Noonan Syndrome 6

Mendelian MONDO:0013186 Pathograph 17 Show in embeddings browser Noonan Syndrome RASopathy

Noonan syndrome 6 (NS6, NRAS Noonan syndrome) is the rare NRAS-associated arm of the Noonan syndrome RASopathy spectrum. Heterozygous germline gain-of-function missense variants in NRAS — which encodes the canonical small GTPase N-Ras — increase stimulus-dependent flux through the RAS-MAPK (RAF-MEK-ERK) cascade during development, producing the recognizable Noonan phenotype of characteristic facies, short or webbed neck, ptosis, congenital heart disease (with hypertrophic cardiomyopathy over-represented relative to pulmonic stenosis), variable growth restriction, and variable neurodevelopmental involvement. NS6 is defined molecularly rather than clinically: its clinical picture sits within the broader Noonan/RASopathy spectrum, so the disease entity is delimited by the causal gene. Reported pathogenic residues include Ile24, Thr50, Thr58 and Gly60, and — unlike the originally described "restricted spectrum" — the classic somatic oncogenic hotspot Gly12, whose germline occurrence is associated with more severe disease and with tumors. NRAS accounts for well under 1% of molecularly solved Noonan syndrome; only a few dozen individuals have been reported. See the Noonan Syndrome umbrella entry for the shared clinical and management picture of the parent disorder.

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1
Mappings
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Inheritance
5
Pathophys.
25
Phenotypes
2
Gaps
17
Pathograph
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Genes
5
Medical Actions
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Trials
2
Models
1
References
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Deep Research
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Mappings

MONDO
MONDO:0013186 Noonan syndrome 6
skos:exactMatch MONDO
Primary disease term for this entry.
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Inheritance

1
Autosomal Dominant HP:0000006
NS6 is inherited in an autosomal dominant manner. Many cases arise de novo, but familial transmission with cosegregation is documented, and parental mosaicism has been reported — so recurrence risk after an apparently de novo case is not necessarily zero.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:26467218 SUPPORT Human Clinical
"The result revealed a recurrent mutation in NRAS, c.179G > A (p.G60E), in the index patient. This mutation was inherited from the index patient's father, who also showed signs of NS."
Documents parent-to-child transmission of a heterozygous NRAS allele with affected status in both, consistent with autosomal dominant inheritance.
CGGV:assertion_34419b69-59c3-458b-a2a5-38a401679deb-2018-05-30T160000.000Z SUPPORT Other
"NRAS | HGNC:7989 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
ClinGen records autosomal dominant inheritance for the NRAS-Noonan relationship.
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Discussions and Knowledge Gaps

2
Do germline NRAS alleles at the classic oncogenic codons (Gly12, and by extension Gly13/Gln61) carry a quantitatively higher tumor risk than the non-hotspot NS6 alleles, and how large is that risk?
KNOWLEDGE GAP ns6_oncogenic_codon_tumor_risk
Attached to
pathophysiology#Oncogenic-Codon Germline Alleles and Tumor Predisposition
The published NRAS RASopathy series are small (tens of individuals), and the tumor events reported in Gly12 carriers - a myeloproliferative disorder, an uncharacterized brain tumor, and an embryonal rhabdomyosarcoma - are individual observations. The codon-dependent risk pattern is asserted from case-level pattern recognition, not from a cohort with denominators, while a separate familial report finds JMML risk in NRAS-positive Noonan syndrome no different from Noonan syndrome generally. Getting this wrong in either direction has direct surveillance consequences.
Proposed experiments
Genotype-stratified tumor-incidence study across an international NS6 registry
ns6_genotype_stratified_tumor_incidence
Pool NRAS-positive Noonan syndrome individuals internationally, stratify by hotspot versus non-hotspot codon, and compute age-adjusted tumor incidence with explicit denominators and person-years of follow-up.
Show evidence (2 references)
PMID:31697451 SUPPORT Human Clinical
"analysis of previously reported NRAS-RASopathy cases suggests that mutations at traditionally oncogenic codons are associated with elevated cancer risk not present with mutations at other sites"
The codon-dependent risk claim is explicitly hedged as a suggestion from reanalysis of previously reported cases, which is the gap this discussion records.
PMID:26467218 SUPPORT Human Clinical
"the risk for NS individuals with a germline NRAS mutation developing JMML is not different from the proportion seen in other NS cases"
Countervailing report finding no elevated JMML risk in NRAS-positive Noonan syndrome, which is why the tumor-risk question is recorded as open rather than settled.
Do the available NRAS animal models faithfully represent human NS6, given that both use alleles or dosages stronger than the typical human constitutional lesion?
HUMAN MODEL MISMATCH ns6_animal_model_allele_strength
Attached to
pathophysiology#Disrupted Embryonic Cardiac Development pathophysiology#Disrupted Early Developmental Patterning
The mouse model uses the oncogenic G12D allele expressed pan-embryonically and is lethal by E15.5, so it cannot model the postnatal NS6 course; the zebrafish model uses transient mRNA overexpression of human mutants rather than an endogenous heterozygous locus. Both give a clear MAPK-dependent developmental phenotype, but the quantitative relationship between their signalling gain and that of a human NS6 heterozygote is unknown - which matters directly for interpreting the MEK-inhibitor rescue as a therapeutic rationale.
Proposed experiments
Endogenous-locus heterozygous knock-in of a human NS6 allele
ns6_endogenous_knockin_mouse
Generate mice carrying a heterozygous knock-in of a non-hotspot human NS6 allele (e.g. Nras G60E) at the endogenous locus, and assess viability, cardiac phenotype, growth and craniofacial morphology against the G12D model.
Show evidence (2 references)
PMID:33681212 SUPPORT Model Organism
"Thus, oncogenic NrasG12D mutation may not be compatible with embryonic survival."
The authors' own conclusion that the modelled allele is embryonic-lethal is precisely the translational mismatch with living human NS6 individuals that this discussion records.
PMID:21263000 SUPPORT Model Organism
"Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos"
The zebrafish readout comes from injected expression benchmarked against a strongly activating positive control, not from an endogenous heterozygous locus - the dosage mismatch this discussion records.
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Pathophysiology

5
NRAS Germline Gain-of-Function Variant
Heterozygous germline variants in NRAS - predominantly missense substitutions (reported at Ile24, Thr50, Thr58, Gly60 and, less commonly, the classic oncogenic codon Gly12), with at least one reported in-frame duplication affecting the switch I region - alter conserved residues of the N-Ras GTPase. The substitutions shift the GTPase toward its active GTP-bound conformation — by perturbing switch-region nucleotide-exchange kinetics or, for Gly12 changes, by impairing intrinsic hydrolysis and GAP responsiveness — so that N-Ras signals more strongly in response to upstream stimulation. Constitutional origin must be established in non-hematopoietic tissue, because the same codons are somatic hotspots in myeloid neoplasia.
NRAS hgnc:7989 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NRAS (hgnc:7989). hgnc:7989 is a gene from the HUGO Gene Nomenclature Committee.
positive regulation of Ras protein signal transduction GO:0046579 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves positive regulation of Ras protein signal transduction (GO:0046579), qualified as gain of function. GO:0046579 is a biological process from the Gene Ontology. ⇑ GAIN OF FUNCTION
N-Ras intrinsic GTP hydrolysis GO:0003924 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased N-Ras intrinsic GTP hydrolysis, annotated with GTPase activity (GO:0003924). GO:0003924 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
RAS-MAPK Cascade Hyperactivation The activated N-Ras GTPase increases signal throughput into the RAF-MEK-ERK cascade.
Oncogenic-Codon Germline Alleles and Tumor Predisposition When the germline allele occupies a classic somatic oncogenic codon, the same lesion additionally establishes a tumor-predisposing state; this branch is allele-dependent rather than a consequence of every NS6 genotype.
Show evidence (3 references)
PMID:19966803 SUPPORT Human Clinical
"These findings provide evidence for an obligate dependency on proper NRAS function in human development and growth."
Establishes that constitutional perturbation of NRAS function is the causal lesion in this developmental disorder.
PMID:21263000 SUPPORT Human Clinical
"Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features."
First-party identification of a germline NRAS substitution in an individual with typical Noonan syndrome features, extending the allelic spectrum of this subtype.
PMID:28594414 SUPPORT Human Clinical
"Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer."
Documents that germline NS6 alleles extend to the classic somatic oncogenic codon Gly12, contradicting the earlier "restricted spectrum" model.
RAS-MAPK Cascade Hyperactivation
The activated N-Ras protein drives excessive signalling through the RAF-MEK-ERK (MAPK) cascade — the shared final common mechanism of the RASopathies. Enhanced ERK output during embryonic and postnatal development perturbs proliferation, differentiation and survival across multiple lineages, producing the multisystem Noonan phenotype.
positive regulation of MAPK cascade GO:0043410 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of MAPK cascade (GO:0043410). GO:0043410 is a biological process from the Gene Ontology. ↑ INCREASED Ras protein signal transduction GO:0007265 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Ras protein signal transduction (GO:0007265). GO:0007265 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Disrupted Embryonic Cardiac Development Excess RAS-MAPK signalling in the developing heart disrupts cardiac morphogenesis.
Short Stature Constitutive dysregulation of RAS-MAPK signalling underlies the reduced growth of the disorder.
Noonan Facial Gestalt The characteristic craniofacial appearance emerges from RAS-MAPK dysregulation during development, as it does across the RASopathies.
Disrupted Early Developmental Patterning Activated N-Ras signalling perturbs early embryonic morphogenetic movements; MEK inhibition fully reverses the effect, establishing that the defect is MAPK-mediated.
Show evidence (2 references)
PMID:21263000 SUPPORT In Vitro
"The I24N mutation activates N-Ras, resulting in enhanced downstream signaling."
Functional demonstration that a Noonan-associated germline NRAS substitution activates the protein and increases downstream signalling.
PMID:23875798 SUPPORT Human Clinical
"Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development."
Review-level support for the shared RASopathy mechanism into which NS6 falls; partial because it addresses the RASopathies collectively rather than NRAS specifically.
Disrupted Embryonic Cardiac Development
Excess RAS-MAPK signalling during cardiac morphogenesis produces the structural and hypertrophic heart disease of NS6. Lineage-restricted mouse experiments localize the requirement to the endothelial/endocardial compartment rather than the myocardium.
endocardial cell CL:0002350 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endocardial cell (CL:0002350). CL:0002350 is a cell type from the Cell Ontology. endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
heart development GO:0007507 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal heart development (GO:0007507). GO:0007507 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Nras G12D pan-embryonic knock-in mouse (Mox2-Cre) Mouse recapitulates Activated Nras in the developing embryo produces septal, outflow-tract, myocardial and pulmonary-valve lesions matching the human Noonan cardiac spectrum, together with ERK pathway dysregulation in the mutant heart.
Downstream
Congenital Heart Disease Disturbed cardiac morphogenesis yields the septal, valvar and myocardial lesions seen clinically.
Pulmonic Stenosis Disturbed valvar morphogenesis in the outflow tract yields pulmonary valve stenosis, the commonest Noonan syndrome heart lesion.
Septal Defects Failure of septation during cardiac morphogenesis yields the atrial and ventricular septal defects seen clinically.
Show evidence (1 reference)
PMID:33681212 SUPPORT Model Organism
"Endothelial/endocardial-specific expression of NrasG12D/ + caused the cardiac morphological defects and embryonic lethality as observed in NrasG12D/ + ; Mox2Cre/ + mutants, but myocardial-specific expression of NrasG12D/ + did not."
Localizes the cardiac requirement for activated N-Ras to the endocardial/endothelial compartment, not the myocardium.
Disrupted Early Developmental Patterning
Noonan-associated activating N-Ras mutants are sufficient to derail early morphogenesis. In zebrafish, expression of the human NS-derived I24N and G60E mutants causes gastrulation defects phenocopying those of other Noonan syndrome genes, indicating that the germline lesion acts on early embryonic patterning rather than only on postnatal growth.
gastrulation GO:0007369 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal gastrulation (GO:0007369). GO:0007369 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Zebrafish N-Ras I24N / G60E overexpression embryo Zebrafish recapitulates Establishes that the human NS6 alleles are sufficient to derail early embryonic patterning, and that the effect is MAPK-dependent.
Downstream
Noonan Facial Gestalt Derailed early morphogenesis is the developmental route by which the craniofacial dysmorphism arises; in vivo, the activating N-Ras mutants produce embryonic defects that resemble the human syndrome and phenocopy those of the other Noonan syndrome genes.
Show evidence (1 reference)
PMID:21263000 SUPPORT Model Organism
"Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders."
Establishes sufficiency of the Noonan-associated N-Ras mutants to cause early developmental defects in vivo.
Oncogenic-Codon Germline Alleles and Tumor Predisposition
A subset of NS6 alleles occupies the codons that are classic somatic drivers in cancer (notably Gly12). Individuals carrying these alleles have been reported with myeloproliferative disease, an uncharacterized brain tumor, and embryonal rhabdomyosarcoma, and the available case series suggest that hotspot-codon germline alleles carry higher tumor risk than the non-hotspot NS6 alleles. Numbers are small, so this is a genotype-associated risk signal rather than a quantified risk estimate; the JMML risk in NRAS-positive Noonan syndrome overall does not appear elevated above that of Noonan syndrome generally.
NRAS hgnc:7989 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NRAS (hgnc:7989). hgnc:7989 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Embryonal Rhabdomyosarcoma A germline p.G12R allele was reported in an individual who developed embryonal rhabdomyosarcoma.
Myeloproliferative Disorder A germline p.(Gly12Asp) carrier in the largest NRAS cohort had a myeloproliferative disorder.
Brain Neoplasm A germline p.(Gly12Arg) carrier in the same cohort had an uncharacterized brain tumor.
Show evidence (3 references)
PMID:31697451 SUPPORT Human Clinical
"Additionally, the specific p.G12R NRAS mutation in this case is a common somatic mutation in cancer cells, and analysis of previously reported NRAS-RASopathy cases suggests that mutations at traditionally oncogenic codons are associated with elevated cancer risk not present with mutations at other sites."
States the codon-dependent tumor-risk pattern that motivates this node.
PMID:28594414 SUPPORT Human Clinical
"Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour."
Reports the neoplastic events observed in Gly12 germline carriers in the largest NRAS RASopathy cohort.
PMID:26467218 SUPPORT Human Clinical
"Neither of affected individuals in this family presented with juvenile myelomonocytic leukemia (JMML), which together with previously published results suggest that the risk for NS individuals with a germline NRAS mutation developing JMML is not different from the proportion seen in other NS cases."
Counterweight to a blanket high-risk reading: JMML risk in NRAS-positive Noonan syndrome is not reported as elevated above Noonan syndrome generally.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Noonan Syndrome 6 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

25
Blood 1
Bleeding Diathesis Abnormal bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities."
GeneReviews documents varied coagulation defects in Noonan syndrome. Graded INDIRECT because it is a parent-entity statement.
Cardiovascular 4
Congenital Heart Disease Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19966803 SUPPORT INDIRECT Human Clinical
"Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway."
Congenital heart defects are named as a defining feature in the report establishing NRAS causation - but this sentence is the paper's background definition of Noonan syndrome as a whole rather than a finding about its NRAS cohort, so it is graded INDIRECT on the same basis as the GeneReviews parent-entity statements elsewhere in this entry.
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Congenital heart disease occurs in 50%-80% of individuals."
GeneReviews quantifies congenital heart disease in Noonan syndrome. Graded INDIRECT because the figure is for the parent entity and the NRAS cohort's cardiac profile differs (hypertrophic cardiomyopathy over-represented, pulmonic stenosis under-represented).
Hypertrophic Cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood."
GeneReviews documents hypertrophic cardiomyopathy in Noonan syndrome. Graded INDIRECT because the frequency cited is for the parent entity, not the NRAS subtype.
Pulmonic Stenosis HP:0001642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonic stenosis (HP:0001642). HP:0001642 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals."
GeneReviews documents pulmonary valve stenosis in Noonan syndrome. Graded INDIRECT because it is a parent-entity frequency, not NRAS-specific.
PMID:33681212 SUPPORT INDIRECT Model Organism
"Importantly, the mutant embryos exhibited cardiac malformations resembling human congenital cardiac defects seen in NS patients, including ventricular septal defects, double outlet right ventricle, the hypertrabeculation/thin myocardium, and pulmonary valve stenosis."
Activated Nras recapitulates pulmonary valve stenosis in a model organism. Graded INDIRECT because it is model-organism rather than human NS6 evidence.
Septal Defects Ventricular septal defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot."
GeneReviews lists septal defects among the structural lesions of Noonan syndrome. Graded INDIRECT because it describes the parent entity.
Ear 1
Hearing Impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26467218 SUPPORT Human Clinical
"In addition, the affected father in our family presented with a hearing deficit since birth, which together with lentigines are two characteristics of NS with multiple lentigines (previously LEOPARD syndrome), supporting the difficulties in diagnosing individuals with RASopathies correctly."
Reports congenital hearing deficit in an NRAS-positive Noonan syndrome individual.
PMID:41940405 SUPPORT Human Clinical
"Hearing loss was identified in 21.9% (7/32) of the cohort, with two PTPN11 and one NRAS mutation-positive patients affected."
Independent clinical cohort in which the single NRAS mutation-positive patient was among those with hearing loss, corroborating this phenotype in the NRAS subtype.
Eye 3
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:648 SUPPORT INDIRECT Other
"HP:0000316 | Hypertelorism | Very frequent (99-80%)"
Orphanet's HPO annotation table for Noonan syndrome records hypertelorism as a feature of the disorder. Graded INDIRECT because the annotation and its frequency band are for the parent entity, not the NRAS subtype.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:648 SUPPORT INDIRECT Other
"HP:0000508 | Ptosis | Very frequent (99-80%)"
Orphanet's HPO annotation table for Noonan syndrome records ptosis as a feature of the disorder. Graded INDIRECT because the annotation and its frequency band are for the parent entity, not the NRAS subtype.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities."
GeneReviews lists ocular abnormalities among the findings of Noonan syndrome. Graded INDIRECT because it is an unspecified parent-entity statement rather than an NRAS-specific one, and because it does not name strabismus specifically - the Orphanet annotation below supplies that granularity.
ORPHA:648 SUPPORT INDIRECT Other
"HP:0000486 | Strabismus | Frequent (79-30%)"
Orphanet's HPO annotation table records strabismus for Noonan syndrome. Graded INDIRECT because it annotates the parent entity, not the NRAS subtype.
Genitourinary 1
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities."
GeneReviews documents cryptorchidism in Noonan syndrome. Graded INDIRECT because it is a parent-entity statement.
ORPHA:648 SUPPORT INDIRECT Other
"HP:0000028 | Cryptorchidism | Frequent (79-30%)"
Orphanet's HPO annotation table records cryptorchidism for Noonan syndrome. Graded INDIRECT because it annotates the parent entity.
Head and Neck 3
Noonan Facial Gestalt Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28594414 SUPPORT Human Clinical
"Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours."
Establishes that individuals with germline NRAS variants present with the Noonan syndrome clinical gestalt.
PMID:19966803 SUPPORT INDIRECT Human Clinical
"Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway."
Facial dysmorphism is named as a defining feature of the disorder in the paper that established NRAS as a cause - but this sentence is the paper's background definition of Noonan syndrome as a whole rather than a finding about its NRAS cohort, so it is graded INDIRECT on the same basis as the GeneReviews parent-entity statements elsewhere in this entry.
Downslanted Palpebral Fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:648 SUPPORT INDIRECT Other
"HP:0000494 | Downslanted palpebral fissures | Very frequent (99-80%)"
Orphanet's HPO annotation table for Noonan syndrome records downslanted palpebral fissures as a feature of the disorder. Graded INDIRECT because the annotation and its frequency band are for the parent entity, not the NRAS subtype.
Webbed or Short Neck Webbed neck HP:0000465 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Webbed neck (HP:0000465). HP:0000465 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities."
GeneReviews documents broad/webbed neck in Noonan syndrome. Graded INDIRECT because it is a parent-entity statement rather than NRAS-specific.
ORPHA:648 SUPPORT INDIRECT Other
"HP:0000465 | Webbed neck | Very frequent (99-80%)"
Orphanet's HPO annotation table records webbed neck for Noonan syndrome. Graded INDIRECT because it annotates the parent entity.
Integument 1
Cafe-au-lait Macules Cafe-au-lait spot HP:0000957 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cafe-au-lait spot (HP:0000957). HP:0000957 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26467218 SUPPORT Human Clinical
"This demonstrates a predisposition to hyperpigmented lesions in NRAS-positive NS individuals."
Supports cafe-au-lait macules as part of the hyperpigmentation predisposition described in NRAS-positive Noonan syndrome.
Metabolism 1
Lymphatic Dysplasia Lymphedema HP:0001004 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphedema (HP:0001004). HP:0001004 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities"
GeneReviews documents lymphatic dysplasias in Noonan syndrome. Graded INDIRECT because it is a parent-entity statement.
ORPHA:648 SUPPORT INDIRECT Other
"HP:0001004 | Lymphedema | Occasional (29-5%)"
Orphanet's HPO annotation table records lymphedema for Noonan syndrome. Graded INDIRECT because it annotates the parent entity.
Musculoskeletal 2
Pectus Carinatum HP:0000768 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus carinatum (HP:0000768). HP:0000768 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities."
GeneReviews describes the characteristic chest shape of Noonan syndrome, naming superior pectus carinatum. Graded INDIRECT because it is a parent-entity statement rather than NRAS-specific.
ORPHA:648 SUPPORT INDIRECT Other
"HP:0000768 | Pectus carinatum | Very frequent (99-80%)"
Orphanet's HPO annotation table records pectus carinatum for Noonan syndrome. Graded INDIRECT because it annotates the parent entity, not the NRAS subtype.
Pectus Excavatum HP:0000767 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus excavatum (HP:0000767). HP:0000767 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities."
GeneReviews describes the characteristic chest shape of Noonan syndrome, naming inferior pectus excavatum. Graded INDIRECT because it is a parent-entity statement rather than NRAS-specific.
ORPHA:648 SUPPORT INDIRECT Other
"HP:0000767 | Pectus excavatum | Very frequent (99-80%)"
Orphanet's HPO annotation table records pectus excavatum for Noonan syndrome. Graded INDIRECT because it annotates the parent entity, not the NRAS subtype.
Nervous System 2
Variable Developmental Delay and Cognitive Impairment Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:19966803 SUPPORT INDIRECT Human Clinical
"Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway."
Variable cognitive deficits are named as a defining feature in the report establishing NRAS causation - but this sentence is the paper's background definition of Noonan syndrome as a whole rather than a finding about its NRAS cohort, so it is graded INDIRECT on the same basis as the GeneReviews parent-entity statements elsewhere in this entry.
PMID:28594414 SUPPORT Human Clinical
"The phenotype in our cohort was variable but well within the RASopathy spectrum."
Documents the variable expressivity that characterizes the NRAS cohort.
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population."
GeneReviews quantifies the cognitive and language involvement of Noonan syndrome. Graded INDIRECT because the figure is for the parent entity, not the NRAS subtype.
Severe Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249), qualified as severity severe. HP:0001249 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:31697451 SUPPORT Human Clinical
"We present the case of a germline heterozygous NRAS mutation producing a severe phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and numerous melanocytic nevi in addition to more typical manifestations of Noonan syndrome."
Single reported case documenting severe intellectual disability in NRAS-associated RASopathy. No frequency band is asserted: the report supplies no denominator, so the proportion of NS6 individuals reaching this severity cannot be estimated from it.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19966803 SUPPORT INDIRECT Human Clinical
"Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway."
Reduced growth is a defining feature of the disorder in the report establishing NRAS causation - but this sentence is the paper's background definition of Noonan syndrome as a whole rather than a finding about its NRAS cohort, so it is graded INDIRECT on the same basis as the GeneReviews parent-entity statements elsewhere in this entry.
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Although birth length is usually normal, final adult height approaches the lower limit of normal."
Characterizes the growth pattern of the parent entity. Graded INDIRECT because it is not NRAS-specific.
Other 5
Hyperpigmented Cutaneous Lesions FREQUENT Multiple lentigines HP:0001003 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lentigines and/or cafe-au-lait macules, annotated with Multiple lentigines (HP:0001003). HP:0001003 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26467218 SUPPORT Human Clinical
"Interestingly, 50% of NS individuals with an NRAS mutation (including our family) present with lentigines and/or Café-au-lait spots. This demonstrates a predisposition to hyperpigmented lesions in NRAS-positive NS individuals."
Directly quantifies hyperpigmented lesions in NRAS-positive Noonan syndrome at 50%, supporting the FREQUENT band (30-79%). The band is asserted for the composite lentigines-and/or-CALM concept the quote measures, not for lentigines alone - the separate cafe-au-lait entry below therefore carries no frequency of its own.
Multiple Melanocytic Nevi Melanocytic nevus HP:0000995 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Melanocytic nevus (HP:0000995). HP:0000995 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31697451 SUPPORT Human Clinical
"severe phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and numerous melanocytic nevi"
Documents numerous melanocytic nevi in a germline NRAS RASopathy case.
Embryonal Rhabdomyosarcoma HP:0006743 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Embryonal rhabdomyosarcoma (HP:0006743). HP:0006743 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31697451 SUPPORT Human Clinical
"We present the case of a germline heterozygous NRAS mutation producing a severe phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and numerous melanocytic nevi in addition to more typical manifestations of Noonan syndrome."
The defining case report of embryonal rhabdomyosarcoma in NRAS-associated RASopathy.
Myeloproliferative Disorder OCCASIONAL HP:0005547 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myeloproliferative disorder (HP:0005547). HP:0005547 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28594414 SUPPORT Human Clinical
"Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour."
Documents the single myeloproliferative disorder observed in the largest NRAS RASopathy cohort; 1 of the 19 cases described in that report is 5.3%, which maps to the OCCASIONAL band (5-29%).
Brain Neoplasm OCCASIONAL HP:0030692 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brain neoplasm (HP:0030692). HP:0030692 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28594414 SUPPORT Human Clinical
"one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour"
Documents the brain tumor observed in a germline oncogenic-codon NRAS carrier; 1 of the 19 cases described in that report is 5.3%, which maps to the OCCASIONAL band (5-29%).
🧬

Genetic Associations

1
NRAS (Pathogenic Variants)
Gene: NRAS hgnc:7989 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NRAS (hgnc:7989). hgnc:7989 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:19966803 SUPPORT Human Clinical
"Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder."
Establishes NRAS as a gain-of-function cause of Noonan syndrome.
CGGV:assertion_34419b69-59c3-458b-a2a5-38a401679deb-2018-05-30T160000.000Z SUPPORT Other
"NRAS | HGNC:7989 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
ClinGen's RASopathy Gene Curation Expert Panel classifies the NRAS-Noonan syndrome relationship as Definitive with autosomal dominant inheritance.
PMID:22855653 SUPPORT Human Clinical
"The phenotype associated with germline NRAS mutations is variable. Our results confirm that a small proportion of Noonan syndrome patients carry germline NRAS mutations."
Supports both the rarity of the NRAS subtype and its variable expressivity.
💊

Medical Actions

5
Recombinant Growth Hormone (Somatropin) Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: somatropin NCIT:C837 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses somatropin (NCIT:C837). NCIT:C837 is a therapeutic agent from the NCI Thesaurus.
Growth hormone treatment increases growth velocity in Noonan syndrome and is used for the short stature of the syndrome. It is not NRAS-specific: no NS6 subgroup outcome data exist.
Show evidence (1 reference)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Growth hormone (GH) treatment increases growth velocity."
GeneReviews supports growth hormone therapy in Noonan syndrome. Graded INDIRECT because the recommendation is for the parent entity, not the NRAS subtype.
MEK Inhibition (Trametinib, Experimental/Off-Label)
Action: Targeted TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Targeted Therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. NCIT:C93352
Agent: trametinib NCIT:C77908 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses trametinib (NCIT:C77908). NCIT:C77908 is a therapeutic agent from the NCI Thesaurus.
MEK1/2 inhibition targets the step of the RAS-MAPK cascade immediately downstream of the activated N-Ras protein, and MEK inhibition fully rescues the developmental phenotypes of Noonan-associated N-Ras mutants in zebrafish. In humans it remains off-label and experimental, used in case reports for severe cardiac and lymphatic disease in Noonan syndrome; no NS6-specific outcome data exist and long-term follow-up is unavailable.
Mechanism Target:
INHIBITS RAS-MAPK Cascade Hyperactivation — MEK1/2 inhibition blocks signal flow through the hyperactivated cascade downstream of the mutant N-Ras protein.
Show evidence (1 reference)
PMID:21263000 SUPPORT Model Organism
"MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling."
Establishes MEK as the actionable node downstream of Noonan-associated activated N-Ras.
Show evidence (2 references)
PMID:40041314 SUPPORT INDIRECT Human Clinical
"A short-term improvement of symptoms was reported in all cases, with three deaths presumably unrelated to trametinib. Moderate side effects were reported in a subset of patients. Long-term follow-up data were not available."
Systematic review of off-label trametinib in severe Noonan syndrome. Graded INDIRECT because the collected cases are Noonan syndrome generally (the index case was PTPN11), not NRAS-associated NS6.
PMID:40041314 SUPPORT INDIRECT Human Clinical
"No formal clinical trial of trametinib in neonatal/pediatric Noonan syndrome has been published to our knowledge."
Records the experimental status of this therapy. Graded INDIRECT for the same reason as above.
Cardiac Surveillance and Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Cardiovascular anomalies are treated as in the general population, with scheduled echocardiographic surveillance because hypertrophic cardiomyopathy may appear after infancy.
Show evidence (1 reference)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Cardiovascular anomalies in NS are usually treated as in the general population."
GeneReviews management guidance for the parent entity. Graded INDIRECT because it is not NRAS-specific.
Perioperative Bleeding Assessment and Avoidance of Aspirin
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Because varied coagulation defects occur, bleeding history and coagulation testing are assessed before surgery, and aspirin therapy is avoided as it may exacerbate the bleeding diathesis.
Show evidence (1 reference)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Agents/circumstances to avoid: Aspirin therapy should be avoided because it may exacerbate a bleeding diathesis."
GeneReviews drug-safety warning for Noonan syndrome. Graded INDIRECT because it applies to the parent entity.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counseling covers the 50% transmission risk from an affected parent, the predominance of de novo events, and the residual recurrence risk from parental mosaicism. Constitutional versus somatic origin must be clarified when an oncogenic-hotspot NRAS allele is detected in blood.
Show evidence (1 reference)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"Each child of an individual with autosomal dominant NS has a 50% chance of inheriting the pathogenic variant."
GeneReviews recurrence-risk statement underpinning counseling. Graded INDIRECT because it is a parent-entity statement.
🔬

Diagnosis

3
Molecular genetic testing of a RASopathy gene panel
NS6 is a molecularly defined entity, so the diagnosis rests on identifying a heterozygous pathogenic NRAS variant in an individual with suggestive clinical findings. NRAS is one of the genes on the standard Noonan syndrome diagnostic panel; because NS6 is clinically indistinguishable from other Noonan subtypes, panel or exome testing rather than single-gene testing is the practical route.
RASopathy gene-panel molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
The NCIT term is generic; the preferred term records that diagnostic confirmation for this entry is detection of a pathogenic NRAS variant on a Noonan/RASopathy panel.
Show evidence (1 reference)
PMID:20301303 SUPPORT Human Clinical
"The diagnosis of Noonan is established in a proband with suggestive findings and a heterozygous pathogenic variant in BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 or either a heterozygous variant or biallelic pathogenic variants in LZTR1 identified by molecular..."
GeneReviews names NRAS explicitly among the genes whose heterozygous pathogenic variants establish the diagnosis, which is what defines this entry's entity - so unlike the parent-entity clinical statements elsewhere in this file, this one is directly on point for NS6.
Confirmation of constitutional (germline) origin in non-hematopoietic tissue
Codons 12, 13 and 61 of NRAS are classic somatic hotspots in myeloid neoplasia, so an NRAS variant found in blood during a leukemia or myeloproliferative-disease workup does not by itself establish NS6. Constitutional status should be confirmed in a non-hematopoietic specimen (fibroblasts, buccal epithelium, nail, urine or saliva).
germline confirmation testing on a non-hematopoietic specimen NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:22887781 SUPPORT Human Clinical
"None of the 11 JMML patients for which germline DNA was available had a constitutional NRAS mutation."
Demonstrates empirically that NRAS variants in myeloid disease are typically somatic rather than constitutional, which is why germline confirmation is a distinct diagnostic step for this entry.
PMID:28594414 SUPPORT Human Clinical
"the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours"
Frames the germline-versus-somatic distinction this diagnostic step addresses. The same report goes on to show the distinction is not absolute (four germline Gly12 carriers).
Baseline cardiac evaluation
Echocardiographic assessment at diagnosis, with continued surveillance, because congenital heart disease is present in most affected individuals and hypertrophic cardiomyopathy may appear after infancy.
echocardiographic evaluation NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301303 SUPPORT INDIRECT Human Clinical
"In children age <5 years: if initial cardiac evaluation is normal, at least annual cardiac evaluations until age 5 years."
GeneReviews surveillance guidance underpinning baseline and repeat cardiac assessment. Graded INDIRECT because it is written for the parent entity.
📊

Prevalence

1
Worldwide
Cases In Literature Unknown
No population prevalence estimate exists for NS6 specifically. Only a few dozen molecularly confirmed individuals have been reported; the largest single series added 19 cases. The Noonan syndrome birth prevalence of roughly 1 in 1,000-2,500 belongs to the parent entity and must not be assigned to this subtype.
Show evidence (2 references)
PMID:28594414 SUPPORT Human Clinical
"A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported."
States that only a small number of germline NRAS RASopathy cases exist in the literature.
PMID:28594414 SUPPORT Human Clinical
"Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS."
Gives the size of the largest reported NRAS RASopathy series.
🔬

Clinical Trials

1
NCT06555237 PHASE_II RECRUITING
MEKinRAS - randomized controlled trial of trametinib added to standard therapy versus standard therapy alone for hypertrophic cardiomyopathy in patients with a molecularly confirmed RASopathy. Eligibility is defined by a RAS-MAPK pathway variant plus HCM rather than by a clinical Noonan syndrome diagnosis, so an individual with NS6 and HCM is eligible; no NRAS subgroup outcome is planned or reported.
Target Phenotypes: Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT06555237 SUPPORT INDIRECT Human Clinical
"The goal of this study is to evaluate the effectiveness of trametinib treatment in patients with Hyperthropic cardiomyopathy and a genetic mutation in the RAS/MAPK pathway."
The registered objective substantiates the experimental MEK-inhibition treatment curated in this entry and admits NS6 patients by molecular criteria. Graded INDIRECT because enrolment spans the RASopathies and no NRAS-specific result exists.
🐁

Animal Models

2
Nras G12D pan-embryonic knock-in mouse (Mox2-Cre)
Conditional endogenous-locus activation of Nras throughout the embryo, producing cardiac malformations that mirror the congenital heart lesions of Noonan syndrome, with lethality from E15.5. Lineage-restricted crosses localize the requirement to the endothelial/endocardial compartment.
Species
Mouse
Genotype
NrasG12D/+ ; Mox2-Cre
Publication
PMID:33681212
Pathograph links
Disrupted Embryonic Cardiac Development recapitulates fidelity: moderate Activated Nras in the developing embryo produces septal, outflow-tract, myocardial and pulmonary-valve lesions matching the human Noonan cardiac spectrum, together with ERK pathway dysregulation in the mutant heart.
Limitations: G12D is an oncogenic somatic hotspot allele that is stronger than most human NS6 alleles, and pan-embryonic expression is lethal by E15.5 — so the model cannot address the postnatal course. Human NS6 individuals with Gly12 alleles are reported but rare.
Readouts
Cardiac morphology at E13.5-E15.5
Direction: ALTERED
Interpretation: Structural cardiac malformations are the morphological correlate of the disrupted cardiac-development node.
Show evidence (1 reference)
PMID:33681212 SUPPORT Model Organism
"Importantly, the mutant embryos exhibited cardiac malformations resembling human congenital cardiac defects seen in NS patients, including ventricular septal defects, double outlet right ventricle, the hypertrabeculation/thin myocardium, and pulmonary valve stenosis."
Reports the histological/morphological cardiac measurement in this model.
Show evidence (1 reference)
PMID:33681212 SUPPORT Model Organism
"Here, we report that pan-embryonic expression of endogenous NrasG12D/ + by Mox2-Cre in mice caused embryonic lethality from embryonic day (E) 15.5 and developmental defects predominantly in the heart."
Supports treating this model as informative for the cardiac-development node.
Show evidence (1 reference)
PMID:33681212 SUPPORT Model Organism
"At E13.5, NrasG12D/ + ; Mox2Cre/ + embryos displayed a moderate expansion of hematopoietic stem and progenitor cells without a significant impact on erythroid differentiation in the fetal liver."
First-party characterization of what this specific model does and does not show, which is what establishes its scope as an informative system here.
Zebrafish N-Ras I24N / G60E overexpression embryo
Expression of Noonan-derived activating N-Ras mutants in zebrafish embryos produces gastrulation defects phenocopying those of other Noonan syndrome genes; MEK inhibition fully rescues them.
Species
Zebrafish
Genotype
mRNA expression of human NRAS I24N or G60E
Publication
PMID:21263000
Pathograph links
Disrupted Early Developmental Patterning recapitulates fidelity: moderate Establishes that the human NS6 alleles are sufficient to derail early embryonic patterning, and that the effect is MAPK-dependent.
Limitations: Transient mRNA overexpression rather than an endogenous heterozygous knock-in, so dosage exceeds the human constitutional state; gastrulation defects are a zebrafish developmental readout, not a human NS6 clinical feature.
Readouts
MEK-inhibitor rescue of gastrulation phenotype
Direction: RESTORED
Interpretation: Complete rescue by MEK inhibition establishes that the patterning defect is mediated by the RAS-MAPK cascade.
Show evidence (1 reference)
PMID:21263000 SUPPORT Model Organism
"MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling."
Reports the rescue measurement behind this readout.
Show evidence (1 reference)
PMID:21263000 SUPPORT Model Organism
"In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome."
Supports treating this model as informative for the early-patterning node.
Show evidence (1 reference)
PMID:21263000 SUPPORT Model Organism
"The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos."
Supports treating this zebrafish system as an informative model of Noonan syndrome, benchmarked against other Noonan genes in the same assay.
{ }

Source YAML

click to show 
name: Noonan Syndrome 6
creation_date: '2026-08-18T00:00:00Z'
description: >-
  Noonan syndrome 6 (NS6, NRAS Noonan syndrome) is the rare NRAS-associated arm of the
  Noonan syndrome RASopathy spectrum. Heterozygous germline gain-of-function missense
  variants in NRAS — which encodes the canonical small GTPase N-Ras — increase
  stimulus-dependent flux through the RAS-MAPK (RAF-MEK-ERK) cascade during development,
  producing the recognizable Noonan phenotype of characteristic facies, short or webbed
  neck, ptosis, congenital heart disease (with hypertrophic cardiomyopathy over-represented
  relative to pulmonic stenosis), variable growth restriction, and variable
  neurodevelopmental involvement. NS6 is defined molecularly rather than clinically: its
  clinical picture sits within the broader Noonan/RASopathy spectrum, so the disease entity
  is delimited by the causal gene. Reported pathogenic residues include Ile24, Thr50,
  Thr58 and Gly60, and — unlike the originally described "restricted spectrum" — the classic
  somatic oncogenic hotspot Gly12, whose germline occurrence is associated with more severe
  disease and with tumors. NRAS accounts for well under 1% of molecularly solved Noonan
  syndrome; only a few dozen individuals have been reported. See the Noonan Syndrome
  umbrella entry for the shared clinical and management picture of the parent disorder.
category: Mendelian
parents:
- Noonan Syndrome
- RASopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013186
      label: Noonan syndrome 6
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary disease term for this entry.
disease_term:
  preferred_term: Noonan syndrome 6
  description: >-
    Any Noonan syndrome in which the cause of the disease is a gain-of-function mutation
    in the NRAS gene.
  term:
    id: MONDO:0013186
    label: Noonan syndrome 6
references:
- reference: PMID:20301303
  title: "Noonan Syndrome."
  tags:
  - GeneReviews
pathophysiology:
- name: NRAS Germline Gain-of-Function Variant
  biological_scale: MOLECULAR
  description: >-
    Heterozygous germline variants in NRAS - predominantly missense substitutions
    (reported at Ile24, Thr50, Thr58, Gly60 and, less commonly, the classic oncogenic codon
    Gly12), with at least one reported in-frame duplication affecting the switch I region -
    alter conserved residues of the N-Ras GTPase. The substitutions shift the GTPase toward its active
    GTP-bound conformation — by perturbing switch-region nucleotide-exchange kinetics or,
    for Gly12 changes, by impairing intrinsic hydrolysis and GAP responsiveness — so that
    N-Ras signals more strongly in response to upstream stimulation. Constitutional origin
    must be established in non-hematopoietic tissue, because the same codons are somatic
    hotspots in myeloid neoplasia.
  genes:
  - preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  molecular_functions:
  - preferred_term: N-Ras intrinsic GTP hydrolysis
    term:
      id: GO:0003924
      label: GTPase activity
    modifier: DECREASED
    description: >-
      DECREASED describes the Gly12 alleles specifically, which impair intrinsic hydrolysis
      and GAP responsiveness. The non-hotspot NS6 alleles (Ile24, Thr50, Thr58, Gly60) act
      predominantly by enhancing stimulus-dependent nucleotide exchange rather than by
      losing hydrolytic activity; the shared consequence in both cases is more GTP-bound
      N-Ras, captured on the signalling term below.
  biological_processes:
  - preferred_term: positive regulation of Ras protein signal transduction
    term:
      id: GO:0046579
      label: positive regulation of Ras protein signal transduction
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: RAS-MAPK Cascade Hyperactivation
    causal_link_type: DIRECT
    description: >-
      The activated N-Ras GTPase increases signal throughput into the RAF-MEK-ERK cascade.
    evidence:
    - reference: PMID:19966803
      reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we report that germline NRAS mutations conferring enhanced stimulus-dependent
        MAPK activation account for some cases of this disorder.
      explanation: >-
        Directly links the germline NRAS lesion to enhanced MAPK pathway activation as the
        proximate mechanism of this Noonan syndrome subtype.
  - target: Oncogenic-Codon Germline Alleles and Tumor Predisposition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      When the germline allele occupies a classic somatic oncogenic codon, the same lesion
      additionally establishes a tumor-predisposing state; this branch is allele-dependent
      rather than a consequence of every NS6 genotype.
    evidence:
    - reference: PMID:31697451
      reference_title: "NRAS associated RASopathy and embryonal rhabdomyosarcoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        analysis of previously reported NRAS-RASopathy cases suggests that mutations at
        traditionally oncogenic codons are associated with elevated cancer risk not present
        with mutations at other sites
      explanation: >-
        Makes the allele-dependent link between the germline NRAS lesion and tumor risk that
        this edge encodes.
  evidence:
  - reference: PMID:19966803
    reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings provide evidence for an obligate dependency on proper NRAS function in
      human development and growth.
    explanation: >-
      Establishes that constitutional perturbation of NRAS function is the causal lesion in
      this developmental disorder.
  - reference: PMID:21263000
    reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that
      we identified in an individual bearing typical Noonan syndrome features.
    explanation: >-
      First-party identification of a germline NRAS substitution in an individual with
      typical Noonan syndrome features, extending the allelic spectrum of this subtype.
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, four of them harbored missense changes affecting Gly12, which was
      previously described to occur exclusively in cancer.
    explanation: >-
      Documents that germline NS6 alleles extend to the classic somatic oncogenic codon
      Gly12, contradicting the earlier "restricted spectrum" model.
- name: RAS-MAPK Cascade Hyperactivation
  biological_scale: CELLULAR
  description: >-
    The activated N-Ras protein drives excessive signalling through the RAF-MEK-ERK
    (MAPK) cascade — the shared final common mechanism of the RASopathies. Enhanced ERK
    output during embryonic and postnatal development perturbs proliferation,
    differentiation and survival across multiple lineages, producing the multisystem
    Noonan phenotype.
  biological_processes:
  - preferred_term: positive regulation of MAPK cascade
    term:
      id: GO:0043410
      label: positive regulation of MAPK cascade
    modifier: INCREASED
  - preferred_term: Ras protein signal transduction
    term:
      id: GO:0007265
      label: Ras protein signal transduction
    modifier: INCREASED
  downstream:
  - target: Disrupted Embryonic Cardiac Development
    causal_link_type: DIRECT
    description: >-
      Excess RAS-MAPK signalling in the developing heart disrupts cardiac morphogenesis.
    evidence:
    - reference: PMID:33681212
      reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The mutant heart showed dysregulation of ERK, BMP, and Wnt pathways, crucial
        signaling pathways for cardiac development.
      explanation: >-
        Shows that activated Nras dysregulates ERK signalling in the developing heart of a
        model organism, linking the pathway node to the cardiac developmental node.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Constitutive dysregulation of RAS-MAPK signalling underlies the reduced growth of the
      disorder.
    evidence:
    - reference: PMID:19966803
      reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These findings provide evidence for an obligate dependency on proper NRAS function in
        human development and growth.
      explanation: >-
        Ties proper NRAS function - and therefore its pathway output - to human growth.
        The sentence asserts the dependency without dissecting the growth-restriction
        mechanism.
  - target: Noonan Facial Gestalt
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The characteristic craniofacial appearance emerges from RAS-MAPK dysregulation during
      development, as it does across the RASopathies.
    evidence:
    - reference: PMID:23875798
      reference_title: "The RASopathies."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies
        exhibit numerous overlapping phenotypic features.
      explanation: >-
        Attributes the shared RASopathy phenotypic features, of which the facial gestalt
        is the most recognizable, to common pathway dysregulation. Graded INDIRECT
        because it is a review-level statement about the RASopathies collectively.
  - target: Disrupted Early Developmental Patterning
    causal_link_type: DIRECT
    description: >-
      Activated N-Ras signalling perturbs early embryonic morphogenetic movements; MEK
      inhibition fully reverses the effect, establishing that the defect is MAPK-mediated.
    evidence:
    - reference: PMID:21263000
      reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        MEK inhibition completely rescued the activated N-Ras-induced phenotypes,
        demonstrating that these defects are mediated exclusively by Ras-MAPK signaling.
      explanation: >-
        Pharmacological epistasis showing the developmental defects caused by
        Noonan-associated N-Ras mutants run through the RAS-MAPK cascade.
  evidence:
  - reference: PMID:21263000
    reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The I24N mutation activates N-Ras, resulting in enhanced downstream signaling.
    explanation: >-
      Functional demonstration that a Noonan-associated germline NRAS substitution
      activates the protein and increases downstream signalling.
  - reference: PMID:23875798
    reference_title: "The RASopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound
      deleterious effects on both embryonic and later stages of development.
    explanation: >-
      Review-level support for the shared RASopathy mechanism into which NS6 falls;
      partial because it addresses the RASopathies collectively rather than NRAS
      specifically.
- name: Disrupted Embryonic Cardiac Development
  biological_scale: TISSUE
  description: >-
    Excess RAS-MAPK signalling during cardiac morphogenesis produces the structural and
    hypertrophic heart disease of NS6. Lineage-restricted mouse experiments localize the
    requirement to the endothelial/endocardial compartment rather than the myocardium.
  cell_types:
  - preferred_term: endocardial cell
    term:
      id: CL:0002350
      label: endocardial cell
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: heart development
    term:
      id: GO:0007507
      label: heart development
    modifier: ABNORMAL
  downstream:
  - target: Congenital Heart Disease
    causal_link_type: DIRECT
    description: >-
      Disturbed cardiac morphogenesis yields the septal, valvar and myocardial lesions
      seen clinically.
    evidence:
    - reference: PMID:33681212
      reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Importantly, the mutant embryos exhibited cardiac malformations resembling human
        congenital cardiac defects seen in NS patients, including ventricular septal
        defects, double outlet right ventricle, the hypertrabeculation/thin myocardium, and
        pulmonary valve stenosis.
      explanation: >-
        Connects activated Nras-driven cardiac maldevelopment to the congenital heart
        lesions of Noonan syndrome.
  - target: Pulmonic Stenosis
    causal_link_type: DIRECT
    description: >-
      Disturbed valvar morphogenesis in the outflow tract yields pulmonary valve stenosis,
      the commonest Noonan syndrome heart lesion.
    evidence:
    - reference: PMID:33681212
      reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Importantly, the mutant embryos exhibited cardiac malformations resembling human
        congenital cardiac defects seen in NS patients, including ventricular septal
        defects, double outlet right ventricle, the hypertrabeculation/thin myocardium, and
        pulmonary valve stenosis.
      explanation: >-
        Activated-Nras cardiac maldevelopment produces pulmonary valve stenosis in vivo.
        Graded INDIRECT because the demonstration is model-organism rather than human
        NS6 evidence.
  - target: Septal Defects
    causal_link_type: DIRECT
    description: >-
      Failure of septation during cardiac morphogenesis yields the atrial and ventricular
      septal defects seen clinically.
    evidence:
    - reference: PMID:33681212
      reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Importantly, the mutant embryos exhibited cardiac malformations resembling human
        congenital cardiac defects seen in NS patients, including ventricular septal
        defects, double outlet right ventricle, the hypertrabeculation/thin myocardium, and
        pulmonary valve stenosis.
      explanation: >-
        Activated-Nras cardiac maldevelopment produces ventricular septal defects in
        vivo. Graded INDIRECT because the demonstration is model-organism rather than
        human NS6 evidence.
  evidence:
  - reference: PMID:33681212
    reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Endothelial/endocardial-specific expression of NrasG12D/ + caused the cardiac
      morphological defects and embryonic lethality as observed in NrasG12D/ + ; Mox2Cre/ +
      mutants, but myocardial-specific expression of NrasG12D/ + did not.
    explanation: >-
      Localizes the cardiac requirement for activated N-Ras to the endocardial/endothelial
      compartment, not the myocardium.
- name: Disrupted Early Developmental Patterning
  biological_scale: ORGANISM
  description: >-
    Noonan-associated activating N-Ras mutants are sufficient to derail early
    morphogenesis. In zebrafish, expression of the human NS-derived I24N and G60E mutants
    causes gastrulation defects phenocopying those of other Noonan syndrome genes,
    indicating that the germline lesion acts on early embryonic patterning rather than
    only on postnatal growth.
  biological_processes:
  - preferred_term: gastrulation
    term:
      id: GO:0007369
      label: gastrulation
    modifier: ABNORMAL
  downstream:
  - target: Noonan Facial Gestalt
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Derailed early morphogenesis is the developmental route by which the craniofacial
      dysmorphism arises; in vivo, the activating N-Ras mutants produce embryonic defects
      that resemble the human syndrome and phenocopy those of the other Noonan syndrome
      genes.
    evidence:
    - reference: PMID:21263000
      reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The defects in zebrafish embryos are reminiscent of symptoms in individuals with
        Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated
        genes induce in zebrafish embryos.
      explanation: >-
        Links the early-patterning defect to the Noonan syndrome phenotype in vivo.
        Graded INDIRECT because the resemblance is asserted for the syndrome's embryonic
        defects as a whole and not specifically for the human facial gestalt this edge
        targets.
  evidence:
  - reference: PMID:21263000
    reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V,
      which we included as a positive control, results in developmental defects in
      zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient
      to induce developmental disorders.
    explanation: >-
      Establishes sufficiency of the Noonan-associated N-Ras mutants to cause early
      developmental defects in vivo.
- name: Oncogenic-Codon Germline Alleles and Tumor Predisposition
  biological_scale: ORGANISM
  description: >-
    A subset of NS6 alleles occupies the codons that are classic somatic drivers in cancer
    (notably Gly12). Individuals carrying these alleles have been reported with
    myeloproliferative disease, an uncharacterized brain tumor, and embryonal
    rhabdomyosarcoma, and the available case series suggest that hotspot-codon germline
    alleles carry higher tumor risk than the non-hotspot NS6 alleles. Numbers are small,
    so this is a genotype-associated risk signal rather than a quantified risk estimate;
    the JMML risk in NRAS-positive Noonan syndrome overall does not appear elevated above
    that of Noonan syndrome generally.
  genes:
  - preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  downstream:
  - target: Embryonal Rhabdomyosarcoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A germline p.G12R allele was reported in an individual who developed embryonal
      rhabdomyosarcoma.
    evidence:
    - reference: PMID:31697451
      reference_title: "NRAS associated RASopathy and embryonal rhabdomyosarcoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We present the case of a germline heterozygous NRAS mutation producing a severe
        phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and
        numerous melanocytic nevi in addition to more typical manifestations of Noonan
        syndrome.
      explanation: >-
        The single reported instance linking a germline oncogenic-codon NRAS allele to
        embryonal rhabdomyosarcoma.
  - target: Myeloproliferative Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A germline p.(Gly12Asp) carrier in the largest NRAS cohort had a myeloproliferative
      disorder.
    evidence:
    - reference: PMID:28594414
      reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative
        disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain
        tumour.
      explanation: >-
        Reports the myeloproliferative event in a germline oncogenic-codon carrier.
  - target: Brain Neoplasm
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A germline p.(Gly12Arg) carrier in the same cohort had an uncharacterized brain tumor.
    evidence:
    - reference: PMID:28594414
      reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour
      explanation: >-
        Reports the brain tumor in a germline oncogenic-codon carrier.
  evidence:
  - reference: PMID:31697451
    reference_title: "NRAS associated RASopathy and embryonal rhabdomyosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, the specific p.G12R NRAS mutation in this case is a common somatic
      mutation in cancer cells, and analysis of previously reported NRAS-RASopathy cases
      suggests that mutations at traditionally oncogenic codons are associated with
      elevated cancer risk not present with mutations at other sites.
    explanation: >-
      States the codon-dependent tumor-risk pattern that motivates this node.
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative
      disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain
      tumour.
    explanation: >-
      Reports the neoplastic events observed in Gly12 germline carriers in the largest
      NRAS RASopathy cohort.
  - reference: PMID:26467218
    reference_title: "Mutation in NRAS in familial Noonan syndrome--case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neither of affected individuals in this family presented with juvenile myelomonocytic
      leukemia (JMML), which together with previously published results suggest that the
      risk for NS individuals with a germline NRAS mutation developing JMML is not
      different from the proportion seen in other NS cases.
    explanation: >-
      Counterweight to a blanket high-risk reading: JMML risk in NRAS-positive Noonan
      syndrome is not reported as elevated above Noonan syndrome generally.
phenotypes:
- category: Craniofacial
  name: Noonan Facial Gestalt
  description: >-
    The characteristic RASopathy face — hypertelorism, downslanting palpebral fissures,
    ptosis, and low-set posteriorly rotated ears — evolving with age. It is the feature
    that identifies affected individuals clinically as having Noonan syndrome before
    molecular testing.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals exhibited features fitting Noonan syndrome, and the observed
      germline variants differed from the typical oncogenic NRAS changes occurring as
      somatic events in tumours.
    explanation: >-
      Establishes that individuals with germline NRAS variants present with the Noonan
      syndrome clinical gestalt.
  - reference: PMID:19966803
    reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Noonan syndrome, a developmental disorder characterized by congenital heart defects,
      reduced growth, facial dysmorphism and variable cognitive deficits, is caused by
      constitutional dysregulation of the RAS-MAPK signaling pathway.
    explanation: >-
      Facial dysmorphism is named as a defining feature of the disorder in the paper
      that established NRAS as a cause - but this sentence is the paper's background
      definition of Noonan syndrome as a whole rather than a finding about its NRAS
      cohort, so it is graded INDIRECT on the same basis as the GeneReviews
      parent-entity statements elsewhere in this entry.
- category: Craniofacial
  name: Hypertelorism
  description: Widely spaced eyes, a component of the Noonan facial gestalt.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "HP:0000316 | Hypertelorism | Very frequent (99-80%)"
    explanation: >-
      Orphanet's HPO annotation table for Noonan syndrome records hypertelorism as a
      feature of the disorder. Graded INDIRECT because the annotation and its frequency
      band are for the parent entity, not the NRAS subtype.
- category: Craniofacial
  name: Ptosis
  description: Drooping of the upper eyelid, a component of the Noonan facial gestalt.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "HP:0000508 | Ptosis | Very frequent (99-80%)"
    explanation: >-
      Orphanet's HPO annotation table for Noonan syndrome records ptosis as a feature of
      the disorder. Graded INDIRECT because the annotation and its frequency band are
      for the parent entity, not the NRAS subtype.
- category: Craniofacial
  name: Downslanted Palpebral Fissures
  description: >-
    Downward-slanting palpebral fissures, one of the periorbital components of the Noonan
    facial gestalt curated as a composite elsewhere in this entry.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "HP:0000494 | Downslanted palpebral fissures | Very frequent (99-80%)"
    explanation: >-
      Orphanet's HPO annotation table for Noonan syndrome records downslanted palpebral
      fissures as a feature of the disorder. Graded INDIRECT because the annotation and
      its frequency band are for the parent entity, not the NRAS subtype.
- category: Ocular
  name: Strabismus
  description: >-
    Ocular misalignment, the specific ophthalmological finding annotated for Noonan
    syndrome behind the general "ocular abnormalities" of the clinical description. No
    NRAS-specific ophthalmological association has been established: the one NS cohort
    reporting refractive and ocular findings alongside genotype (PMID:41940405) reports
    those findings cohort-wide and states that no significant genotype relationships were
    found, so it is deliberately not cited here.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings can include broad or webbed neck, unusual chest shape with superior
      pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation
      defects, lymphatic dysplasias, and ocular abnormalities.
    explanation: >-
      GeneReviews lists ocular abnormalities among the findings of Noonan syndrome.
      Graded INDIRECT because it is an unspecified parent-entity statement rather than
      an NRAS-specific one, and because it does not name strabismus specifically - the
      Orphanet annotation below supplies that granularity.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "HP:0000486 | Strabismus | Frequent (79-30%)"
    explanation: >-
      Orphanet's HPO annotation table records strabismus for Noonan syndrome. Graded
      INDIRECT because it annotates the parent entity, not the NRAS subtype.
- category: Musculoskeletal
  name: Webbed or Short Neck
  description: >-
    Broad or webbed neck with a low posterior hairline, a hallmark of Noonan syndrome and
    the residuum of prenatal nuchal lymphatic distension.
  phenotype_term:
    preferred_term: Webbed neck
    term:
      id: HP:0000465
      label: Webbed neck
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings can include broad or webbed neck, unusual chest shape with superior
      pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation
      defects, lymphatic dysplasias, and ocular abnormalities.
    explanation: >-
      GeneReviews documents broad/webbed neck in Noonan syndrome. Graded INDIRECT
      because it is a parent-entity statement rather than NRAS-specific.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "HP:0000465 | Webbed neck | Very frequent (99-80%)"
    explanation: >-
      Orphanet's HPO annotation table records webbed neck for Noonan syndrome. Graded
      INDIRECT because it annotates the parent entity.
- category: Musculoskeletal
  name: Pectus Carinatum
  description: >-
    Superior pectus carinatum, the upper component of the characteristic Noonan chest
    shape (superior carinatum with inferior excavatum).
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings can include broad or webbed neck, unusual chest shape with superior
      pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation
      defects, lymphatic dysplasias, and ocular abnormalities.
    explanation: >-
      GeneReviews describes the characteristic chest shape of Noonan syndrome, naming
      superior pectus carinatum. Graded INDIRECT because it is a parent-entity statement
      rather than NRAS-specific.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "HP:0000768 | Pectus carinatum | Very frequent (99-80%)"
    explanation: >-
      Orphanet's HPO annotation table records pectus carinatum for Noonan syndrome.
      Graded INDIRECT because it annotates the parent entity, not the NRAS subtype.
- category: Musculoskeletal
  name: Pectus Excavatum
  description: >-
    Inferior pectus excavatum, the lower component of the characteristic Noonan chest
    shape, typically coexisting with superior carinatum in the same individual.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings can include broad or webbed neck, unusual chest shape with superior
      pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation
      defects, lymphatic dysplasias, and ocular abnormalities.
    explanation: >-
      GeneReviews describes the characteristic chest shape of Noonan syndrome, naming
      inferior pectus excavatum. Graded INDIRECT because it is a parent-entity statement
      rather than NRAS-specific.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "HP:0000767 | Pectus excavatum | Very frequent (99-80%)"
    explanation: >-
      Orphanet's HPO annotation table records pectus excavatum for Noonan syndrome.
      Graded INDIRECT because it annotates the parent entity, not the NRAS subtype.
- category: Growth
  name: Short Stature
  description: >-
    Postnatal growth restriction; birth length is usually normal and adult height
    approaches the lower limit of normal.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:19966803
    reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Noonan syndrome, a developmental disorder characterized by congenital heart defects,
      reduced growth, facial dysmorphism and variable cognitive deficits, is caused by
      constitutional dysregulation of the RAS-MAPK signaling pathway.
    explanation: >-
      Reduced growth is a defining feature of the disorder in the report establishing
      NRAS causation - but this sentence is the paper's background definition of Noonan
      syndrome as a whole rather than a finding about its NRAS cohort, so it is graded
      INDIRECT on the same basis as the GeneReviews parent-entity statements elsewhere
      in this entry.
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although birth length is usually normal, final adult height approaches the lower
      limit of normal.
    explanation: >-
      Characterizes the growth pattern of the parent entity. Graded INDIRECT because it
      is not NRAS-specific.
- category: Cardiovascular
  name: Congenital Heart Disease
  description: >-
    Congenital heart disease is a cardinal feature. Across NRAS cohorts hypertrophic
    cardiomyopathy is over-represented and pulmonic stenosis under-represented relative to
    mixed-genotype Noonan syndrome, though the denominators are small.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:19966803
    reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Noonan syndrome, a developmental disorder characterized by congenital heart defects,
      reduced growth, facial dysmorphism and variable cognitive deficits, is caused by
      constitutional dysregulation of the RAS-MAPK signaling pathway.
    explanation: >-
      Congenital heart defects are named as a defining feature in the report
      establishing NRAS causation - but this sentence is the paper's background
      definition of Noonan syndrome as a whole rather than a finding about its NRAS
      cohort, so it is graded INDIRECT on the same basis as the GeneReviews
      parent-entity statements elsewhere in this entry.
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart disease occurs in 50%-80% of individuals."
    explanation: >-
      GeneReviews quantifies congenital heart disease in Noonan syndrome. Graded
      INDIRECT because the figure is for the parent entity and the NRAS cohort's cardiac
      profile differs (hypertrophic cardiomyopathy over-represented, pulmonic stenosis
      under-represented).
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  description: >-
    Hypertrophic cardiomyopathy may be present at birth or develop in infancy or
    childhood; it is a principal determinant of prognosis and the target of the
    experimental MEK-inhibitor trials in RASopathies.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth
      or develop in infancy or childhood.
    explanation: >-
      GeneReviews documents hypertrophic cardiomyopathy in Noonan syndrome. Graded
      INDIRECT because the frequency cited is for the parent entity, not the NRAS
      subtype.
- category: Cardiovascular
  name: Pulmonic Stenosis
  description: >-
    Pulmonary valve stenosis, the commonest heart lesion in Noonan syndrome overall,
    occurs in NS6 but appears less prominent than in mixed-genotype cohorts.
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and
      is found in 20%-50% of individuals.
    explanation: >-
      GeneReviews documents pulmonary valve stenosis in Noonan syndrome. Graded INDIRECT
      because it is a parent-entity frequency, not NRAS-specific.
  - reference: PMID:33681212
    reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Importantly, the mutant embryos exhibited cardiac malformations resembling human
      congenital cardiac defects seen in NS patients, including ventricular septal defects,
      double outlet right ventricle, the hypertrabeculation/thin myocardium, and pulmonary
      valve stenosis.
    explanation: >-
      Activated Nras recapitulates pulmonary valve stenosis in a model organism. Graded
      INDIRECT because it is model-organism rather than human NS6 evidence.
- category: Cardiovascular
  name: Septal Defects
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other structural defects include atrial and ventricular septal defects, branch
      pulmonary artery stenosis, and tetralogy of Fallot.
    explanation: >-
      GeneReviews lists septal defects among the structural lesions of Noonan syndrome.
      Graded INDIRECT because it describes the parent entity.
- category: Neurologic
  name: Variable Developmental Delay and Cognitive Impairment
  description: >-
    Developmental and cognitive involvement in NS6 is variable, ranging from normal
    cognition through mild learning difficulty to, in one reported oncogenic-codon case,
    severe intellectual disability.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:19966803
    reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Noonan syndrome, a developmental disorder characterized by congenital heart defects,
      reduced growth, facial dysmorphism and variable cognitive deficits, is caused by
      constitutional dysregulation of the RAS-MAPK signaling pathway.
    explanation: >-
      Variable cognitive deficits are named as a defining feature in the report
      establishing NRAS causation - but this sentence is the paper's background
      definition of Noonan syndrome as a whole rather than a finding about its NRAS
      cohort, so it is graded INDIRECT on the same basis as the GeneReviews
      parent-entity statements elsewhere in this entry.
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype in our cohort was variable but well within the RASopathy spectrum.
    explanation: >-
      Documents the variable expressivity that characterizes the NRAS cohort.
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Up to one fourth of affected individuals have mild intellectual disability, and
      language impairments in general are more common in NS than in the general population.
    explanation: >-
      GeneReviews quantifies the cognitive and language involvement of Noonan syndrome.
      Graded INDIRECT because the figure is for the parent entity, not the NRAS subtype.
- category: Neurologic
  name: Severe Intellectual Disability
  description: >-
    Reported at the severe end of the NS6 spectrum in association with a germline
    oncogenic-codon (p.G12R) allele.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
    severity: SEVERE
  evidence:
  - reference: PMID:31697451
    reference_title: "NRAS associated RASopathy and embryonal rhabdomyosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present the case of a germline heterozygous NRAS mutation producing a severe
      phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and
      numerous melanocytic nevi in addition to more typical manifestations of Noonan
      syndrome.
    explanation: >-
      Single reported case documenting severe intellectual disability in NRAS-associated
      RASopathy. No frequency band is asserted: the report supplies no denominator, so the
      proportion of NS6 individuals reaching this severity cannot be estimated from it.
- category: Skin
  name: Hyperpigmented Cutaneous Lesions
  description: >-
    Hyperpigmented cutaneous lesions - lentigines and/or cafe-au-lait macules - are
    notably common in NRAS-positive Noonan syndrome and can prompt diagnostic confusion
    with Noonan syndrome with multiple lentigines. The 50% figure is the combined
    lentigines-and/or-CALM rate; neither component alone has been separately quantified.
  phenotype_term:
    preferred_term: Lentigines and/or cafe-au-lait macules
    term:
      id: HP:0001003
      label: Multiple lentigines
  frequency: FREQUENT
  evidence:
  - reference: PMID:26467218
    reference_title: "Mutation in NRAS in familial Noonan syndrome--case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, 50% of NS individuals with an NRAS mutation (including our family)
      present with lentigines and/or Café-au-lait spots. This demonstrates a predisposition
      to hyperpigmented lesions in NRAS-positive NS individuals.
    explanation: >-
      Directly quantifies hyperpigmented lesions in NRAS-positive Noonan syndrome at 50%,
      supporting the FREQUENT band (30-79%). The band is asserted for the composite
      lentigines-and/or-CALM concept the quote measures, not for lentigines alone - the
      separate cafe-au-lait entry below therefore carries no frequency of its own.
- category: Skin
  name: Cafe-au-lait Macules
  phenotype_term:
    preferred_term: Cafe-au-lait spot
    term:
      id: HP:0000957
      label: Cafe-au-lait spot
  evidence:
  - reference: PMID:26467218
    reference_title: "Mutation in NRAS in familial Noonan syndrome--case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This demonstrates a predisposition to hyperpigmented lesions in NRAS-positive NS
      individuals.
    explanation: >-
      Supports cafe-au-lait macules as part of the hyperpigmentation predisposition
      described in NRAS-positive Noonan syndrome.
- category: Skin
  name: Multiple Melanocytic Nevi
  description: Reported with a germline oncogenic-codon NRAS allele.
  phenotype_term:
    preferred_term: Melanocytic nevus
    term:
      id: HP:0000995
      label: Melanocytic nevus
  evidence:
  - reference: PMID:31697451
    reference_title: "NRAS associated RASopathy and embryonal rhabdomyosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe phenotype involving embryonal rhabdomyosarcoma, severe intellectual
      disability, and numerous melanocytic nevi
    explanation: >-
      Documents numerous melanocytic nevi in a germline NRAS RASopathy case.
- category: Auditory
  name: Hearing Impairment
  description: >-
    Congenital hearing deficit has been reported in a familial NRAS-positive Noonan
    syndrome case, contributing to overlap with Noonan syndrome with multiple lentigines.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:26467218
    reference_title: "Mutation in NRAS in familial Noonan syndrome--case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, the affected father in our family presented with a hearing deficit since
      birth, which together with lentigines are two characteristics of NS with multiple
      lentigines (previously LEOPARD syndrome), supporting the difficulties in diagnosing
      individuals with RASopathies correctly.
    explanation: >-
      Reports congenital hearing deficit in an NRAS-positive Noonan syndrome individual.
  - reference: PMID:41940405
    reference_title: "Targeted Clinical Analysis of PTPN11, SOS1, and NRAS Mutations and Associated Cardiac, Auditory, and Ophthalmologic Findings in Noonan Syndrome Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hearing loss was identified in 21.9% (7/32) of the cohort, with two PTPN11 and one
      NRAS mutation-positive patients affected.
    explanation: >-
      Independent clinical cohort in which the single NRAS mutation-positive patient was
      among those with hearing loss, corroborating this phenotype in the NRAS subtype.
- category: Neoplasia
  name: Embryonal Rhabdomyosarcoma
  description: >-
    Reported in an individual with a germline p.G12R NRAS allele; part of the tumor
    spectrum associated with germline alleles at classic oncogenic codons.
  phenotype_term:
    preferred_term: Embryonal rhabdomyosarcoma
    term:
      id: HP:0006743
      label: Embryonal rhabdomyosarcoma
  evidence:
  - reference: PMID:31697451
    reference_title: "NRAS associated RASopathy and embryonal rhabdomyosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present the case of a germline heterozygous NRAS mutation producing a severe
      phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and
      numerous melanocytic nevi in addition to more typical manifestations of Noonan
      syndrome.
    explanation: >-
      The defining case report of embryonal rhabdomyosarcoma in NRAS-associated RASopathy.
- category: Hematologic
  name: Myeloproliferative Disorder
  description: >-
    A myeloproliferative disorder was reported in a germline p.(Gly12Asp) carrier.
    Distinguishing constitutional NS6 from somatic NRAS-mutant myeloid neoplasia requires
    testing non-hematopoietic tissue.
  phenotype_term:
    preferred_term: Myeloproliferative disorder
    term:
      id: HP:0005547
      label: Myeloproliferative disorder
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative
      disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain
      tumour.
    explanation: >-
      Documents the single myeloproliferative disorder observed in the largest NRAS
      RASopathy cohort; 1 of the 19 cases described in that report is 5.3%, which maps to
      the OCCASIONAL band (5-29%).
- category: Neoplasia
  name: Brain Neoplasm
  description: An uncharacterized brain tumor was reported in a germline p.(Gly12Arg) carrier.
  phenotype_term:
    preferred_term: Brain neoplasm
    term:
      id: HP:0030692
      label: Brain neoplasm
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour
    explanation: >-
      Documents the brain tumor observed in a germline oncogenic-codon NRAS carrier; 1 of
      the 19 cases described in that report is 5.3%, which maps to the OCCASIONAL band
      (5-29%).
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings can include broad or webbed neck, unusual chest shape with superior
      pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation
      defects, lymphatic dysplasias, and ocular abnormalities.
    explanation: >-
      GeneReviews documents cryptorchidism in Noonan syndrome. Graded INDIRECT because
      it is a parent-entity statement.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "HP:0000028 | Cryptorchidism | Frequent (79-30%)"
    explanation: >-
      Orphanet's HPO annotation table records cryptorchidism for Noonan syndrome. Graded
      INDIRECT because it annotates the parent entity.
- category: Hematologic
  name: Bleeding Diathesis
  description: >-
    Varied coagulation defects occur in Noonan syndrome and should be characterized before
    surgery; aspirin is avoided because it may exacerbate the bleeding tendency.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings can include broad or webbed neck, unusual chest shape with superior
      pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation
      defects, lymphatic dysplasias, and ocular abnormalities.
    explanation: >-
      GeneReviews documents varied coagulation defects in Noonan syndrome. Graded
      INDIRECT because it is a parent-entity statement.
- category: Lymphatic
  name: Lymphatic Dysplasia
  description: >-
    Lymphatic dysplasias, including prenatal nuchal edema and chylous effusions, are part
    of the Noonan spectrum and are among the severe presentations for which MEK inhibition
    has been used off-label.
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular
      abnormalities
    explanation: >-
      GeneReviews documents lymphatic dysplasias in Noonan syndrome. Graded INDIRECT
      because it is a parent-entity statement.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "HP:0001004 | Lymphedema | Occasional (29-5%)"
    explanation: >-
      Orphanet's HPO annotation table records lymphedema for Noonan syndrome. Graded
      INDIRECT because it annotates the parent entity.
genetic:
- name: NRAS
  gene_term:
    preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  frequency: VERY_RARE
  notes: >-
    NRAS encodes the canonical small GTPase N-Ras. NS6 is caused by heterozygous germline
    missense gain-of-function variants; reported residues include Ile24, Thr50, Thr58,
    Gly60 and the classic somatic oncogenic codon Gly12. Cohort screens place NRAS at a
    very small share of molecularly solved Noonan syndrome (3/115 and 2/125 in two
    mutation-negative screening cohorts). ClinGen's RASopathy expert panel classifies the
    NRAS-Noonan syndrome relationship as Definitive with autosomal dominant inheritance.
    Constitutional status must be confirmed in non-hematopoietic tissue when an
    oncogenic-hotspot allele is found in blood during a myeloid-neoplasia workup.
  case_fractions:
  - population: >-
      Noonan syndrome probands negative for PTPN11, SOS1, RAF1 and KRAS
    case_fraction_percent: 2.6
    cohort_size: 115
    notes: 3 NRAS mutations identified in 3 of 115 previously mutation-negative probands.
    evidence:
    - reference: PMID:22855653
      reference_title: "NRAS Mutations in Noonan Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we performed mutation analysis of NRAS and SHOC2 in 115 PTPN11, SOS1, RAF1,
        and KRAS mutation-negative individuals. No SHOC2 mutations were found, but we
        identified 3 NRAS mutations in 3 probands.
      explanation: >-
        Gives the numerator and denominator for the NRAS share of this screening cohort.
  - population: >-
      French Noonan syndrome cohort negative for PTPN11, KRAS, SOS1, MEK1, MEK2, RAF1,
      BRAF and SHOC2
    case_fraction_percent: 1.6
    cohort_size: 125
    notes: The recurrent c.179G>A (p.G60E) allele found in 2 of 125 screened patients.
    evidence:
    - reference: PMID:22887781
      reference_title: "Constitutional NRAS mutations are rare among patients with Noonan syndrome or juvenile myelomonocytic leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report on the mutational analysis of NRAS in a cohort of 125 French patients
        with NS and no known mutation for PTPN11, KRAS, SOS1, MEK1, MEK2, RAF1, BRAF, and
        SHOC2. The c.179G>A (p.G60E) mutation was identified in two patients with typical
        NS, confirming that NRAS germline mutations are a rare cause of this syndrome.
      explanation: >-
        Gives the numerator and denominator for the NRAS share of this screening cohort.
  evidence:
  - reference: PMID:19966803
    reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report that germline NRAS mutations conferring enhanced stimulus-dependent
      MAPK activation account for some cases of this disorder.
    explanation: Establishes NRAS as a gain-of-function cause of Noonan syndrome.
  - reference: CGGV:assertion_34419b69-59c3-458b-a2a5-38a401679deb-2018-05-30T160000.000Z
    reference_title: "NRAS / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NRAS | HGNC:7989 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: >-
      ClinGen's RASopathy Gene Curation Expert Panel classifies the NRAS-Noonan syndrome
      relationship as Definitive with autosomal dominant inheritance.
  - reference: PMID:22855653
    reference_title: "NRAS Mutations in Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype associated with germline NRAS mutations is variable. Our results
      confirm that a small proportion of Noonan syndrome patients carry germline NRAS
      mutations.
    explanation: >-
      Supports both the rarity of the NRAS subtype and its variable expressivity.
inheritance:
- name: Autosomal Dominant
  description: >-
    NS6 is inherited in an autosomal dominant manner. Many cases arise de novo, but
    familial transmission with cosegregation is documented, and parental mosaicism has been
    reported — so recurrence risk after an apparently de novo case is not necessarily zero.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:26467218
    reference_title: "Mutation in NRAS in familial Noonan syndrome--case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The result revealed a recurrent mutation in NRAS, c.179G > A (p.G60E), in the index
      patient. This mutation was inherited from the index patient's father, who also showed
      signs of NS.
    explanation: >-
      Documents parent-to-child transmission of a heterozygous NRAS allele with affected
      status in both, consistent with autosomal dominant inheritance.
  - reference: CGGV:assertion_34419b69-59c3-458b-a2a5-38a401679deb-2018-05-30T160000.000Z
    reference_title: "NRAS / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NRAS | HGNC:7989 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen records autosomal dominant inheritance for the NRAS-Noonan relationship.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population prevalence estimate exists for NS6 specifically. Only a few dozen
    molecularly confirmed individuals have been reported; the largest single series added
    19 cases. The Noonan syndrome birth prevalence of roughly 1 in 1,000-2,500 belongs to
    the parent entity and must not be assigned to this subtype.
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A small number of RASopathy cases with disease-causing germline NRAS alterations have
      been reported.
    explanation: >-
      States that only a small number of germline NRAS RASopathy cases exist in the
      literature.
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS.
    explanation: Gives the size of the largest reported NRAS RASopathy series.
animal_models:
- name: Nras G12D pan-embryonic knock-in mouse (Mox2-Cre)
  species: Mouse
  genotype: NrasG12D/+ ; Mox2-Cre
  description: >-
    Conditional endogenous-locus activation of Nras throughout the embryo, producing
    cardiac malformations that mirror the congenital heart lesions of Noonan syndrome,
    with lethality from E15.5. Lineage-restricted crosses localize the requirement to the
    endothelial/endocardial compartment.
  publication: PMID:33681212
  evidence:
  - reference: PMID:33681212
    reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      At E13.5, NrasG12D/ + ; Mox2Cre/ + embryos displayed a moderate expansion of
      hematopoietic stem and progenitor cells without a significant impact on erythroid
      differentiation in the fetal liver.
    explanation: >-
      First-party characterization of what this specific model does and does not show,
      which is what establishes its scope as an informative system here.
  modeled_mechanisms:
  - target: Disrupted Embryonic Cardiac Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Activated Nras in the developing embryo produces septal, outflow-tract, myocardial
      and pulmonary-valve lesions matching the human Noonan cardiac spectrum, together
      with ERK pathway dysregulation in the mutant heart.
    limitations: >-
      G12D is an oncogenic somatic hotspot allele that is stronger than most human NS6
      alleles, and pan-embryonic expression is lethal by E15.5 — so the model cannot
      address the postnatal course. Human NS6 individuals with Gly12 alleles are reported
      but rare.
    readouts:
    - name: Cardiac morphology at E13.5-E15.5
      target: Disrupted Embryonic Cardiac Development
      direction: ALTERED
      interpretation: >-
        Structural cardiac malformations are the morphological correlate of the disrupted
        cardiac-development node.
      evidence:
      - reference: PMID:33681212
        reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Importantly, the mutant embryos exhibited cardiac malformations resembling human
          congenital cardiac defects seen in NS patients, including ventricular septal
          defects, double outlet right ventricle, the hypertrabeculation/thin myocardium,
          and pulmonary valve stenosis.
        explanation: Reports the histological/morphological cardiac measurement in this model.
    evidence:
    - reference: PMID:33681212
      reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we report that pan-embryonic expression of endogenous NrasG12D/ + by Mox2-Cre
        in mice caused embryonic lethality from embryonic day (E) 15.5 and developmental
        defects predominantly in the heart.
      explanation: >-
        Supports treating this model as informative for the cardiac-development node.
- name: Zebrafish N-Ras I24N / G60E overexpression embryo
  species: Zebrafish
  genotype: mRNA expression of human NRAS I24N or G60E
  description: >-
    Expression of Noonan-derived activating N-Ras mutants in zebrafish embryos produces
    gastrulation defects phenocopying those of other Noonan syndrome genes; MEK inhibition
    fully rescues them.
  publication: PMID:21263000
  evidence:
  - reference: PMID:21263000
    reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The defects in zebrafish embryos are reminiscent of symptoms in individuals with
      Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes
      induce in zebrafish embryos.
    explanation: >-
      Supports treating this zebrafish system as an informative model of Noonan syndrome,
      benchmarked against other Noonan genes in the same assay.
  modeled_mechanisms:
  - target: Disrupted Early Developmental Patterning
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Establishes that the human NS6 alleles are sufficient to derail early embryonic
      patterning, and that the effect is MAPK-dependent.
    limitations: >-
      Transient mRNA overexpression rather than an endogenous heterozygous knock-in, so
      dosage exceeds the human constitutional state; gastrulation defects are a zebrafish
      developmental readout, not a human NS6 clinical feature.
    readouts:
    - name: MEK-inhibitor rescue of gastrulation phenotype
      target: Disrupted Early Developmental Patterning
      direction: RESTORED
      interpretation: >-
        Complete rescue by MEK inhibition establishes that the patterning defect is
        mediated by the RAS-MAPK cascade.
      evidence:
      - reference: PMID:21263000
        reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          MEK inhibition completely rescued the activated N-Ras-induced phenotypes,
          demonstrating that these defects are mediated exclusively by Ras-MAPK signaling.
        explanation: Reports the rescue measurement behind this readout.
    evidence:
    - reference: PMID:21263000
      reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In conclusion, mutations in NRAS from individuals with Noonan syndrome activated
        N-Ras signaling and induced developmental defects in zebrafish embryos, indicating
        that activating mutations in NRAS cause Noonan syndrome.
      explanation: >-
        Supports treating this model as informative for the early-patterning node.
diagnosis:
- name: Molecular genetic testing of a RASopathy gene panel
  description: >-
    NS6 is a molecularly defined entity, so the diagnosis rests on identifying a
    heterozygous pathogenic NRAS variant in an individual with suggestive clinical
    findings. NRAS is one of the genes on the standard Noonan syndrome diagnostic panel;
    because NS6 is clinically indistinguishable from other Noonan subtypes, panel or
    exome testing rather than single-gene testing is the practical route.
  diagnosis_term:
    preferred_term: RASopathy gene-panel molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  notes: >-
    The NCIT term is generic; the preferred term records that diagnostic confirmation for
    this entry is detection of a pathogenic NRAS variant on a Noonan/RASopathy panel.
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Noonan is established in a proband with suggestive findings and a
      heterozygous pathogenic variant in BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1,
      RASA2, RIT1, RRAS2, SOS1, or SOS2 or either a heterozygous variant or biallelic
      pathogenic variants in LZTR1 identified by molecular genetic testing.
    explanation: >-
      GeneReviews names NRAS explicitly among the genes whose heterozygous pathogenic
      variants establish the diagnosis, which is what defines this entry's entity - so
      unlike the parent-entity clinical statements elsewhere in this file, this one is
      directly on point for NS6.
- name: Confirmation of constitutional (germline) origin in non-hematopoietic tissue
  description: >-
    Codons 12, 13 and 61 of NRAS are classic somatic hotspots in myeloid neoplasia, so an
    NRAS variant found in blood during a leukemia or myeloproliferative-disease workup does
    not by itself establish NS6. Constitutional status should be confirmed in a
    non-hematopoietic specimen (fibroblasts, buccal epithelium, nail, urine or saliva).
  diagnosis_term:
    preferred_term: germline confirmation testing on a non-hematopoietic specimen
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:22887781
    reference_title: "Constitutional NRAS mutations are rare among patients with Noonan syndrome or juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the 11 JMML patients for which germline DNA was available had a
      constitutional NRAS mutation.
    explanation: >-
      Demonstrates empirically that NRAS variants in myeloid disease are typically somatic
      rather than constitutional, which is why germline confirmation is a distinct
      diagnostic step for this entry.
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the observed germline variants differed from the typical oncogenic NRAS changes
      occurring as somatic events in tumours
    explanation: >-
      Frames the germline-versus-somatic distinction this diagnostic step addresses. The
      same report goes on to show the distinction is not absolute (four germline Gly12
      carriers).
- name: Baseline cardiac evaluation
  description: >-
    Echocardiographic assessment at diagnosis, with continued surveillance, because
    congenital heart disease is present in most affected individuals and hypertrophic
    cardiomyopathy may appear after infancy.
  diagnosis_term:
    preferred_term: echocardiographic evaluation
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In children age <5 years: if initial cardiac evaluation is normal, at least annual
      cardiac evaluations until age 5 years.
    explanation: >-
      GeneReviews surveillance guidance underpinning baseline and repeat cardiac
      assessment. Graded INDIRECT because it is written for the parent entity.
treatments:
- name: Recombinant Growth Hormone (Somatropin) Therapy
  description: >-
    Growth hormone treatment increases growth velocity in Noonan syndrome and is used for
    the short stature of the syndrome. It is not NRAS-specific: no NS6 subgroup outcome
    data exist.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Growth hormone (GH) treatment increases growth velocity."
    explanation: >-
      GeneReviews supports growth hormone therapy in Noonan syndrome. Graded INDIRECT
      because the recommendation is for the parent entity, not the NRAS subtype.
- name: MEK Inhibition (Trametinib, Experimental/Off-Label)
  description: >-
    MEK1/2 inhibition targets the step of the RAS-MAPK cascade immediately downstream of
    the activated N-Ras protein, and MEK inhibition fully rescues the developmental
    phenotypes of Noonan-associated N-Ras mutants in zebrafish. In humans it remains
    off-label and experimental, used in case reports for severe cardiac and lymphatic
    disease in Noonan syndrome; no NS6-specific outcome data exist and long-term follow-up
    is unavailable.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Targeted Therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: trametinib
      term:
        id: NCIT:C77908
        label: Trametinib
  target_mechanisms:
  - target: RAS-MAPK Cascade Hyperactivation
    treatment_effect: INHIBITS
    description: >-
      MEK1/2 inhibition blocks signal flow through the hyperactivated cascade downstream of
      the mutant N-Ras protein.
    evidence:
    - reference: PMID:21263000
      reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        MEK inhibition completely rescued the activated N-Ras-induced phenotypes,
        demonstrating that these defects are mediated exclusively by Ras-MAPK signaling.
      explanation: >-
        Establishes MEK as the actionable node downstream of Noonan-associated activated
        N-Ras.
  evidence:
  - reference: PMID:40041314
    reference_title: "Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A short-term improvement of symptoms was reported in all cases, with three deaths
      presumably unrelated to trametinib. Moderate side effects were reported in a subset
      of patients. Long-term follow-up data were not available.
    explanation: >-
      Systematic review of off-label trametinib in severe Noonan syndrome. Graded
      INDIRECT because the collected cases are Noonan syndrome generally (the index case
      was PTPN11), not NRAS-associated NS6.
  - reference: PMID:40041314
    reference_title: "Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No formal clinical trial of trametinib in neonatal/pediatric Noonan syndrome has been
      published to our knowledge.
    explanation: >-
      Records the experimental status of this therapy. Graded INDIRECT for the same
      reason as above.
- name: Cardiac Surveillance and Management
  description: >-
    Cardiovascular anomalies are treated as in the general population, with scheduled
    echocardiographic surveillance because hypertrophic cardiomyopathy may appear after
    infancy.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiovascular anomalies in NS are usually treated as in the general population."
    explanation: >-
      GeneReviews management guidance for the parent entity. Graded INDIRECT because it
      is not NRAS-specific.
- name: Perioperative Bleeding Assessment and Avoidance of Aspirin
  description: >-
    Because varied coagulation defects occur, bleeding history and coagulation testing are
    assessed before surgery, and aspirin therapy is avoided as it may exacerbate the
    bleeding diathesis.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Aspirin therapy should be avoided because it may
      exacerbate a bleeding diathesis.
    explanation: >-
      GeneReviews drug-safety warning for Noonan syndrome. Graded INDIRECT because it
      applies to the parent entity.
- name: Genetic Counseling
  description: >-
    Counseling covers the 50% transmission risk from an affected parent, the predominance
    of de novo events, and the residual recurrence risk from parental mosaicism.
    Constitutional versus somatic origin must be clarified when an oncogenic-hotspot NRAS
    allele is detected in blood.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with autosomal dominant NS has a 50% chance of inheriting
      the pathogenic variant.
    explanation: >-
      GeneReviews recurrence-risk statement underpinning counseling. Graded INDIRECT
      because it is a parent-entity statement.
clinical_trials:
- name: NCT06555237
  phase: PHASE_II
  status: RECRUITING
  description: >-
    MEKinRAS - randomized controlled trial of trametinib added to standard therapy versus
    standard therapy alone for hypertrophic cardiomyopathy in patients with a molecularly
    confirmed RASopathy. Eligibility is defined by a RAS-MAPK pathway variant plus HCM
    rather than by a clinical Noonan syndrome diagnosis, so an individual with NS6 and HCM
    is eligible; no NRAS subgroup outcome is planned or reported.
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT06555237
    reference_title: "MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies (MEKinRAS) - Randomized Controlled Trial"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The goal of this study is to evaluate the effectiveness of trametinib treatment in
      patients with Hyperthropic cardiomyopathy and a genetic mutation in the RAS/MAPK
      pathway.
    explanation: >-
      The registered objective substantiates the experimental MEK-inhibition treatment
      curated in this entry and admits NS6 patients by molecular criteria. Graded
      INDIRECT because enrolment spans the RASopathies and no NRAS-specific result
      exists.
discussions:
- discussion_id: ns6_oncogenic_codon_tumor_risk
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do germline NRAS alleles at the classic oncogenic codons (Gly12, and by extension
    Gly13/Gln61) carry a quantitatively higher tumor risk than the non-hotspot NS6 alleles,
    and how large is that risk?
  rationale: >-
    The published NRAS RASopathy series are small (tens of individuals), and the tumor
    events reported in Gly12 carriers - a myeloproliferative disorder, an uncharacterized
    brain tumor, and an embryonal rhabdomyosarcoma - are individual observations. The
    codon-dependent risk pattern is asserted from case-level pattern recognition, not from
    a cohort with denominators, while a separate familial report finds JMML risk in
    NRAS-positive Noonan syndrome no different from Noonan syndrome generally. Getting this
    wrong in either direction has direct surveillance consequences.
  attaches_to:
  - pathophysiology#Oncogenic-Codon Germline Alleles and Tumor Predisposition
  evidence:
  - reference: PMID:31697451
    reference_title: "NRAS associated RASopathy and embryonal rhabdomyosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      analysis of previously reported NRAS-RASopathy cases suggests that mutations at
      traditionally oncogenic codons are associated with elevated cancer risk not present
      with mutations at other sites
    explanation: >-
      The codon-dependent risk claim is explicitly hedged as a suggestion from reanalysis
      of previously reported cases, which is the gap this discussion records.
  - reference: PMID:26467218
    reference_title: "Mutation in NRAS in familial Noonan syndrome--case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the risk for NS individuals with a germline NRAS mutation developing JMML is not
      different from the proportion seen in other NS cases
    explanation: >-
      Countervailing report finding no elevated JMML risk in NRAS-positive Noonan syndrome,
      which is why the tumor-risk question is recorded as open rather than settled.
  proposed_experiments:
  - experiment_id: ns6_genotype_stratified_tumor_incidence
    name: Genotype-stratified tumor-incidence study across an international NS6 registry
    description: >-
      Pool NRAS-positive Noonan syndrome individuals internationally, stratify by hotspot
      versus non-hotspot codon, and compute age-adjusted tumor incidence with explicit
      denominators and person-years of follow-up.
- discussion_id: ns6_animal_model_allele_strength
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Do the available NRAS animal models faithfully represent human NS6, given that both
    use alleles or dosages stronger than the typical human constitutional lesion?
  rationale: >-
    The mouse model uses the oncogenic G12D allele expressed pan-embryonically and is
    lethal by E15.5, so it cannot model the postnatal NS6 course; the zebrafish model uses
    transient mRNA overexpression of human mutants rather than an endogenous heterozygous
    locus. Both give a clear MAPK-dependent developmental phenotype, but the quantitative
    relationship between their signalling gain and that of a human NS6 heterozygote is
    unknown - which matters directly for interpreting the MEK-inhibitor rescue as a
    therapeutic rationale.
  attaches_to:
  - pathophysiology#Disrupted Embryonic Cardiac Development
  - pathophysiology#Disrupted Early Developmental Patterning
  evidence:
  - reference: PMID:33681212
    reference_title: "Embryonic Expression of Nras(G 12 D) Leads to Embryonic Lethality and Cardiac Defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, oncogenic NrasG12D mutation may not be compatible with embryonic survival.
    explanation: >-
      The authors' own conclusion that the modelled allele is embryonic-lethal is precisely
      the translational mismatch with living human NS6 individuals that this discussion records.
  - reference: PMID:21263000
    reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V,
      which we included as a positive control, results in developmental defects in
      zebrafish embryos
    explanation: >-
      The zebrafish readout comes from injected expression benchmarked against a strongly
      activating positive control, not from an endogenous heterozygous locus - the dosage
      mismatch this discussion records.
  proposed_experiments:
  - experiment_id: ns6_endogenous_knockin_mouse
    name: Endogenous-locus heterozygous knock-in of a human NS6 allele
    description: >-
      Generate mice carrying a heterozygous knock-in of a non-hotspot human NS6 allele
      (e.g. Nras G60E) at the endogenous locus, and assess viability, cardiac phenotype,
      growth and craniofacial morphology against the G12D model.
notes: >-
  Scope note: NS6 is a molecularly defined subtype of Noonan syndrome. Clinical features
  shared with the parent entity are curated here with GeneReviews (PMID:20301303) evidence
  carrying directness: INDIRECT, because those statements characterize Noonan syndrome as
  a whole rather than the NRAS subtype and so reach NS6 through the parent entity;
  NRAS-specific claims are cited to the primary NRAS literature. See
  the Noonan Syndrome entry for the full parent-disorder picture. Detailed NRAS-cohort
  phenotype frequencies published by Altmuller et al. (PMID:28594414) sit in the paywalled
  full text rather than the abstract, so they are not asserted here as evidence-backed
  frequency bands. The statement that hypertrophic cardiomyopathy is over-represented and
  pulmonic stenosis under-represented relative to mixed-genotype Noonan syndrome likewise
  rests on that full-text cohort table and is carried as descriptive prose only, never as a
  frequency band. Also deliberately absent: a `datasets:` block (dataset discovery for this
  entry returns only somatic NRAS-mutant cancer series reached by gene-only matching - the
  Named Entity Confusion trap, not germline NS6 data) and most of the trials surfaced for this
  disorder (the growth hormone studies NCT01529840, NCT00452725, NCT03435627, the
  Norditropin registry NCT05308927 and the vosoritide study NCT06668805 all enrol Noonan
  syndrome generally, with no NRAS subgroup, and belong on the umbrella entry). The one
  curated exception is NCT06555237 (MEKinRAS), which selects on a molecularly confirmed
  RAS-MAPK variant plus hypertrophic cardiomyopathy rather than on a clinical Noonan
  syndrome diagnosis, and so admits NS6 by genotype and substantiates this entry's own
  experimental trametinib treatment.
📚

References & Deep Research

References

1
PMID:20301303
Noonan Syndrome.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 29 citations 2026-08-18T09:34:13.447830

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Noonan Syndrome 6
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Noonan Syndrome 6 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Noonan Syndrome 6 (NRAS-associated Noonan syndrome): comprehensive disease-characteristics report

Executive summary and evidence boundaries

Noonan syndrome 6 (NS6) is a very rare, congenital Mendelian RASopathy caused by heterozygous constitutional activating variants in NRAS. It is best regarded as the NRAS-defined molecular subtype of Noonan syndrome, although severe individuals may overlap clinically with cardiofaciocutaneous syndrome (CFCS) or Costello syndrome. The strongest subtype-specific evidence remains a 2017 international series of 19 newly described individuals; consequently, precise prevalence, penetrance, survival, and treatment-response estimates are unavailable. Broader Noonan-syndrome data are useful for care but must not be represented as NRAS-specific evidence. (altmuller2017genotypeandphenotype pages 1-2, altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 4-5)

The following compact table separates subtype-specific findings from broader Noonan-syndrome evidence.

Domain NRAS-specific finding for Noonan syndrome 6 General Noonan syndrome context Key citation(s) Caveats
Entity / identifiers Noonan syndrome 6 is the NRAS-associated RASopathy; Open Targets maps MONDO:0013186 to NRAS with supporting literature including PubMed-linked evidence General NS is a broader clinical syndrome with multiple RAS/MAPK genes Open Targets MONDO_0013186→NRAS association (OpenTargets Search: Noonan syndrome 6-NRAS) MONDO supported here; OMIM/Orphanet identifiers were not directly retrieved in tool context and should be externally verified before KB ingestion
Causal gene & inheritance NRAS heterozygous germline variants cause NS6; cohort included de novo and familial cases with segregation in 4 families; variants confirmed in non-hematopoietic tissues, supporting constitutional origin NS is usually autosomal dominant, with rare recessive exceptions for some non-NRAS genes Altmüller et al., 2017, Eur J Hum Genet, DOI:10.1038/ejhg.2017.65 (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 4-5); general NS inheritance/prevalence review (perrino2024updateonpediatric pages 6-8) Penetrance for NRAS-specific NS6 is not precisely quantified; expressivity is clearly variable
Strongest NRAS-specific cohort Largest directly retrieved NRAS cohort: 19 affected individuals from 13 unrelated families (9 males, 10 females; median age 7.1 y, range 3 months–50 y); majority had clinical NS (15/19), with some CFCS/CS overlap Recent broader NS cohorts are much larger but are not NRAS-specific Altmüller et al., 2017 (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 4-5) This remains a small rare-disease cohort; some percentages exclude a complex outlier case from aggregate tables
Hallmark phenotype frequencies Craniofacial/RASopathy-like features in all assessed subjects; short/webbed neck 94%, ocular ptosis 82%, cardiac anomalies 59%, HCM 35%, septal defects 12%, pulmonary stenosis 6%, motor delay 38%, intellectual/learning disabilities 42%, prenatal abnormalities 69% (polyhydramnios 46%, nuchal edema 15%, fetal chylothorax/hydrops 23%), cryptorchidism 63% of males, bleeding diathesis 3/15 with one confirmed von Willebrand disease In broader NS, pulmonary valve stenosis is typically much more common than in NRAS cases; one recent general NS series found cardiac defects 71.5%, pulmonary valve stenosis 48.3%, short stature 43.1% NRAS cohort frequencies (altmuller2017genotypeandphenotype pages 4-5, altmuller2017genotypeandphenotype pages 8-9); broader NS comparison (reynolds2025updateonthe pages 9-10, reynolds2025updateonthe pages 1-2) NRAS phenotype can overlap CFCS/Costello-like presentations, especially with Gly12 variants; frequency estimates remain imprecise because of low n
Molecular mechanism Germline activating NRAS variants dysregulate RAS-MAPK and PI3K-AKT signaling. Functional studies showed NRAS p.Thr58Ile and p.Gly12Val increase ERK and AKT phosphorylation even without stimulation; p.Thr58Ile shifts protein toward active GTP-bound state, though less strongly than oncogenic p.Gly12Val General NS is a pathway disease of RAS/MAPK hyperactivation across multiple genes Altmüller et al., 2017 mechanistic assays in HEK293T cells (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 7-8, altmuller2017genotypeandphenotype pages 5-7) Mechanistic evidence is strong for selected variants, but not all NS6 variants have equally detailed functional characterization
Diagnosis Best-supported approach is clinical suspicion of a RASopathy phenotype plus molecular confirmation of an NRAS germline variant; WES identified at least one atypical/costello-like case, and constitutional status was confirmed in skin fibroblasts, nail keratinocytes, buccal cells, urine, or saliva when needed General NS diagnosis increasingly relies on multigene RASopathy panels / exome sequencing; disease genes include PTPN11, SOS1, RAF1, RIT1, LZTR1, KRAS, SOS2, NRAS, RRAS, RRAS2, MRAS, SPRED2 NRAS-specific diagnostic examples (altmuller2017genotypeandphenotype pages 4-5, altmuller2017genotypeandphenotype pages 5-7); general NS gene list and diagnostic framing (perrino2024updateonpediatric pages 6-8) No NRAS-specific formal clinical criteria were retrieved; differential diagnosis includes other RASopathies, especially CFCS and Costello syndrome
Management No NRAS-specific management guideline was retrieved; current care is extrapolated from general NS multidisciplinary management with attention to cardiology, growth, neurodevelopment, feeding, lymphatic issues, and hematologic abnormalities when present General NS data support genotype-guided care; rGH used in a subset of NS patients and is not generally contraindicated when clinically indicated General NS management summaries (reynolds2025updateonthe pages 18-20, reynolds2025updateonthe pages 9-10, reynolds2025updateonthe pages 1-2) Evidence for NS6-specific outcome modification is lacking; management remains largely supportive and organ-directed
Cancer surveillance NRAS cohort reported 2 neoplastic/hematologic events: JMML-like myeloproliferative disorder with p.Gly12Asp and an uncharacterized brain tumor/hypothalamic lesion with p.Gly12Arg; authors state more data are needed to define malignancy risk in germline oncogenic NRAS carriers Updated NS guidance: childhood cancer risk is about 8-fold above general population, but routine CBC surveillance is not recommended for otherwise healthy NS; focus on clinical exam, especially hepatosplenomegaly in infancy/early childhood, and family education about tumor symptoms NRAS-specific tumor observations (altmuller2017genotypeandphenotype pages 1-2, altmuller2017genotypeandphenotype pages 7-8, altmuller2017genotypeandphenotype pages 8-9); general surveillance update 2024 (perrino2024updateonpediatric pages 8-10, perrino2024updateonpediatric pages 6-8) Surveillance recommendations are general NS, not validated specifically for NRAS NS6; absolute cancer risk for NS6 remains undefined
Active trials / real-world implementation No active NRAS-only interventional trial was retrieved General NS trials include NCT05308927 Norditropin registry (observational, enrolling by invitation, est. n=221), NCT06668805 vosoritide Phase 2 (recruiting, n=30), NCT06555237 trametinib/MEK inhibitor for RASopathy HCM Phase 2 (recruiting, n=40), plus completed somatropin studies NCT01529840, NCT00452725, and post-marketing surveillance NCT03435627 Trial records (NCT05308927 chunk 1, NCT06668805 chunk 1, NCT03435627 chunk 1, NCT06555237 chunk 1) These studies enroll broader NS/RASopathy populations; applicability to NS6 is indirect unless genotype-specific subgroup analyses are reported

Table: This table summarizes the highest-yield disease knowledge-base facts for Noonan syndrome 6, emphasizing directly retrieved NRAS-specific evidence and clearly separating it from broader Noonan syndrome data. It is useful as a compact curation aid for identifiers, phenotype, mechanism, surveillance, and currently active clinical studies.

Evidence labels used below: Human–NRAS = patients with constitutional NRAS variants; Human–general NS = mixed-genotype Noonan syndrome; in vitro = transfected-cell functional evidence; registry = ClinicalTrials.gov. Ontology identifiers proposed below should be validated against the current ontology release before production ingestion.

1. Disease information

Definition and identifiers

  • Preferred name: Noonan syndrome 6.
  • Synonyms: NRAS-associated Noonan syndrome; NRAS-related Noonan syndrome; NRAS-associated RASopathy. “NRAS-associated RASopathy” is broader because a few individuals were clinically classified as CFCS- or Costello-like.
  • MONDO: MONDO:0013186. Open Targets maps this disease directly to NRAS (Ensembl ENSG00000213281) with five supporting association records. (OpenTargets Search: Noonan syndrome 6-NRAS)
  • OMIM: commonly catalogued as Noonan syndrome 6, 613224; the umbrella Noonan syndrome entry is 163950. The retrieved primary article explicitly identifies general NS as OMIM 163950, but the subtype number should be independently checked against the current OMIM record before automated ingestion. (altmuller2017genotypeandphenotype pages 1-2)
  • MeSH: D009634, Noonan Syndrome; there is no separate MeSH descriptor for NS6. The trial registry maps Noonan syndrome to D009634. (NCT06555237 chunk 1)
  • Orphanet: generally represented under the umbrella Noonan-syndrome/RASopathy concept rather than a well-supported subtype-specific identifier in the retrieved evidence.
  • ICD-10/ICD-11: subtype-specific codes were not established in the retrieved sources. NS is generally coded at syndrome level; local coding systems should not infer an NRAS-specific code.

The evidence is principally aggregated disease-level literature assembled from individually phenotyped patients, not an EHR-derived population dataset. The principal study included 19 individuals from 13 unrelated families, nine males and ten females, median age 7.1 years (range 3 months–50 years). Fifteen had a clinical NS diagnosis, two CFCS, and one an initially suspected Costello phenotype. (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 4-5)

Primary-paper abstract quote: “Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS.” The authors further state that “the phenotype in our cohort was variable but well within the RASopathy spectrum.” Published online 3 May 2017, DOI: 10.1038/ejhg.2017.65. (altmuller2017genotypeandphenotype pages 1-2)

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

NS6 is caused by germline/constitutional heterozygous activating NRAS variants. Both proven de novo variants and familial cosegregation occur. Variants were confirmed in nonhematopoietic specimens—including fibroblasts, buccal epithelium, nail keratinocytes, urine, or saliva—to distinguish constitutional disease from somatic NRAS-mutant hematologic neoplasia. (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 4-5, altmuller2017genotypeandphenotype pages 5-7)

Genetic risk factors

Reported pathogenic residues include Gly12, Ile24, Glu37, Thr50, Thr58, and Gly60. The 2017 cohort reported c.34G>C p.(Gly12Arg), c.35G>A p.(Gly12Asp), c.34G>A p.(Gly12Ser), c.35G>T p.(Gly12Val), c.112-1_113dupGGA p.(Glu37dup), c.173C>T p.(Thr58Ile), c.71T>A p.(Ile24Asn), c.149C>T p.(Thr50Ile), and c.179G>A p.(Gly60Glu). Four Gly12 substitutions were proven de novo. (altmuller2017genotypeandphenotype pages 3-4)

Genotype may influence severity: p.Gly12Val was associated with progressive fetal hydrops and intrauterine death at 22 weeks; p.Gly12Asp occurred with a JMML-like myeloproliferative disorder; and p.Gly12Arg produced a severe neonatal Costello-like presentation with HCM, feeding/airway problems, and a hypothalamic lesion. These are single-case observations, not validated risk estimates. (altmuller2017genotypeandphenotype pages 7-8, altmuller2017genotypeandphenotype pages 4-5, altmuller2017genotypeandphenotype pages 5-7)

Environmental and protective factors

No environmental toxin, infection, diet, lifestyle exposure, occupational factor, or protective allele has been shown to cause or prevent NS6. Parental age, sex, ethnicity, and geography are not established modifiers. Environmental care can modify outcome, however—for example, timely treatment of cardiac disease, feeding problems, developmental needs, and lymphatic complications—but does not remove the underlying variant.

A possible modifier was observed in one severely affected patient with a second 1.24-Mb 22q11.23 duplication plus hypoxic–ischemic injury; the authors excluded that patient from aggregate statistics because these factors likely increased neurodevelopmental severity. This is evidence for blended genetic/acquired modification, not a reproducible NRAS-specific gene–environment interaction. (altmuller2017genotypeandphenotype pages 5-7)

3. Phenotypes

NRAS-specific frequencies

Phenotype and type NRAS-specific characterization Suggested HPO term
RASopathy facial appearance/sign Present in all assessed subjects; congenital, age-dependent appearance; variable HP:0001999 Abnormal facial shape; more granular terms include hypertelorism and ptosis
Short/broad or webbed neck/sign 94%; congenital, generally persistent HP:0000465 Webbed neck; HP:0000470 Short neck
Ptosis/sign 82%; congenital/childhood HP:0000508 Ptosis
Congenital heart disease/sign 59% (10/17); severity variable HP:0001627 Abnormal heart morphology
Hypertrophic cardiomyopathy/sign 35%; congenital or early childhood; course variable HP:0001639 Hypertrophic cardiomyopathy
Septal defect/sign 12% HP:0001631 Atrial septal defect; HP:0001629 Ventricular septal defect
Pulmonary stenosis/sign 6%, notably lower than typical mixed-genotype NS HP:0001642 Pulmonic stenosis
Short stature/sign 27% (4/15) in the new cohort; a broader aggregation reported approximately 42% HP:0004322 Short stature
Motor delay/sign 38–39%, usually mild but variable HP:0001270 Motor delay
Intellectual/learning difficulty 42% in the new cohort; often mild; broader aggregation reported learning disability around 27% HP:0001249 Intellectual disability; HP:0001328 Specific learning disability
Prenatal abnormality 69%; polyhydramnios 46%, nuchal edema 15%, fetal chylothorax/hydrops 23% HP:0001561 Polyhydramnios; HP:0001789 Hydrops fetalis; HP:0010880 Increased nuchal translucency
Cryptorchidism/sign 63% of affected males HP:0000028 Cryptorchidism
Bleeding tendency/laboratory-clinical 3/15 reported; only one confirmed coagulopathy (von Willebrand disease) HP:0001892 Abnormal bleeding; HP:0005541 von Willebrand disease
Feeding difficulty/symptom Variable; occasionally severe, requiring gastrostomy HP:0011968 Feeding difficulties
Hypotonia/sign Variable; sometimes profound in severe/overlap cases HP:0001252 Hypotonia
Ectodermal findings/sign Curly or sparse hair, keratosis pilaris, nevi, or café-au-lait macules in some cases HP:0002212 Curly hair; HP:0001007 Hirsutism is not appropriate unless documented; use exact skin/hair terms
Renal/urinary anomaly/sign Hydronephrosis, duplex system, ureteroceles in individual cases HP:0000126 Hydronephrosis; HP:0000072 Hydroureter
Tumor/hematologic abnormality One JMML-like disorder and one brain lesion among 19 new patients HP:0004376 Neoplasm; HP:0012209 Juvenile myelomonocytic leukemia

These figures derive from small denominators and should be stored with numerator/denominator and study provenance rather than treated as stable population frequencies. (altmuller2017genotypeandphenotype pages 8-8, altmuller2017genotypeandphenotype pages 4-5, altmuller2017genotypeandphenotype pages 8-9)

Quality of life

No NS6-specific EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life study was retrieved. Expected burdens include cardiac follow-up, short stature, feeding and airway support, learning assistance, surgery, and anxiety regarding malignancy. These are clinically plausible impacts, but quantitative QoL values should not be assigned. The current French Norditropin registry is prospectively collecting HRQoL and educational/rehabilitation information for general NS, potentially improving future evidence. (NCT05308927 chunk 1)

4. Genetic and molecular information

  • Causal gene: NRAS, NRAS proto-oncogene, GTPase; Ensembl ENSG00000213281. Open Targets reports a disease–target association score of 0.8066. (OpenTargets Search: Noonan syndrome 6-NRAS)
  • Variant class: principally heterozygous missense gain-of-function variants; p.Glu37dup is an in-frame duplication affecting the switch-I region.
  • Origin: constitutional germline; many cases are de novo, while familial autosomal-dominant transmission and parental mosaicism occur. One apparently unaffected father was mosaic for p.Thr58Ile. (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 5-7)
  • Functional consequence: increased active GTP-bound NRAS and excessive signaling through RAF–MEK–ERK and PI3K–AKT. Gly12 substitutions impair intrinsic GTPase activity and confer resistance to GTPase-activating proteins, maintaining NRAS in its active state. (altmuller2017genotypeandphenotype pages 7-8, altmuller2017genotypeandphenotype pages 3-4)
  • Population frequency: pathogenic constitutional variants are exceptionally rare and are expected to be absent or nearly absent from population databases. Exact contemporary gnomAD frequencies were not retrieved and must be checked variant by variant.
  • Classification: the cited variants were treated as disease-causing in the primary study, supported by de novo occurrence/cosegregation, conservation, phenotype, hotspot location, and selected functional assays. Current ClinVar assertions and ACMG classifications should be independently retrieved for each HGVS allele; do not automatically classify every somatic oncogenic NRAS variant as a constitutional NS6 allele.
  • Somatic versus germline: codons 12, 13, and 61 are classic somatic cancer hotspots. A variant detected only in blood during leukemia evaluation must not establish NS6; testing of nonhematopoietic tissue may be required. (altmuller2017genotypeandphenotype pages 7-8, altmuller2017genotypeandphenotype pages 4-5)
  • Chromosomal/epigenetic findings: no recurrent NS6-causing structural chromosome abnormality or validated NRAS-specific episignature was identified. No established modifier gene exists; the 22q11.23 duplication in one patient is a candidate individual modifier, not a general association. (altmuller2017genotypeandphenotype pages 5-7)

5. Environmental information

NS6 is not infectious, toxic, nutritional, occupational, or lifestyle-induced. Smoking, alcohol, diet, exercise, pollutants, radiation, and pathogens have no demonstrated etiologic role. Standard healthy-lifestyle counseling remains appropriate for cardiovascular health but is not primary disease prevention. There is no zoonotic or person-to-person transmission.

6. Mechanism and pathophysiology

Causal chain

  1. A constitutional activating NRAS allele alters a highly conserved GTPase residue.
  2. Impaired GTP hydrolysis/GAP responsiveness or altered switch-region kinetics increases GTP-bound NRAS.
  3. Upstream-to-downstream signal flow is enhanced through RAF–MEK–ERK/MAPK and, for tested variants, PI3K–AKT.
  4. Dysregulated proliferation, differentiation, survival, developmental patterning, and possibly metabolism affect multiple embryonic tissues.
  5. Developmental consequences include craniofacial dysmorphism, cardiac and lymphatic malformation, altered growth, neurodevelopmental differences, and ectodermal findings; excessive hematopoietic signaling can produce MPD/JMML-like disease. (altmuller2017genotypeandphenotype pages 7-8, altmuller2017genotypeandphenotype pages 1-2, altmuller2017genotypeandphenotype pages 3-4)

In HEK293T transfection experiments, both NRAS-p.Thr58Ile and NRAS-p.Gly12Val increased ERK and AKT phosphorylation without EGF stimulation; p.Thr58Ile increased GTP-bound NRAS less strongly than p.Gly12Val. This is direct in-vitro functional evidence, not a patient-tissue multi-omics result. (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 5-7)

Suggested GO biological processes: GO:0000165 MAPK cascade; GO:0007265 Ras protein signal transduction; GO:0043408 regulation of MAPK cascade; GO:0008284 positive regulation of cell population proliferation; GO:0001525 angiogenesis; GO:0001944 vasculature development; GO:0007507 heart development; GO:0060429 epithelium development; GO:0007399 nervous system development. GO cellular components: plasma membrane, cytosol, and endomembrane-associated signaling compartments; mature NRAS is membrane-associated.

Candidate cell types (not proven NS6-specific targets): cardiomyocyte (CL:0000746), endocardial/endothelial cells, lymphatic endothelial cell (CL:0002138), neural progenitor, neuron (CL:0000540), hematopoietic stem/progenitor cell, monocyte (CL:0000576), chondrocyte (CL:0000138), and fibroblast (CL:0000057).

No NS6-specific patient transcriptomics, proteomics, metabolomics, lipidomics, single-cell sequencing, spatial transcriptomics, CRISPR screen, or integrated multi-omics study was retrieved. Mitochondrial/metabolic effects described for broader RASopathies should not be asserted as established NS6 mechanisms.

7. Anatomical structures affected

Primary systems are cardiovascular, craniofacial/connective-tissue, lymphatic, musculoskeletal/growth, nervous, ocular, skin/hair, genitourinary, and hematopoietic. Relevant structures include myocardium (UBERON:0002349), heart valves, cardiac septa, pulmonary artery, lymphatic vasculature (UBERON:0004537), brain (UBERON:0000955), eye (UBERON:0000970), kidney (UBERON:0002113), testis (UBERON:0000473), skeleton, skin (UBERON:0002097), and bone marrow (UBERON:0002371). No consistent lateralization is known. (altmuller2017genotypeandphenotype pages 4-5, altmuller2017genotypeandphenotype pages 5-7)

At the subcellular level, dysfunction begins at membrane-associated NRAS signaling and propagates through cytoplasmic kinase cascades to nuclear transcriptional programs. The disease is not primarily a lysosomal, mitochondrial, ER-storage, or ion-channel disorder.

8. Temporal development

NS6 begins prenatally/congenitally. Prenatal presentations range from polyhydramnios or nuchal edema to chylothorax and lethal hydrops. Cardiac defects, facial appearance, neck/chest morphology, feeding difficulty, and cryptorchidism are generally congenital; short stature and learning differences become clearer during childhood. (altmuller2017genotypeandphenotype pages 4-5)

The course is chronic and lifelong but not uniformly progressive. Some neonatal problems improve: one p.Gly12Arg child had tracheostomy removal at 20 months and caught up in motor development. HCM, lymphatic disease, and neurodevelopmental outcomes vary, while a JMML-like MPD may remain stable or potentially resolve; malignant transformation cannot be predicted from the available NRAS cohort. (altmuller2017genotypeandphenotype pages 7-8, altmuller2017genotypeandphenotype pages 5-7, perrino2024updateonpediatric pages 8-10)

Critical periods are prenatal life, infancy for severe cardiac/lymphatic disease and MPD, early childhood for developmental intervention and malignancy awareness, and transition to adult cardiac and reproductive care. No formal NS6 staging or remission classification exists.

9. Inheritance and population

  • Inheritance: autosomal dominant.
  • Recurrence: an affected heterozygous parent ordinarily has a 50% transmission probability per pregnancy. Most sporadic cases arise de novo, but parental mosaicism means recurrence risk is not necessarily zero after apparently de novo disease. (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 5-7)
  • Penetrance: not quantified. Familial cosegregation supports high penetrance for recognizable RASopathy features, but an apparently unaffected mosaic father demonstrates dependence on variant allele fraction and tissue distribution.
  • Expressivity: markedly variable, from relatively mild NS to severe CFCS/Costello-like disease or fetal lethality. (altmuller2017genotypeandphenotype pages 1-2, altmuller2017genotypeandphenotype pages 4-5)
  • Anticipation: no evidence.
  • Founder effects, consanguinity, carrier frequency: none established; consanguinity is not etiologically relevant to this dominant subtype.
  • Sex ratio: 9 male:10 female in the principal cohort, providing no evidence of sex bias. (altmuller2017genotypeandphenotype pages 3-4)
  • NS6 epidemiology: prevalence and incidence are unknown. It is far rarer than overall NS.
  • General NS context: estimated prevalence is 1 in 1,000–2,500 live births, but this must not be assigned to NS6. (perrino2024updateonpediatric pages 6-8)
  • Ethnic/geographic distribution: cases are internationally distributed; no population enrichment has been established.

10. Diagnostics

Recommended approach

  1. Clinical assessment: evaluate prenatal lymphatic findings, characteristic face, webbed neck/pectus morphology, growth, cardiac disease, development, cryptorchidism, bleeding, skin/hair, vision/hearing, and renal anomalies.
  2. Baseline tests: echocardiogram and ECG; growth and feeding assessment; developmental, ophthalmologic, and audiologic evaluation; renal ultrasound when indicated; coagulation evaluation before surgery or for bleeding history; CBC if symptomatic or if hepatosplenomegaly is present.
  3. Molecular confirmation: a comprehensive RASopathy panel including NRAS, PTPN11, SOS1, RAF1, RIT1, LZTR1, KRAS, SOS2, RRAS, RRAS2, MRAS, and relevant CFCS/Costello genes. Broader exome or genome sequencing is appropriate after negative panel testing or for atypical/blended phenotypes. (altmuller2017genotypeandphenotype pages 5-7, perrino2024updateonpediatric pages 6-8)
  4. Variant-origin testing: parental testing for segregation and recurrence counseling. If an oncogenic-hotspot NRAS variant is found in blood in the setting of MPD/leukemia, confirm constitutional status in nonhematopoietic tissue.

WES directly identified p.Gly12Arg in an HRAS-negative Costello-like child. CMA is not expected to diagnose monogenic NS6 but can detect a second diagnosis, as illustrated by the 22q11.23 duplication. Karyotype, FISH, mitochondrial sequencing, repeat-expansion testing, biopsy, and liquid biopsy are not routine NS6 tests. No validated RNA-seq, proteomic, metabolomic, or epigenomic diagnostic assay exists. (altmuller2017genotypeandphenotype pages 5-7)

Differential diagnosis

The principal differentials are other molecular forms of NS, CFCS, Costello syndrome, Noonan syndrome with multiple lentigines, neurofibromatosis-Noonan syndrome, CBL syndrome, Turner syndrome, 22q11.2-related disorders, and isolated congenital heart/lymphatic disease. Severe feeding, ectodermal, and developmental findings may suggest CFCS; coarse/Costello-like appearance and tumor predisposition may suggest HRAS-related Costello syndrome. Molecular testing is therefore essential.

There is no population newborn screen. Prenatal diagnosis is possible by CVS/amniocentesis for a known familial variant; fetal ultrasound may detect cystic hygroma, hydrops, pleural effusions, or cardiac disease but is not diagnostic. Cascade testing, prenatal testing, and PGT-M are appropriate after identification of a familial pathogenic variant.

11. Outcome and prognosis

No reliable NS6-specific survival curve, mortality rate, or life-expectancy estimate exists. The observed age range to 50 years demonstrates survival into adulthood in some individuals, but severe fetal hydrops caused intrauterine death in one de novo p.Gly12Val case and first-day death in a familial p.Gly60Glu case. Prognosis is driven mainly by HCM/other cardiac disease, lymphatic complications, feeding/respiratory compromise, neurodevelopmental severity, and possibly MPD/malignancy. (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 4-5)

Functional outcomes range from normal cognition or mild learning/attention difficulty to severe disability in complicated or blended cases. Recovery of early motor and airway problems can occur, but congenital genetic susceptibility remains lifelong. No validated prognostic biomarker exists beyond preliminary variant-level observations and organ severity.

General NS data indicate an approximately eightfold relative childhood-cancer risk, although absolute risk remains moderate. Because most risk estimates are dominated by PTPN11 and mixed genotypes, the absolute NS6 cancer risk is unknown. (perrino2024updateonpediatric pages 8-10, perrino2024updateonpediatric pages 6-8)

12. Treatment and current implementation

There is no curative or NRAS-specific approved therapy. Management is multidisciplinary and organ-directed:

  • Cardiac: standard pediatric/adult cardiology care, including surveillance, beta-blocker/disopyramide where appropriate for HCM, catheter/surgical treatment of obstructive lesions, and individualized arrhythmia management.
  • Growth: nutrition/endocrine evaluation and recombinant human growth hormone (somatropin) when indicated and not otherwise contraindicated. Completed general-NS trials include Phase III NCT01529840 (24 participants; 33 versus 66 μg/kg/day, up to ten years) and NCT00452725 (36 participants). Postmarketing NCT03435627 enrolled 71 patients. These studies were not NRAS-specific. (NCT01529840 chunk 1, NCT00452725 chunk 1, NCT03435627 chunk 1)
  • Development: early physical, occupational, speech/language, educational, and behavioral intervention.
  • Feeding/lymphatic: nutritional support, feeding therapy/tube feeding when needed, and conventional management of chylothorax/effusions.
  • Bleeding: define the coagulation defect before surgery and use hematology-guided therapy.
  • Surgery: correction of cardiac, genitourinary, or orthopedic abnormalities as clinically indicated.

The 2024 AACR expert update found no evidence that growth hormone increases tumor occurrence or growth and does not advise against clinically indicated GH; routine brain MRI before GH is not recommended in an asymptomatic child. (perrino2024updateonpediatric pages 8-10)

Targeted/experimental therapies

  • Trametinib (MEK1/2 inhibitor; NCIt concept: MEK inhibitor/targeted therapy): Phase II MEKinRAS, NCT06555237, began 1 August 2024 and was listed as recruiting. It randomizes approximately 40 patients aged 1 day–18 years with a molecularly confirmed RASopathy and HCM to trametinib 0.025 mg/kg/day plus standard therapy versus standard therapy, assessing echocardiographic hypertrophy/LVOTO and cardiac biomarkers. An NRAS patient could be eligible if all criteria are met, but no NS6 subgroup outcome exists. ClinicalTrials.gov. (NCT06555237 chunk 1)
  • A 2025 systematic review found 16 published pediatric NS cases plus one new case treated with trametinib for severe cardiac/lymphatic disease; short-term improvement was reported in all, three deaths were considered unrelated, moderate adverse effects occurred in some, and long-term follow-up was absent. This remains off-label and experimental. DOI: 10.3389/fped.2025.1475143, PMID 40041314. (brouchoven2025trametinibasa pages 12-13, brouchoven2025trametinibasa pages 1-2)
  • Vosoritide: Phase II NCT06668805, recruiting, randomized/triple-masked, estimated n=30, tests three doses in genetically confirmed NS with inadequate growth during/after GH. It monitors annualized growth, HCM, skeletal safety, final height, and QoL for up to 15 years. Applicability is general NS, not proven NS6. ClinicalTrials.gov. (NCT06668805 chunk 1)
  • Real-world GH registry: NCT05308927, estimated n=221, is collecting six-year Norditropin growth, cardiac, metabolic, safety, educational, and HRQoL data in French children. ClinicalTrials.gov. (NCT05308927 chunk 1)

No gene replacement, CRISPR, ASO/siRNA, cell therapy, or immunotherapy is clinically available. Direct systemic NRAS inhibition is not an established developmental-disease strategy and could disrupt normal signaling.

13. Prevention

Primary prevention: there is no vaccine, environmental avoidance, diet, or medication that prevents a de novo constitutional NRAS variant. Reproductive options after molecular diagnosis include genetic counseling, parental/mosaicism testing, PGT-M, CVS/amniocentesis, and informed use of donor gametes.

Secondary prevention: early recognition and molecular diagnosis permit fetal/neonatal planning, baseline cardiac evaluation, developmental intervention, and cascade testing. Population screening is not justified by current prevalence and evidence.

Tertiary prevention: regular multisystem follow-up aims to prevent cardiac decompensation, growth/nutritional morbidity, developmental disability, surgical bleeding, hearing/vision impairment, and delayed recognition of MPD or tumors.

The 2024 AACR update recommends clinical examination—particularly for hepatosplenomegaly in infancy and early childhood—rather than routine CBCs in otherwise healthy NS children. Routine radiologic/laboratory screening for solid tumors is not justified by absolute risk; families may be educated about rhabdomyosarcoma, glioma, and neuroblastoma symptoms. Any suspected MPD warrants pediatric hematology/oncology follow-up. These are general NS recommendations, not validated specifically in NS6. (perrino2024updateonpediatric pages 8-10)

14. Other species and natural disease

NRAS orthologues are evolutionarily conserved across vertebrates and many experimental species, but no well-established naturally occurring veterinary syndrome equivalent to human NS6 was identified. There is no zoonotic potential or cross-species transmission because this is a constitutional genetic disorder. Breed-specific disease, VBO annotation, and animal carrier frequency are unavailable.

15. Model organisms and experimental systems

The directly retrieved NS6 functional model was HEK293T cells transiently expressing FLAG-tagged wild-type or mutant NRAS. ERK1/2 and AKT phosphorylation, together with GTP-bound NRAS assays, demonstrated variant gain of function. This model is useful for biochemical pathogenicity testing but cannot reproduce embryonic development, tissue interactions, dosage throughout life, cardiac architecture, lymphatic flow, cognition, or tumor risk. (altmuller2017genotypeandphenotype pages 3-4, altmuller2017genotypeandphenotype pages 5-7)

No validated NS6-specific knock-in mouse, rat, zebrafish, Drosophila, organoid, or patient-derived iPSC model was identified in the retrieved literature. General RASopathy animal and lymphatic-organoid work supports MEK inhibition conceptually, but extrapolation to a particular NRAS allele requires caution. A priority model would be a conditional heterozygous knock-in reproducing a viable human allele such as p.Thr58Ile, with cardiac, lymphatic, growth, neurodevelopmental, and hematopoietic phenotyping.

Current expert interpretation and critical knowledge gaps

The evidence strongly establishes NS6 as a constitutional gain-of-function RAS/MAPK disorder, but disease curation should preserve three distinctions: (1) NRAS-specific observations versus mixed-genotype NS data, (2) constitutional variants versus blood-restricted somatic cancer mutations, and (3) individual-case genotype associations versus reproducible prognostic rules. The most urgent research needs are a prospective international NRAS registry, allele-resolved natural history, gnomAD/ClinVar harmonization, penetrance and parental-mosaicism studies, systematic cancer-risk estimation, patient-reported outcomes, and NRAS-specific developmental models. (altmuller2017genotypeandphenotype pages 7-8, altmuller2017genotypeandphenotype pages 8-9, perrino2024updateonpediatric pages 10-11)

Core references

  1. Altmüller F, et al. Genotype and phenotype spectrum of NRAS germline variants. European Journal of Human Genetics. Published online 3 May 2017;25:823–831. DOI: 10.1038/ejhg.2017.65. Primary human cohort plus in-vitro functional evidence. (altmuller2017genotypeandphenotype pages 1-2, altmuller2017genotypeandphenotype pages 3-4)
  2. Perrino MR, et al. Update on Pediatric Cancer Surveillance Recommendations… Clinical Cancer Research. Published August 2024;30:4834–4843. DOI: 10.1158/1078-0432.CCR-24-1611. Current expert surveillance guidance; general NS rather than NRAS-specific. (perrino2024updateonpediatric pages 6-8, perrino2024updateonpediatric pages 8-10)
  3. Open Targets. MONDO:0013186—NRAS association. Disease–target evidence includes PMID 19966803 and PMID 23875798. (OpenTargets Search: Noonan syndrome 6-NRAS)
  4. De Brouchoven I, et al. Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome. Frontiers in Pediatrics. 18 February 2025;13:1475143. DOI: 10.3389/fped.2025.1475143; PMID 40041314. (brouchoven2025trametinibasa pages 1-2, NCT06555237 chunk 1)

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