LEOPARD syndrome 1: genes and variants

Genes linked to LEOPARD syndrome 1

• PTPN11: Tyrosine-protein phosphatase non-receptor type 11

  Its SHP2 phosphatase activity promotes RAS-MAPK signaling downstream of many receptor tyrosine kinases and cytokine receptors. Germline dysregulating variants cause Noonan-spectrum disorders, while somatic activating variants drive juvenile myelomonocytic leukemia and other cancers.

  16 disease-causing and 29 uncertain variants in PTPN11 are linked to LEOPARD syndrome 1.

• RAF1: RAF proto-oncogene serine/threonine-protein kinase

  It relays activated RAS signals to MEK and ERK and also participates in survival and developmental pathways. Germline activating variants cause Noonan syndrome and related RASopathies, while oncogenic activation contributes to selected cancers.

  4 disease-causing and 14 uncertain variants in RAF1 are linked to LEOPARD syndrome 1.

• 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.

  2 disease-causing and 23 uncertain variants in BRAF are linked to LEOPARD syndrome 1.

Where LEOPARD syndrome 1 variants cluster

• PTPN11 SH2 1 (positions 6–102): 6 of 16 disease-causing changes, 2.3× more than its size predicts.

Known disease-causing variants in LEOPARD syndrome 1

Which prediction tools work for LEOPARD syndrome 1

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

• AlphaMissense: 98 out of 100
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 91 out of 100
• EVE: 90 out of 100
• MutPred2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 88 out of 100
• MetaLR: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100

Same protein, different disease

• RASopathy is also caused by PTPN11 variants; they fall partly in the same places as the LEOPARD syndrome 1 variants (51 disease-causing).
• Noonan syndrome is also caused by PTPN11 variants; they fall partly in the same places as the LEOPARD syndrome 1 variants (44 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by PTPN11 variants; they fall partly in the same places as the LEOPARD syndrome 1 variants (29 disease-causing).
• Metachondromatosis is also caused by PTPN11 variants; they fall partly in the same places as the LEOPARD syndrome 1 variants (11 disease-causing).
• Monogenic short statue is also caused by PTPN11 variants; they fall partly in the same places as the LEOPARD syndrome 1 variants (6 disease-causing).
• RASopathy is also caused by RAF1 variants; they fall partly in the same places as the LEOPARD syndrome 1 variants (28 disease-causing).
• Noonan syndrome is also caused by RAF1 variants; they fall in the same places as the LEOPARD syndrome 1 variants (14 disease-causing).
• Dilated cardiomyopathy 1NN is also caused by RAF1 variants; they fall mostly in different places as the LEOPARD syndrome 1 variants (5 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by RAF1 variants; they fall partly in the same places as the LEOPARD syndrome 1 variants (4 disease-causing).
• RASopathy is also caused by BRAF variants; they fall mostly in different places as the LEOPARD syndrome 1 variants (36 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by BRAF variants; they fall mostly in different places as the LEOPARD syndrome 1 variants (26 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by BRAF variants; they fall mostly in different places as the LEOPARD syndrome 1 variants (17 disease-causing).
• Noonan syndrome is also caused by BRAF variants; they fall mostly in different places as the LEOPARD syndrome 1 variants (11 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by BRAF variants; they fall mostly in different places as the LEOPARD syndrome 1 variants (10 disease-causing).

Diseases related to LEOPARD syndrome 1

• RASopathy, also linked to BRAF, PTPN11 and RAF1
• Noonan syndrome, also linked to BRAF, PTPN11 and RAF1
• Noonan syndrome and Noonan-related syndrome, also linked to BRAF, PTPN11 and RAF1
• Noonan syndrome with multiple lentigines, also linked to BRAF and PTPN11
• Hypertrophic cardiomyopathy, also linked to BRAF
• Cardiofaciocutaneous syndrome, also linked to BRAF
• Cardio-facio-cutaneous syndrome, also linked to BRAF
• Acute myeloid leukemia, also linked to PTPN11
• Colorectal cancer, also linked to BRAF
• Non-small cell lung carcinoma, also linked to BRAF
• Costello syndrome, also linked to BRAF
• Melanoma, cutaneous malignant, susceptibility to, 8, also linked to BRAF

Frequently asked questions

Which genes are linked to LEOPARD syndrome 1?

In CATVariant, LEOPARD syndrome 1 is linked to 3 analyzed proteins: PTPN11 (Tyrosine-protein phosphatase non-receptor type 11), RAF1 (RAF proto-oncogene serine/threonine-protein kinase) and BRAF (Serine/threonine-protein kinase B-raf).

How many genetic variants are linked to LEOPARD syndrome 1?

104 variants: 22 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 66 are of uncertain significance or have conflicting reports.

Which uncertain variants in LEOPARD syndrome 1 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 LEOPARD syndrome 1?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 17 disease-causing and 27 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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