Description
RASopathies Eligibility (29373.1)

Relevant diseases:
- Noonan syndrome
- Noonan syndrome plus other features - Cardio-facio-cutaneous syndrome
- LEOPARD syndrome
- Costello syndrome
- Legius syndrome

RASopathies Inclusion
- At least 2 of the suggestive clinical features: - Early feeding difficulty/ failure to thrive
- Relative macrocephaly
- Short stature
- Developmental disability
- At least 1 of:
- Cardiomyopathy
- Congenital heart disease
- Arrhythmia
- Suggestive malignancy ( bladder carcinoma, Rhabdomyosarcoma, Leukaemia, phaeochromocytoma)
- Skin abnormalities (hyperkeratosis, cafe-au-lait patches, ulerythema oophorogenes, keratosis pilaris, excess
palmar skin)

RASopathies Exclusion Criteria
- Low birth weight for gestation
Prior Genetic Testing:
- Results should have been reviewed for all genetic tests undertaken. This includes review of available exome sequencing data, but where this is the case can be limited to genes specified within disease-relevant in silico panels. The patient is not eligible if a pathogenic variant has been identified in any gene related to their phenotype.
- Standard local genetic testing and nationally commissioned testing for this phenotype should have been completed AND
- Testing should be undertaken for any individual gene for which diagnostic yield is >10% for this phenotype AND
- The following specific gene tests are advised as a means of limiting the re-discovery of recognised pathogenic variants that could be more efficiently identified through the existing catalogue of UKGTN tests:

RASopathy Prior Testing Prior Testing Prior Testing Prior Testing Prior Testing Prior Testing Genes
- PTPN11, RAF1, BRAF, SOS1, KRAS, HRAS, NRAS, SHOC2, CBL, SPRED1, MAP2K1, MAP2K2

These requirements will be kept under continual review during the main programme and may be subject to change.
Panel Activity

12 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Andrea Haworth (ACGS, Congenica)

    Group: Other biotech or pharmaceutical
    Workplace: Other clinical service

  • Helen Savage (Congenica Ltd)

    Group: Other biotech or pharmaceutical
    Workplace: Other clinical service

  • Ellen Thomas (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Rebecca Foulger (Genomics England curator)

    Group: Other
    Workplace: Other

  • Alice Gardham (Genomics England)

    Group: Other
    Workplace: Other

  • Zornitza Stark (Australian Genomics)

    Group: Other
    Workplace: Other clinical service

  • Ivone Leong (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Mehdi Montazer (Mashhad University of Medical Sciences)

    Group: Other
    Workplace: Other

  • Arina Puzriakova (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Irina Ziravecka (BKUS)

    Group: Other
    Workplace: Other

26 Entities

26 reviewed, 22 green

List Entity Reviews Mode of inheritance Details
26 Entitiess
Green Green List (high evidence)
BRAF
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • LEOPARD syndrome 3 613707
  • Cardiofaciocutaneous syndrome 115150
  • Noonan syndrome 7 613706
Tags
Green Green List (high evidence)
CBL
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia 613563
Tags
Green Green List (high evidence)
HRAS
3 reviews
2 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Costello syndrome, 218040
Tags
Green Green List (high evidence)
17q11.2 recurrent region (includes NF1) Loss
ISCA-37431-Loss
Region
1 review
 MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • dysmorphic features, cardiac anomalies and mental retardation
  • 613675
  • variable facial dysmorphism, cafe-au-lait spots, neurofibromas and Lisch nodules in the iris, mental retardation, developmental delay, an excessive number of early-onset neurofibromas and an increased risk for malignant peripheral nerve sheath tumors
  • NEUROFIBROMATOSIS 1 MICRODELETION SYNDROME
  • NF1 MICRODELETION SYNDROME
  • Chromosome 17q11.2 deletion syndrome, 1.4Mb
Tags
Green Green List (high evidence)
KRAS
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Noonan syndrome 3 609942
  • Cardiofaciocutaneous syndrome 2 615278
Tags
Green Green List (high evidence)
LZTR1
3 reviews
2 green 		BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • Noonan syndrome 10 616564
  • Schwannomatosis-2, susceptibility to 615670
  • Noonan syndrome 2, 605275
Tags
Green Green List (high evidence)
MAP2K1
3 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Cardiofaciocutaneous syndrome 3, 615279
  • LEOPARD syndrome
  • ?Noonan syndrome
Tags
Green Green List (high evidence)
MAP2K2
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • UKGTN
Phenotypes
  • Cardiofaciocutaneous syndrome 4 615280
Tags
Green Green List (high evidence)
MRAS
2 reviews
2 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
  • Expert Review Green
Phenotypes
  • Noonan syndrome 11, OMIM:618499
  • Noonan syndrome 11, MONDO:0032786
Tags
Green Green List (high evidence)
NF1
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Neurofibromatosis-Noonan syndrome 601321
  • Neurofibromatosis, type 1 162200
Tags
Green Green List (high evidence)
NRAS
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Noonan syndrome 6 613224
  • Cardio-Facio-cutanenous syndrome
Tags
Green Green List (high evidence)
PPP1CB
1 review
 MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Other
Phenotypes
  • Noonan syndrome-like disorder with loose anagen hair 2, 617506
  • Rasopathy with developmental delay, short stature and sparse slow-growing hair
Tags
Green Green List (high evidence)
PTPN11
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • LEOPARD syndrome 1 151100
  • Noonan syndrome 1 163950
Tags
Green Green List (high evidence)
RAF1
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • LEOPARD syndrome 2 611554
  • Noonan syndrome 5 611553
Tags
Green Green List (high evidence)
RIT1
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Noonan syndrome 8 615355
Tags
Green Green List (high evidence)
RRAS
3 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
  • Expert Review Green
Phenotypes
  • RRAS-related atypical Noonan syndrome
Tags
Green Green List (high evidence)
RRAS2
2 reviews
2 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
  • Expert Review Green
Phenotypes
  • Noonan syndrome 12, 618624
Tags
Green Green List (high evidence)
SHOC2
3 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Noonan syndrome-like with loose anagen hair 1, 607721
Tags
Green Green List (high evidence)
SOS1
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Noonan syndrome 4 610733
Tags
Green Green List (high evidence)
SOS2
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • Noonan syndrome 9 616559
Tags
  • curated-variant-list
Green Green List (high evidence)
SPRED1
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Legius syndrome 611431
Tags
Green Green List (high evidence)
SPRED2
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • developmental delay
  • intellectual disability
  • cardiac defects
  • short stature
  • skeletal anomalies
  • a typical facial gestalt
Tags
Amber Amber List (moderate evidence)
RASA2
3 reviews
 MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Other
Phenotypes
  • Noonan syndrome?
Tags
Red Red List (low evidence)
A2ML1
3 reviews
2 red 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Other
Phenotypes
  • Noonan syndrome
Tags
Red Red List (low evidence)
RREB1
2 reviews
1 red 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Noonan syndrome-like disorder
Tags
No list No list
MAP4K4
1 review
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Literature
Phenotypes
  • neurodevelopmental differences
  • multiple congenital anomalies
Tags

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