
• Non-small cell lung carcinoma is also caused by KRAS variants; they fall partly in the same places as the Cardiofaciocutaneous syndrome variants (5 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by KRAS variants; they fall in the same places as the Cardiofaciocutaneous syndrome variants (4 disease-causing).

Diseases related to Cardiofaciocutaneous syndrome

• RASopathy, also linked to BRAF, KRAS, MAP2K1, MAP2K2 and 1 more
• Noonan syndrome, also linked to BRAF, KRAS, MAP2K1, MAP2K2 and 1 more
• Noonan syndrome and Noonan-related syndrome, also linked to BRAF, KRAS, MAP2K1, MAP2K2 and 1 more
• Hypertrophic cardiomyopathy, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Cardio-facio-cutaneous syndrome, also linked to BRAF, KRAS, MAP2K1 and MAP2K2
• Costello syndrome, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Vascular malformation, also linked to BRAF, KRAS, MAP2K1 and NRAS
• Melanoma, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Colorectal cancer, also linked to BRAF, KRAS and NRAS
• Non-small cell lung carcinoma, also linked to BRAF, KRAS and MAP2K1
• Neurofibromatosis, also linked to MAP2K1 and MAP2K2
• Acute myeloid leukemia, also linked to KRAS and NRAS

Frequently asked questions

Which genes are linked to Cardiofaciocutaneous syndrome?

In CATVariant, Cardiofaciocutaneous syndrome is linked to 5 analyzed proteins: BRAF (Serine/threonine-protein kinase B-raf), MAP2K1 (Dual specificity mitogen-activated protein kinase kinase 1), MAP2K2 (Dual specificity mitogen-activated protein kinase kinase 2), KRAS (GTPase KRas) and NRAS (GTPase NRas).

How many genetic variants are linked to Cardiofaciocutaneous syndrome?

200 variants: 49 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 105 are of uncertain significance or have conflicting reports.

Which uncertain variants in Cardiofaciocutaneous 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 Cardiofaciocutaneous syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.79, based on 29 disease-causing and 30 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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