Costello syndrome: genes and variants

Genes linked to Costello syndrome

• HRAS: GTPase HRas

  Its GTP-bound state activates RAF-MEK-ERK and other pathways downstream of growth-factor receptors. Somatic activating variants drive several cancers, while germline activating variants cause Costello syndrome.

  15 disease-causing and 209 uncertain variants in HRAS are linked to Costello 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.

  0 disease-causing and 1 uncertain variants in BRAF are linked to Costello syndrome.

• ARAF: Serine/threonine-protein kinase A-Raf

  It transmits RAS signals to the MEK-ERK pathway and participates in growth and developmental signaling. Activating germline or somatic variants can cause RASopathy phenotypes and have been identified as oncogenic drivers in selected tumors.

  0 disease-causing and 0 uncertain variants in ARAF are linked to Costello syndrome.

• FGA: Fibrinogen alpha chain

  It contributes the alpha chains of fibrinogen, which thrombin converts into fibrin to form the structural mesh of blood clots. Pathogenic variants can cause afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, thrombosis, or certain hereditary amyloidoses.

  0 disease-causing and 0 uncertain variants in FGA are linked to Costello syndrome.

• FGB: Fibrinogen beta chain

  It contributes the beta chains required for assembly and secretion of functional fibrinogen and subsequent fibrin-clot formation. Pathogenic variants can reduce fibrinogen quantity or alter clot properties, producing bleeding, thrombosis, or both.

  0 disease-causing and 0 uncertain variants in FGB are linked to Costello syndrome.

• FGG: Fibrinogen gamma chain

  It contributes the gamma chains of fibrinogen and provides binding sites important for fibrin polymerization, platelet interactions, and clot stabilization. Pathogenic variants can cause quantitative or qualitative fibrinogen disorders and, in some alleles, hereditary renal amyloidosis.

  0 disease-causing and 0 uncertain variants in FGG are linked to Costello syndrome.

• ITGA2B: Integrin alpha-IIb

  Together with ITGB3, it forms the major platelet fibrinogen receptor that becomes activated during platelet stimulation and drives aggregation. Biallelic loss-of-function variants cause Glanzmann thrombasthenia, a severe inherited platelet-aggregation disorder.

  0 disease-causing and 0 uncertain variants in ITGA2B are linked to Costello syndrome.

• ITGB3: Integrin beta-3

  In platelets it pairs with ITGA2B to bind fibrinogen and mediate aggregation, while in other cells it forms integrins involved in matrix adhesion and signaling. Biallelic loss-of-function variants cause Glanzmann thrombasthenia.

  0 disease-causing and 0 uncertain variants in ITGB3 are linked to Costello 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.

  0 disease-causing and 0 uncertain variants in MAP2K1 are linked to Costello 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.

  0 disease-causing and 0 uncertain variants in MAP2K2 are linked to Costello syndrome.

• MAPK1: Mitogen-activated protein kinase 1

  It converts upstream RAS-RAF-MEK signaling into phosphorylation of cytoplasmic and nuclear targets controlling proliferation, differentiation, and development. Germline dysregulating variants can cause neurodevelopmental RASopathy phenotypes, while pathway hyperactivation is common in cancer.

  0 disease-causing and 0 uncertain variants in MAPK1 are linked to Costello syndrome.

• MAPK3: Mitogen-activated protein kinase 3

  It works with ERK2 to transmit growth-factor and mitogen signals to transcriptional and cytoplasmic targets. Abnormal ERK activation is a hallmark of many RAS-MAPK-driven cancers and developmental syndromes.

  0 disease-causing and 0 uncertain variants in MAPK3 are linked to Costello 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 Costello syndrome.

• SRC: Proto-oncogene tyrosine-protein kinase Src

  It integrates signals from growth-factor receptors, integrins, and other surface proteins to regulate proliferation, adhesion, migration, and survival. Persistent SRC-family signaling promotes invasion and therapy resistance in many cancers and remains an important therapeutic target.

  0 disease-causing and 0 uncertain variants in SRC are linked to Costello syndrome.

• VCL: Vinculin

  It links integrins and cadherins to the actin cytoskeleton at focal adhesions and adherens junctions, transmitting mechanical force between cells and matrix. Pathogenic variants can cause dilated or hypertrophic cardiomyopathy and, in some cases, skeletal myopathy.

  0 disease-causing and 0 uncertain variants in VCL are linked to Costello syndrome.

Known disease-causing variants in Costello syndrome

Uncertain variants in Costello syndrome that look disease-causing

Which prediction tools work for Costello syndrome

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

• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 90 out of 100
• AlphaMissense: 86 out of 100
• MutPred2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 63 out of 100

Same protein, different disease

• RASopathy is also caused by HRAS variants; they fall in the same places as the Costello syndrome variants (6 disease-causing).
• Epidermal nevus is also caused by HRAS variants; they fall in the same places as the Costello syndrome variants (3 disease-causing).
• Thyroid cancer, nonmedullary, 2 is also caused by HRAS variants; they fall in the same places as the Costello syndrome variants (3 disease-causing).

Diseases related to Costello syndrome

• Hypertrophic cardiomyopathy, also linked to ARAF, BRAF, FGA, FGB and 11 more
• Noonan syndrome, also linked to ARAF, BRAF, FGA, FGB and 11 more
• RASopathy, also linked to BRAF, HRAS, MAP2K1, MAP2K2 and 1 more
• Noonan syndrome and Noonan-related syndrome, also linked to BRAF, HRAS, MAP2K1, MAP2K2 and 1 more
• Cardiofaciocutaneous syndrome, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Melanoma, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Cardio-facio-cutaneous syndrome, also linked to BRAF, MAP2K1 and MAP2K2
• Familial dysfibrinogenemia, also linked to FGA, FGB and FGG
• Vascular malformation, also linked to BRAF, MAP2K1 and NRAS
• Afibrinogenemia, also linked to FGA, FGB and FGG
• Glanzmann thrombasthenia, also linked to ITGA2B and ITGB3
• Neurofibromatosis, also linked to MAP2K1 and MAP2K2

Frequently asked questions

Which genes are linked to Costello syndrome?

In CATVariant, Costello syndrome is linked to 15 analyzed proteins: HRAS (GTPase HRas), BRAF (Serine/threonine-protein kinase B-raf), ARAF (Serine/threonine-protein kinase A-Raf), FGA (Fibrinogen alpha chain), FGB (Fibrinogen beta chain), FGG (Fibrinogen gamma chain) and 9 more.

How many genetic variants are linked to Costello syndrome?

241 variants: 15 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 210 are of uncertain significance or have conflicting reports.

Which uncertain variants in Costello syndrome look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example HRAS G60R and HRAS A59S. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Costello syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 13 disease-causing and 86 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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