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Classifications

Harrison's Part

Mechanistic Nosology

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Mappings

MONDO

MONDO:0013186 Noonan syndrome 6

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 (3 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

ClinGen records autosomal dominant inheritance for the NRAS-Noonan relationship.

PMID:28594414 SUPPORT Human Clinical

"The patient ´s father was found to have a mosaicism for the variant in his peripheral blood (Supplementary Figure S1)."

Patient 8 has Thr58Ile in urine, saliva and blood; her father has blood mosaicism and no suggestive RASopathy signs. This establishes parental mosaicism in this family, without quantifying gonadal mosaicism or recurrence risk.

?

Discussions and Knowledge Gaps

8

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

Published NRAS RASopathy series contain few tumor events with heterogeneous ages and follow-up. The 2015 familial literature review predates the expanded oncogenic-codon spectrum and cannot establish equal risk between NRAS and other Noonan genotypes. The 2017 brain mass was unbiopsied and possibly hamartomatous. Allele-stratified lifetime risk therefore remains unresolved.

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"

Historical interpretation from a small, earlier case series; it cannot establish risk equivalence or refute later allele-specific susceptibility.

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 between E15.5 and E17.5, 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.

If NS6 is caused by gain-of-function NRAS alleles that raise RAS-MAPK flux, why do 1p13.2 microdeletions that remove one NRAS copy produce an overlapping Noonan phenotype?

KNOWLEDGE GAP ns6_haploinsufficiency_versus_gain_of_function

Attached to

pathophysiology#NRAS Germline Gain-of-Function Variant pathophysiology#RAS-MAPK Cascade Hyperactivation

The canonical MAPK interpretation of NS6 involves increased signal throughput into RAF-MEK-ERK. A loss-of-dosage lesion converging on a similar clinical picture challenges a simple monotonic MAPK model; it does not establish equivalence across the parallel effector responses, including AKT. Three readings are open and the published data do not separate them: the deletion phenotype may be driven by other genes in the deleted segment rather than by NRAS; reduced N-Ras may perturb pathway output non-monotonically, so that both raising and lowering it degrades developmental signalling; or the shared features may be non-specific enough that clinical overlap does not imply mechanistic convergence. The same loss-and-gain pattern is reported for MAP2K2 and SHOC2, so this is a recurring question about RAS-MAPK dosage rather than an NRAS curiosity. Resolving it bears on whether MEK inhibition is a rational therapy for the deletion phenotype, where it could plausibly make matters worse.

Proposed experiments

NRAS dosage series against developmental RAS-MAPK output

ns6_nras_dosage_series

Compare ERK pathway output and developmental phenotype across an allelic dosage series - NRAS null/heterozygous-null, wild type, and a knock-in non-hotspot NS6 allele - in one system, to test whether pathway output responds non-monotonically to N-Ras dosage or whether the deletion phenotype is carried by neighbouring genes.

Perturbations

Heterozygous NRAS loss versus knock-in NS6 gain-of-function allele

pathophysiology#NRAS Germline Gain-of-Function Variant

NRAS hgnc:7989

Readouts

Phosphorylated ERK as developmental RAS-MAPK output

pathophysiology#RAS-MAPK Cascade Hyperactivation

ERK1 and ERK2 cascade GO:0070371

Direction: ALTERED

Interpretation: A similar developmental phenotype arising from opposite directions of pathway output would support non-monotonic dosage sensitivity; output changing only in the gain-of-function arm would point to neighbouring genes carrying the deletion phenotype.

Show evidence (2 references)

PMID:27561113 SUPPORT Other

"Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences."

The authors state the convergence as a conjecture ("it is conceivable"), which is precisely why it is recorded here as an open question rather than as a competing mechanism in the pathograph.

PMID:19966803 SUPPORT In Vitro

"Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder."

The enhanced MAPK activation component of this claim derives from transfected-cell assays; human sequencing establishes the germline diagnosis.

Which neural, muscular or auditory mechanisms account for NRAS-associated findings?

KNOWLEDGE GAP ns6_neurodevelopmental_attribution

Attached to

phenotypes#Motor Delay phenotypes#Severe Intellectual Disability phenotypes#Muscular Hypotonia phenotypes#Hearing Impairment phenotypes#Congenital Sensorineural Hearing Impairment

Motor delay and hypotonia are separable from intellect, and later catch-up is documented. The severe intellectual-disability case is allele-specific; the extreme 2017 Glu37dup developmental presentation also had a 22q11.23 duplication and hypoxic ischemic injury. The reviewed NRAS sources do not resolve the relative neural, muscular and sensory contributions. A specific causal tissue route for hearing loss is not established.

Show evidence (2 references)

PMID:28594414 SUPPORT Human Clinical

"Motor delay and intellectual or learning disabilities were recorded in 38 and 42% of patients, respectively."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

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.

Which NRAS-specific developmental mechanisms generate the remaining anatomical and cutaneous findings?

KNOWLEDGE GAP ns6_anatomical_and_skin_attribution

Attached to

phenotypes#Downslanted Palpebral Fissures phenotypes#Strabismus phenotypes#Short Neck phenotypes#Pectus Carinatum phenotypes#Pectus Excavatum phenotypes#Patent Ductus Arteriosus phenotypes#Multiple Lentigines phenotypes#Cafe-au-lait Macules phenotypes#Multiple Melanocytic Nevi phenotypes#Macrocephaly phenotypes#Keratosis Pilaris phenotypes#Low Posterior Hairline phenotypes#Curly Hair phenotypes#Sparse Hair phenotypes#Sparse Eyebrows

The reviewed sources establish the clinical findings but do not assign distinct tissue mechanisms to these endpoints. The zebrafish craniofacial evidence supports widening, not every facial feature; the NrasG12D mouse demonstrates ventricular septation and pulmonary valve defects, not a ductal mechanism; the atrial septal pathway link is instead a qualified extrapolation from the RASopathy review. Somatic mosaic NRAS nevus biology cannot automatically establish the mechanism of pigmentation in constitutional NS6. Pectus carinatum remains supported indirectly by parent-Noonan evidence. The clinical NRAS reports identify curly hair, sparse scalp hair and sparse eyebrows, but do not establish their follicular mechanism or demonstrate that the experimental AKT response causes these findings.

Show evidence (2 references)

PMID:21263000 SUPPORT INDIRECT Model Organism

"Expression of N-Ras-I24N led to a significant increase in the angle of the ceratohyal (P<0.05; Student’s t-test) (Fig. 4C,D) and hence we conclude that N-Ras-I24N expression induced craniofacial defects in zebrafish embryos that are reminiscent of the symptoms in individuals with Noonan syndrome."

Ceratohyal-angle changes in a transient-expression zebrafish model support craniofacial widening; translation to human hypertelorism is provisional.

PMID:26467218 SUPPORT Human Clinical

"She has two large Café-au-lait spots on her back and >50 freckles (lentigines) all over her body, especially on her back (Fig. 1b) and arms (Fig. 1c)."

The same p.G60E woman had more than 50 lentigines and two large cafe-au-lait spots; these are separate findings.

What accounts for the heterogeneous prenatal and infantile complications?

KNOWLEDGE GAP ns6_infantile_and_prenatal_attribution

Attached to

phenotypes#Feeding Difficulties in Infancy phenotypes#Upper Airway Obstruction phenotypes#Hyperinsulinemic Hypoglycemia phenotypes#Polyhydramnios phenotypes#Dilatation of the Renal Pelvis

The severe Gly12Arg presentation combines oral aversion, upper airway collapse and hyperinsulinemic hypoglycemia, with subsequent improvement. Their co-occurrence does not identify the NRAS-dependent tissue route or establish that one causes the others. Polyhydramnios is documented separately from hydrops; the series does not identify a uniform mechanism. These are attribution gaps, not evidence that all findings are causally independent. The mild prenatal renal dilation likewise lacks a demonstrated NRAS-specific causal anatomical or functional route.

Show evidence (3 references)

PMID:28594414 SUPPORT Human Clinical

"The postnatal period was complicated by prolonged hyperinsulinemic hypoglycemia, severe feeding dif ﬁculties, including oral aversion and respiratory difﬁculties due to upper airway collapse. She was treated with a percutaneous gastrostomy and a tracheostomy with continuous positive airway..."

Patient 12 with p.Gly12Arg had prolonged postnatal hyperinsulinemic hypoglycemia, severe feeding difficulties and upper-airway collapse. These co-occurring case-specific complications do not establish a single shared mechanism.

PMID:28594414 SUPPORT Human Clinical

"In addition, the majority of patients had prenatal abnormalities (69%) with polyhydramnios being reported in 46% of the cases."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

PMID:28594414 SUPPORT Human Clinical

"Patient 13 — (c.35G4A, p.(Gly12Asp)) is a male born after an uneventful pregnancy except for mild fetal pyelocalyceal dilatation (7 mm) of the left kidney detected on ultrasound scans."

Prenatal mild unilateral renal pelvic/calyceal dilation in the p.Gly12Asp patient, independently of the confounded p.Glu37dup case with complex urinary abnormalities.

Is the reported hypothalamic mass a neoplasm or developmental lesion, and is it attributable to NRAS?

KNOWLEDGE GAP ns6_hypothalamic_mass_identity

Attached to

phenotypes#Hypothalamic Mass

The unbiopsied p.Gly12Arg hypothalamic mass was proposed to be a hamartoma or lipoma. The report discusses it alongside possible tumor predisposition, but its biological nature is unresolved. It is therefore not assigned an established causal tumor-predisposition edge.

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"A brain MRI at 8 months of age revealed an expansive lesion of 0.8x0.7x0.6 cm in the hypothala- mus proposed to represent a hamartoma or lipoma (Supplementary Figure S2)."

The report calls this a tumor-like lesion but proposes hamartoma or lipoma. This supports a suspected mass, not a histologically confirmed malignant brain tumor.

Which human NS6 manifestations, if any, depend on the AKT coactivation observed in transfected cells?

HUMAN MODEL MISMATCH ns6_akt_phenotype_attribution

Attached to

pathophysiology#PI3K-AKT Effector Activation

Thr58Ile and Gly12Val increase basal AKT phosphorylation in an ectopic HEK293T expression assay. The study does not isolate AKT-dependent human developmental outcomes or show comparable activation across all germline NRAS alleles; clinical phenotype fanout therefore remains unresolved.

Show evidence (1 reference)

PMID:28594414 SUPPORT In Vitro

"By contrast, ectopic expression of either NRAS Thr58Ile or NRASGly12Val promoted enhanced activation of ERK and AKT, even in absence of stimulation (Figure 2a)."

Transiently transfected HEK293T cells expressing Thr58Ile or Gly12Val show increased basal AKT phosphorylation. This supports a parallel PI3K-AKT effector arm for these tested alleles, not uniform activation by all NRAS variants.

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Pathophysiology

8

NRAS Germline Gain-of-Function Variant

Heterozygous germline NRAS variants increase signaling through allele-dependent mechanisms. Gly60Glu resists GAP stimulation and accumulates in the GTP-bound state; Thr50Ile enhances signaling without increased GTP loading, with altered membrane orientation proposed. Ile24Asn may alter nucleotide affinity, whereas Thr58Ile and oncogenic Gly12 variants can increase basal signaling. Thus increased nucleotide exchange and stimulus dependence are not universal. Constitutional origin should be assessed in non-hematopoietic tissue because NRAS is also a somatic oncogene.

NRAS hgnc:7989

positive regulation of Ras protein signal transduction GO:0046579 ⇑ GAIN OF FUNCTION

N-Ras intrinsic GTP hydrolysis GO:0003924 ↓ 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.

PI3K-AKT Effector Activation Thr58Ile and Gly12Val NRAS increase basal AKT signaling in transfected cells, in parallel with ERK. The complete PI3K-mediated route is not directly dissected in this experiment.

Show evidence (5 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.

+ 2 more references

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 ↑ INCREASED Ras protein signal transduction GO:0007265 ↑ INCREASED

Downstream

Disrupted Embryonic Cardiac Development Excess signaling is implicated in the NrasG12D mouse cardiac defects, with ERK, BMP and Wnt changes; their individual causal contributions remain unresolved.

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.

Hypertrophic Cardiomyopathy Provisional extrapolation from RASopathy HCM models and pathway-directed rescue; human NRAS HCM is established clinically, but an NRAS-specific myocardial cellular route has not been demonstrated.

Learning Difficulties Constitutional RAS-MAPK dysregulation is implicated in Noonan cognitive deficits; the precise neuronal circuit and contribution of non-neural factors remain unresolved in NRAS cases.

Mild Intellectual Disability Qualified pathway-level explanation shared with Noonan syndrome. In the CFCS-like NRAS case, perinatal injury and hydrocephalus may additionally influence cognitive outcome.

Developmental Lymphatic Dysfunction Provisional extrapolation from other RAS/MAPK-associated Noonan models in which ERK-driven SOX18 overexpression produces excessive lymphatic endothelial proliferation.

Atrial Septal Defect Provisional application of the broader RASopathy mechanism: disrupted Ras signaling alters septal formation. This is not inferred from the NrasG12D mouse ventricular defect, and the NRAS-specific atrial lineage mechanism remains unresolved.

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 INDIRECT Other

"Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development."

Review-level interpretation that Ras/MAPK dysregulation disrupts development across the RASopathies. Its application to the NRAS subtype is indirect; it is not a clinical observation from an NRAS cohort.

Disrupted Embryonic Cardiac Development

Mechanism confidence: Provisional

Embryonic NrasG12D activation disrupts cardiac morphogenesis in mice. Endothelial/endocardial expression recapitulates ventricular septal and pulmonary valve defects; cardiomyocyte-specific expression does not. These experiments support a candidate route for structural NS6 lesions, but do not explain human HCM: the mutant mouse myocardium is thin, and transfer across alleles, dosage and species remains uncertain.

endocardial cell CL:0002350 endothelial cell CL:0000115

heart development GO:0007507 ⚠ 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 Provisional translation of NrasG12D mouse cardiac maldevelopment to the corresponding human structural lesion; the mouse does not reproduce the complete NRAS clinical spectrum.

Pulmonic Stenosis Provisional translation of NrasG12D mouse cardiac maldevelopment to the corresponding human structural lesion; the mouse does not reproduce the complete NRAS clinical spectrum.

Ventricular Septal Defect Provisional translation of NrasG12D mouse cardiac maldevelopment to the corresponding human structural lesion; the mouse does not reproduce the complete NRAS clinical spectrum.

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 ⚠ 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 The NRAS-I24N zebrafish experiments document altered craniofacial cartilage as well as gastrulation defects. They support a provisional developmental contribution to the human gestalt, without establishing every facial component.

Hypertelorism Provisional link from disturbed craniofacial patterning to hypertelorism, supported by the widened-head cartilage phenotype of NRAS-I24N zebrafish.

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

Mechanism confidence: Provisional

Germline NRAS substitutions at oncogenic codons, notably Gly12, may increase tumor susceptibility. Case reports include embryonal rhabdomyosarcoma and JMML-like myeloproliferation; an unbiopsied hypothalamic mass may instead be a hamartoma or lipoma. The authors propose allele-dependent risk, but small, age-heterogeneous series do not establish absolute risk or absence of risk for non-hotspot alleles.

NRAS hgnc:7989

Downstream

Embryonal Rhabdomyosarcoma Provisional tumor-susceptibility relationship proposed from germline oncogenic-codon cases; additional events and age-dependent penetrance are not established.

Myeloproliferative Disorder Provisional tumor-susceptibility relationship proposed from germline oncogenic-codon cases; additional events and age-dependent penetrance are not established.

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."

The NRAS cohort reports a JMML-like myeloproliferative disorder in a p.Gly12Asp infant and an uncharacterized hypothalamic mass in a p.Gly12Arg infant. The latter was proposed to be a hamartoma or lipoma without biopsy, so these are not two confirmed neoplastic events.

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.

Developmental Lymphatic Dysfunction

Mechanism confidence: Provisional

Developmentally abnormal lymphatic channels and transport can impair lymph clearance, causing stasis, reflux and fluid accumulation. RAS-MAPK-driven lymphatic proliferation is established in other Noonan models; applying the route to NRAS disease is provisional. Prenatal lymphatic distension is also a published hypothesis for selected facial, neck and genital findings, rather than their proven universal cause.

Downstream

Lymphedema Impaired lymph drainage can produce this manifestation. The general Noonan mechanism is applied provisionally to NRAS cases, with possible additional cardiac contributions in hydrops.

Cystic Hygroma Impaired lymph drainage can produce this manifestation. The general Noonan mechanism is applied provisionally to NRAS cases, with possible additional cardiac contributions in hydrops.

Hydrops Fetalis Impaired lymph drainage can produce this manifestation. The general Noonan mechanism is applied provisionally to NRAS cases, with possible additional cardiac contributions in hydrops.

Chylothorax Impaired lymph drainage can produce this manifestation. The general Noonan mechanism is applied provisionally to NRAS cases, with possible additional cardiac contributions in hydrops.

Webbed Neck Proposed consequence of prenatal lymphatic obstruction/distension in Noonan syndrome; applicability to individual NRAS cases is uncertain.

Cryptorchidism Proposed consequence of prenatal lymphatic obstruction/distension in Noonan syndrome; applicability to individual NRAS cases is uncertain.

Low-set Ears Proposed consequence of prenatal lymphatic obstruction/distension in Noonan syndrome; applicability to individual NRAS cases is uncertain.

Ptosis Proposed consequence of prenatal lymphatic obstruction/distension in Noonan syndrome; applicability to individual NRAS cases is uncertain.

Fetal Nuchal Edema Impaired prenatal lymph drainage provides a provisional explanation for localized nuchal fluid accumulation. The general Noonan lymphatic mechanism is extrapolated to fetal nuchal edema observed in NRAS cases; its precise anatomic defect is not established.

Show evidence (1 reference)

PMID:40041314 SUPPORT INDIRECT Other

"A spectrum of complex anomalies such as enlargement of lymphatic channels (lymphangiectasia), dysmotility, or central conducting lymphatic anomaly (CCLA) cause inadequate clearing of lymph with resultant stasis and reflux, affecting various organ systems, and resulting in lymphedema,..."

Review-level mechanism in Noonan syndrome: impaired lymph clearance, stasis and reflux cause these fluid findings. Applied indirectly to NRAS-associated lymphatic manifestations.

Coagulation Dysfunction

Coagulation-factor or platelet abnormalities can produce bleeding in Noonan syndrome. In the NRAS series, von Willebrand disease was confirmed in one of the three individuals with bleeding; the other two had no defined coagulopathy. This node represents a contributing mechanism, without assuming that NRAS directly caused von Willebrand disease.

Downstream

Bleeding Diathesis A documented coagulopathy contributes to bleeding in a subset; causal attribution of the coagulopathy to NRAS itself remains uncertain.

Show evidence (1 reference)

PMID:23312968 SUPPORT INDIRECT Other

"Although infants with Noonan syndrome are predisposed to several haematological abnormalities, including transient monocytosis, thrombocytopenia, and myeloproliferative disorder,26 the most common haematologic disorders are abnormalities of bleeding caused by coagulation defects."

Noonan-wide causal relationship between hemostatic defects and bleeding; the NRAS cohort identifies a confirmed coagulopathy in only one individual.

PI3K-AKT Effector Activation

Enhanced basal AKT phosphorylation accompanies ERK activation in HEK293T cells expressing NRAS Thr58Ile or Gly12Val. This experimentally supported parallel effector response does not establish which human NS6 phenotypes depend on PI3K-AKT or that every germline allele has the same effect.

phosphatidylinositol 3-kinase/protein kinase B signal transduction GO:0043491 ↑ INCREASED

Show evidence (1 reference)

PMID:28594414 SUPPORT In Vitro

"By contrast, ectopic expression of either NRAS Thr58Ile or NRASGly12Val promoted enhanced activation of ERK and AKT, even in absence of stimulation (Figure 2a)."

Transiently transfected HEK293T cells expressing Thr58Ile or Gly12Val show increased basal AKT phosphorylation. This supports a parallel PI3K-AKT effector arm for these tested alleles, not uniform activation by all NRAS variants.

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Pathograph

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Phenotypes

48

Blood 2

Myeloproliferative Disorder HP:0005547

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."

One p.Gly12Asp infant in a small, age-heterogeneous NRAS series had a JMML-like myeloproliferative disorder. One event among 19 ascertained individuals is not a population risk estimate.

Bleeding Diathesis OCCASIONAL Abnormal bleeding HP:0001892

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Bleeding diathesis was reported in 3 out of 15 individuals, but only one patient had a con ﬁrmed coagulopathy (von Willebrand disease, patient 8)."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

Cardiovascular 6

Congenital Heart Disease FREQUENT Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Ten out of 17 patients (59%) had cardiac anomalies with hypertrophic cardiomyopathy (HCM) being present in 35% of the cases."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

Hypertrophic Cardiomyopathy FREQUENT HP:0001639

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Ten out of 17 patients (59%) had cardiac anomalies with hypertrophic cardiomyopathy (HCM) being present in 35% of the cases."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

Pulmonic Stenosis OCCASIONAL HP:0001642

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Of note, septal defects and pulmonary stenosis (PST) were reported only in a minority of our cohort (12 and 6%, respectively)."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

Ventricular Septal Defect HP:0001629

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Patient 1— (c.34G4A, p.(Gly12Ser)) presented with typical physical signs of NS: facial anomalies (Figure 3), left ventricular hypertrophy, atrial and ventricular septal defects (corrected by surgery), a persistent ductus arteriosus, and short stature."

The p.Gly12Ser patient had both atrial and ventricular septal defects. Aggregate septal frequencies combine both lesions.

Atrial Septal Defect HP:0001631

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Patient 1— (c.34G4A, p.(Gly12Ser)) presented with typical physical signs of NS: facial anomalies (Figure 3), left ventricular hypertrophy, atrial and ventricular septal defects (corrected by surgery), a persistent ductus arteriosus, and short stature."

The p.Gly12Ser patient had both atrial and ventricular septal defects. Aggregate septal frequencies combine both lesions.

Patent Ductus Arteriosus HP:0001643

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Patient 1— (c.34G4A, p.(Gly12Ser)) presented with typical physical signs of NS: facial anomalies (Figure 3), left ventricular hypertrophy, atrial and ventricular septal defects (corrected by surgery), a persistent ductus arteriosus, and short stature."

Patient 1 with germline NRAS p.Gly12Ser had a persistent ductus arteriosus. The quoted septal defects are separate lesions and their aggregate frequency cannot be assigned to ductus persistence.

Digestive 1

Feeding Difficulties in Infancy HP:0008872

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"The postnatal period was complicated by prolonged hyperinsulinemic hypoglycemia, severe feeding dif ﬁculties, including oral aversion and respiratory difﬁculties due to upper airway collapse. She was treated with a percutaneous gastrostomy and a tracheostomy with continuous positive airway..."

Patient 12 with p.Gly12Arg had severe feeding and upper-airway difficulties; this is a case-specific severe presentation.

Ear 3

Hearing Impairment HP:0000365

Show evidence (1 reference)

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."

The single NRAS-positive patient had hearing loss, with type and onset unspecified. The 7/32 proportion belongs to the whole mixed-genotype cohort and is not an NRAS frequency.

Congenital Sensorineural Hearing Impairment HP:0000407

Show evidence (1 reference)

PMID:26467218 SUPPORT Human Clinical

"Sensorineural hearing impairment was present at birth."

Subtype-specific congenital sensorineural hearing loss in the p.G60E father; no frequency estimate.

Low-set Ears HP:0000369

Show evidence (1 reference)

PMID:26467218 SUPPORT Human Clinical

"At the age of 24 years, she has the following features of NS (Fig. 1a): a large skull (62 cm) with a broad forehead, hypertelorism, down slanted palpebral fissures, bilateral ptosis (especially of her left eye), short and broad neck with a low hairline, and low-set ears with broad helices. Her..."

Adult woman with familial p.G60E NRAS-associated Noonan syndrome; this is subtype-specific clinical examination.

Endocrine 1

Hyperinsulinemic Hypoglycemia HP:0000825

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"The postnatal period was complicated by prolonged hyperinsulinemic hypoglycemia, severe feeding dif ﬁculties, including oral aversion and respiratory difﬁculties due to upper airway collapse. She was treated with a percutaneous gastrostomy and a tracheostomy with continuous positive airway..."

Patient 12 with germline NRAS p.Gly12Arg had prolonged postnatal hyperinsulinemic hypoglycemia. The same case had feeding and airway complications, but this observation does not establish the frequency or beta-cell mechanism of hypoglycemia in NS6.

Eye 3

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:26467218 SUPPORT Human Clinical

"At the age of 24 years, she has the following features of NS (Fig. 1a): a large skull (62 cm) with a broad forehead, hypertelorism, down slanted palpebral fissures, bilateral ptosis (especially of her left eye), short and broad neck with a low hairline, and low-set ears with broad helices. Her..."

Adult woman with familial p.G60E NRAS-associated Noonan syndrome; this is subtype-specific clinical examination.

Ptosis VERY_FREQUENT HP:0000508

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"All assessed subjects had craniofacial features that were classi ﬁed as typical or suggestive for a RASopathy. Short and broad or webbed neck was found in 94%, and ocular ptosis in 82% of the cases."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

Strabismus HP:0000486

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Patient 8 — (c.173C4T, p.(Thr58Ile)) presented with suggestive facial features of NS, ocular ptosis, strabismus, and pectus excavatum, but without cardiac anomalies and short stature."

The individual carried germline NRAS p.Thr58Ile; strabismus is explicitly named.

Genitourinary 2

Cryptorchidism FREQUENT HP:0000028

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Cryptorchidism occurred in 63% of affected males."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

Dilatation of the Renal Pelvis HP:0010946

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Patient 13 — (c.35G4A, p.(Gly12Asp)) is a male born after an uneventful pregnancy except for mild fetal pyelocalyceal dilatation (7 mm) of the left kidney detected on ultrasound scans."

Prenatal mild unilateral renal pelvic/calyceal dilation in the p.Gly12Asp patient, independently of the confounded p.Glu37dup case with complex urinary abnormalities.

Head and Neck 9

Noonan Facial Gestalt Abnormal facial shape HP:0001999

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 Other

"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

Show evidence (1 reference)

PMID:26467218 SUPPORT Human Clinical

"At the age of 24 years, she has the following features of NS (Fig. 1a): a large skull (62 cm) with a broad forehead, hypertelorism, down slanted palpebral fissures, bilateral ptosis (especially of her left eye), short and broad neck with a low hairline, and low-set ears with broad helices. Her..."

Adult woman with familial p.G60E NRAS-associated Noonan syndrome; this is subtype-specific clinical examination.

Webbed Neck HP:0000465

Show evidence (1 reference)

PMID:21263000 SUPPORT Human Clinical

"The 30-year-old patient had been diagnosed with Noonan syndrome and demonstrated the facial features, low posterior hairline, webbing of the neck, pectus excavatum, cryptorchism, mild learning difficulties and mild short stature characteristic of the syndrome."

The molecularly confirmed p.I24N patient had these clinical findings; no component-specific frequency is derived from this single case.

Short Neck HP:0000470

Show evidence (1 reference)

PMID:26467218 SUPPORT Human Clinical

"At the age of 24 years, she has the following features of NS (Fig. 1a): a large skull (62 cm) with a broad forehead, hypertelorism, down slanted palpebral fissures, bilateral ptosis (especially of her left eye), short and broad neck with a low hairline, and low-set ears with broad helices. Her..."

Adult woman with familial p.G60E NRAS-associated Noonan syndrome; this is subtype-specific clinical examination.

Macrocephaly HP:0000256

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Patient 12 — (c.34G4C, p.(Gly12Arg)) had a RASopathy-typical facial phenotype, short webbed neck, macrocephaly, and HCM."

Macrocephaly explicitly documented in the p.Gly12Arg infant.

Cystic Hygroma HP:0000476

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Patient 2 — (c.35G4T, p.(Gly12Val)) was a fetus with a suspected RASopathy based on the ﬁnding of a very large cystic nuchal hygroma (14.3 mm) at 12 weeks of gestation."

Germline p.Gly12Val fetal presentation; no heart defect was detected and no autopsy was available.

Low Posterior Hairline HP:0002162

Show evidence (1 reference)

PMID:21263000 SUPPORT Human Clinical

"The 30-year-old patient had been diagnosed with Noonan syndrome and demonstrated the facial features, low posterior hairline, webbing of the neck, pectus excavatum, cryptorchism, mild learning difficulties and mild short stature characteristic of the syndrome."

The molecularly confirmed p.I24N patient had these clinical findings; no component-specific frequency is derived from this single case.

Fetal Nuchal Edema HP:0034250

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Nuchal oedema and fetal chylothorax/hydrops as prenatal abnormalities were seen in 15 and 23%, respectively."

The 2017 NRAS series reports nuchal edema in 15% of variably assessed prenatal histories. No disease-wide frequency band is assigned, and the source does not specify a nuchal-translucency measurement threshold.

Sparse Eyebrows HP:0045075

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"The suspected clinical diagnosis was CFCS because of typical facial features with substantial supraorbital hypoplasia and prominent ectodermal ﬁndings (curly hair, sparse eyebrows, keratosis pilaris, facial keratosis and multiple nevi), while her motor and intellectual development was only..."

The p.Thr50Ile case specifically documents eyebrow sparseness, not just curly scalp hair. No frequency band is inferred.

Integument 6

Multiple Lentigines HP:0001003

Show evidence (1 reference)

PMID:26467218 SUPPORT Human Clinical

"She has two large Café-au-lait spots on her back and >50 freckles (lentigines) all over her body, especially on her back (Fig. 1b) and arms (Fig. 1c)."

The same p.G60E woman had more than 50 lentigines and two large cafe-au-lait spots; these are separate findings.

Cafe-au-lait Macules Cafe-au-lait spot HP:0000957

Show evidence (1 reference)

PMID:26467218 SUPPORT Human Clinical

"She has two large Café-au-lait spots on her back and >50 freckles (lentigines) all over her body, especially on her back (Fig. 1b) and arms (Fig. 1c)."

The same p.G60E woman had more than 50 lentigines and two large cafe-au-lait spots; these are separate findings.

Multiple Melanocytic Nevi Melanocytic nevus HP:0000995

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 reported germline NRAS case had numerous melanocytic nevi. This single observation establishes occurrence, but supplies no denominator for the frequency of multiple nevi in NS6.

Keratosis Pilaris HP:0032152

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"The suspected clinical diagnosis was CFCS because of typical facial features with substantial supraorbital hypoplasia and prominent ectodermal ﬁndings (curly hair, sparse eyebrows, keratosis pilaris, facial keratosis and multiple nevi), while her motor and intellectual development was only..."

Patient 11 with germline NRAS p.Thr50Ile had keratosis pilaris within a CFCS-like ectodermal presentation. This is a case-specific skin finding, without an allele-wide or disease-wide frequency estimate.

Curly Hair HP:0002212

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"The suspected clinical diagnosis was CFCS because of typical facial features with substantial supraorbital hypoplasia and prominent ectodermal ﬁndings (curly hair, sparse eyebrows, keratosis pilaris, facial keratosis and multiple nevi), while her motor and intellectual development was only..."

Patient 11 carries p.Thr50Ile NRAS and has curly hair. This is a case-level observation, separate from sparse eyebrows or scalp hair.

Sparse Hair HP:0008070

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"She had sparse, thin hair, full lips, deep palmar and plantar creases, several small nevi and one café- au-lait spot."

Patient 12 carries germline p.Gly12Arg NRAS. Sparse hair is supported in this individual; the phrase thin hair does not establish a separate hair-shaft diameter abnormality.

Metabolism 3

Lymphedema HP:0001004

Show evidence (2 references)

PMID:28594414 SUPPORT INDIRECT Human Clinical

"Patient 5 –2— (c.179G4A, p.(Gly60Glu)) is an affected child of a three generation family with obvious features of NS in her father and grandfather. She died on the ﬁrst day of life from severe hydrops. Post- mortem MRI revealed bilateral pleural effusions, a small pericardial effusion and left..."

The p.Gly60Glu neonate died with severe hydrops, and Table 1 records neonatal lymphatic edema in this patient and the p.Gly60Glu patient 6.

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.

Hydrops Fetalis HP:0001789

Show evidence (2 references)

PMID:28594414 SUPPORT Human Clinical

"Progressive hydrops foetalis developed, eventually leading to intrauterine death at 22 weeks of gestation. No autopsy data were available but hydropic appearance of the fetus was reported."

The preceding case identification establishes germline NRAS p.Gly12Val. This passage documents progressive fetal hydrops and intrauterine death at 22 weeks; no autopsy was available.

PMID:28594414 SUPPORT Human Clinical

"Patient 5 –2— (c.179G4A, p.(Gly60Glu)) is an affected child of a three generation family with obvious features of NS in her father and grandfather. She died on the ﬁrst day of life from severe hydrops. Post- mortem MRI revealed bilateral pleural effusions, a small pericardial effusion and left..."

The germline NRAS p.Gly60Glu neonate died on the first day of life with severe hydrops and pleural/pericardial effusions. This independently demonstrates that hydrops is not confined to oncogenic-codon alleles.

Chylothorax HP:0010310

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Nuchal oedema and fetal chylothorax/hydrops as prenatal abnormalities were seen in 15 and 23%, respectively."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment. Table 1 specifies congenital/neonatal chylothorax in patient 6.

Musculoskeletal 4

Pectus Carinatum HP:0000768

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

Show evidence (1 reference)

PMID:21263000 SUPPORT Human Clinical

"The 30-year-old patient had been diagnosed with Noonan syndrome and demonstrated the facial features, low posterior hairline, webbing of the neck, pectus excavatum, cryptorchism, mild learning difficulties and mild short stature characteristic of the syndrome."

The molecularly confirmed p.I24N patient had these clinical findings; no component-specific frequency is derived from this single case.

Embryonal Rhabdomyosarcoma HP:0006743

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.

Muscular Hypotonia HP:0001252

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"She exhibited marked muscular hypotonia in infancy."

The preceding clinical paragraph identifies patient 1 with p.Gly12Ser.

Nervous System 5

Motor Delay FREQUENT HP:0001270

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Motor delay and intellectual or learning disabilities were recorded in 38 and 42% of patients, respectively."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

Severe Intellectual Disability HP:0010864

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.

Hypothalamic Mass Abnormal hypothalamus morphology HP:0012286

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"A brain MRI at 8 months of age revealed an expansive lesion of 0.8x0.7x0.6 cm in the hypothala- mus proposed to represent a hamartoma or lipoma (Supplementary Figure S2)."

The report calls this a tumor-like lesion but proposes hamartoma or lipoma. This supports a suspected mass, not a histologically confirmed malignant brain tumor.

Learning Difficulties Specific learning disability HP:0001328

Show evidence (1 reference)

PMID:21263000 SUPPORT Human Clinical

"The 30-year-old patient had been diagnosed with Noonan syndrome and demonstrated the facial features, low posterior hairline, webbing of the neck, pectus excavatum, cryptorchism, mild learning difficulties and mild short stature characteristic of the syndrome."

The molecularly confirmed p.I24N patient had these clinical findings; no component-specific frequency is derived from this single case.

Mild Intellectual Disability HP:0001256

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"The suspected clinical diagnosis was CFCS because of typical facial features with substantial supraorbital hypoplasia and prominent ectodermal ﬁndings (curly hair, sparse eyebrows, keratosis pilaris, facial keratosis and multiple nevi), while her motor and intellectual development was only..."

This NRAS-associated RASopathy case supports mild ID; the authors separately describe perinatal confounders, so it does not establish an allele-wide cognitive outcome.

Prenatal and Birth 1

Polyhydramnios HP:0001561

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"In addition, the majority of patients had prenatal abnormalities (69%) with polyhydramnios being reported in 46% of the cases."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

Respiratory 1

Upper Airway Obstruction HP:0002781

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"The postnatal period was complicated by prolonged hyperinsulinemic hypoglycemia, severe feeding dif ﬁculties, including oral aversion and respiratory difﬁculties due to upper airway collapse. She was treated with a percutaneous gastrostomy and a tracheostomy with continuous positive airway..."

Patient 12 with p.Gly12Arg had severe feeding and upper-airway difficulties; this is a case-specific severe presentation.

Growth 1

Short Stature OCCASIONAL HP:0004322

Show evidence (1 reference)

PMID:28594414 SUPPORT Human Clinical

"Similarly, short stature was present in only 4 out of 15 cases (27%)."

The 2017 series comprises 19 individuals from 13 families with NRAS-associated RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic encephalopathy; denominators vary with ascertainment.

🧬

Genetic Associations

1

NRAS (Pathogenic Variants)

Gene: NRAS hgnc:7989 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:19966803 SUPPORT In Vitro

"Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder."

The enhanced MAPK activation component of this claim derives from transfected-cell assays; human sequencing establishes the germline diagnosis.

CGGV:assertion_34419b69-59c3-458b-a2a5-38a401679deb-2018-05-30T160000.000Z SUPPORT Other

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

6

Recombinant Growth Hormone (Somatropin) Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: somatropin NCIT:C837

Platform: Protein replacement

Growth hormone can increase growth velocity in Noonan syndrome. One p.G60E woman with partial GH deficiency had an excellent childhood response and reached 164.5 cm; this single case does not establish average NS6 efficacy or long-term safety.

Show evidence (3 references)

PMID:20301303 SUPPORT INDIRECT Human Clinical

"Growth hormone (GH) treatment increases growth velocity."

GeneReviews summarizes increased growth velocity with GH treatment in Noonan syndrome. Applied indirectly because the reported treatment effect is not specific to NRAS.

PMID:26467218 SUPPORT Human Clinical

"Her FH is 164.5 cm ( −0.45 SDS) and weight of 60 kg (+0.3 SDS)."

Final height in the p.G60E woman following childhood GH treatment; the preceding case history documents treatment and partial GH deficiency.

PMID:26467218 SUPPORT Human Clinical

"She had low endogenous growth hormone (GH) secretion defined as “partial GH deficiency”, and started GH therapy within a formal clinical trial (NovoNordisk) from 6.5 years of age. She was treated with GH (dose of 66 μg/kg/day) and responded exceptionally well and treatment was dis- continued..."

The p.G60E woman received GH and had an excellent response; a single patient cannot quantify subtype-wide effectiveness.

MEK Inhibition (Trametinib, Experimental/Off-Label)

Action: Targeted Therapy NCIT:C93352

Agent: trametinib NCIT:C77908

Platform: Small molecule

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 Other

"No formal clinical trial of trametinib in neonatal/pediatric Noonan syndrome has been published to our knowledge."

The authors describe the published literature as of their review, not an observed treatment outcome. This supports the experimental status of trametinib in general Noonan syndrome and applies indirectly to NRAS-associated NS6.

Cardiac Surveillance and Management

Action: supportive care 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 Other

"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 care 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 Other

"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 counseling 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.

Childhood Myeloproliferative Disorder Surveillance

Action: clinical surveillance for childhood myeloproliferative disorder Ontology label: Physical Examination NCIT:C20989

The 2024 AACR consensus recommends physical examination for hepatosplenomegaly from birth or diagnosis, every three months through age one year, then at each well-child visit until age five and as indicated by symptoms, regardless of Noonan genotype. Obtain a CBC for illness or hepatosplenomegaly and refer suspected MPD to pediatric hematology/oncology. Routine CBC in healthy asymptomatic children and routine imaging or laboratory surveillance for solid tumors are not recommended; families may receive symptom education. These are general Noonan recommendations applied to NS6, not NRAS-specific evidence of surveillance benefit.

Show evidence (4 references)

PMID:39196581 SUPPORT INDIRECT Other

"Clinical exam remains the mainstay of early intervention, and all patients, regardless of genotype, are recommended to have close monitoring including physical examination for hepatosplenomegaly especially during infancy and early childhood (Table 2)."

The AACR consensus recommends clinical monitoring across Noonan genotypes, including NRAS by scope. This is expert advice rather than an NRAS-specific surveillance-outcome study.

PMID:39196581 SUPPORT INDIRECT Other

"There is no evidence that in otherwise healthy children with NS or CBL syndrome, surveillance with complete blood counts (CBC) is beneficial. Therefore, routine CBC has been removed from surveillance, in alignment with other CPS predisposing to leukemia (See related manuscript through the..."

Routine blood-count screening is not recommended for healthy asymptomatic children. This does not apply to a child with suspected MPD, illness or hepatosplenomegaly.

PMID:39196581 SUPPORT INDIRECT Other

"Every 3 months through age 1y, then at every well child visit until age 5y, and as needed for clinical symptoms."

Table 2 starts monitoring at birth or diagnosis; CBC is indicated when ill or when hepatosplenomegaly is found, and abnormal findings warrant an experienced hematologist.

+ 1 more reference

🔬

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

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

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

Show evidence (1 reference)

PMID:20301303 SUPPORT INDIRECT Other

"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.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Noonan Syndrome 6:

Somatic NRAS-mutant myeloid neoplasia MONDO:0011908

Overlapping Features The NRAS codons mutated in NS6 - Gly12 above all - are the same codons mutated somatically in juvenile myelomonocytic leukemia and related myeloid neoplasms, so an NRAS variant found in blood or bone marrow does not by itself distinguish a constitutional RASopathy from an acquired clonal lesion. The distinction is made by demonstrating the variant in a non-hematopoietic tissue, and it is not academic: the germline-versus-somatic call carries different prognosis and different management. NS6 is additionally the entity in which the two can coexist, because a germline oncogenic-codon allele is itself a myeloid tumor-predisposing state.

Distinguishing Features

Demonstration of the NRAS variant in a non-hematopoietic tissue (skin fibroblasts, buccal cells) establishes constitutional origin and favors NS6.
Extra-hematopoietic Noonan features - characteristic facies, congenital heart disease, short stature - favor NS6 over an isolated somatic myeloid lesion.

Show evidence (1 reference)

PMID:42193013 SUPPORT INDIRECT Human Clinical

"The distinction between germline and somatic mutations profoundly influences prognosis"

Establishes that separating a constitutional RASopathy allele from an acquired myeloid one changes prognosis, which is why this differential is a management question and not just a labelling one. Graded INDIRECT because the statement is made across the RAS-pathway JMML genes rather than for NRAS specifically.

Other molecularly defined Noonan syndrome subtypes MONDO:0018997

Overlapping Features NS6 is delimited by its gene, not by its clinical picture, which sits inside the shared Noonan phenotype. PTPN11, SOS1, RAF1, RIT1, KRAS, SOS2, LZTR1, BRAF, SHOC2, CBL and PPP1CB variants all produce an overlapping presentation, and PTPN11 alone accounts for a much larger share of Noonan syndrome than NRAS. Discrimination is molecular: a RASopathy gene panel, not the phenotype, assigns the subtype.

Distinguishing Features

Only a pathogenic NRAS variant assigns NS6; the clinical phenotype does not separate it from the other Noonan subtypes.
NRAS is among the rarest Noonan genes, so a Noonan phenotype is far more likely to carry a PTPN11 variant on prior probability alone.

Show evidence (2 references)

PMID:41988663 SUPPORT Human Clinical

"pathogenic variants were identified across 13 genes, with PTPN11 being the most frequent (26/45, 57.8%), followed by PPP1CB and several less frequent genes including SOS1, SOS2, LZTR1, RAF1, MAP2K1, KRAS, NRAS, BRAF, CBL, NF1, and SHOC2"

A consecutive molecularly confirmed Noonan cohort in which NRAS is one of thirteen causal genes and PTPN11 dominates, which is the prior-probability point this differential rests on.

PMID:41496802 SUPPORT Human Clinical

"Additional variants, likely to represent clinically significant findings, were identified in PTPN11 (n = 11), RAF1 (n = 4), SOS1 (n = 3), RIT1 (n = 3), KRAS (n = 1), NRAS (n = 1), SOS2 (n = 1), and BRAF (n = 1)."

A referred RASopathy series in which a single NRAS case sits among the other Noonan genes, quantifying how rarely NRAS is the answer.

Costello syndrome and other germline RASopathies MONDO:0009026

Overlapping Features Costello syndrome (HRAS) is the nearest neighbour conceptually, since it is the other RASopathy caused by a germline variant in a canonical RAS GTPase, and it shares the craniofacial, cardiac, growth and tumor-predisposition axes with NS6. Cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Legius syndrome and neurofibromatosis type 1 complete the germline RASopathy differential. These are separated by their distinctive cutaneous findings and by gene, not by the shared RAS-MAPK phenotype.

Distinguishing Features

Costello syndrome carries deep palmar/plantar creases, papillomata and a characteristic solid-tumor risk profile not typical of NS6.
Cutaneous findings (lentigines, keratosis pilaris, cafe-au-lait macules) discriminate several germline RASopathies clinically before genotyping.

Show evidence (2 references)

PMID:40518121 SUPPORT INDIRECT Human Clinical

"The germline RASopathies include neurofibromatosis type 1 (not discussed in detail in this review), Noonan syndrome, Noonan syndrome with multiple lentigines, Legius syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, and cardiofaciocutaneous syndrome."

Enumerates the germline RASopathy set that NS6 must be distinguished from. Graded INDIRECT because it defines the differential group at the RASopathy level rather than naming NRAS.

PMID:40532825 SUPPORT INDIRECT Human Clinical

"Many RASopathies can be clinically diagnosed based on their cutaneous findings, thus it is essential for dermatologists to be comfortable differentiating RASopathies for accurate diagnosis and appropriate management."

Supports the cutaneous axis as the clinical discriminator within this differential group. Graded INDIRECT for the same reason as above.

1p13.2 microdeletion (NRAS haploinsufficiency)

Overlapping Features Contiguous-gene deletions at 1p13.2 that remove NRAS produce a phenotype overlapping Noonan syndrome, and are not NS6. The distinction matters because the two are mechanistically opposite: NS6 is caused by a gain-of-function missense allele, whereas the deletion leaves one functional copy. A sequencing-only workflow that finds no pathogenic NRAS variant will miss the deletion, so copy-number analysis is the test that separates them.

Distinguishing Features

A 1p13.2 copy-number loss with no pathogenic NRAS sequence variant identifies the deletion rather than NS6.
Deletion cases carry the phenotypes of the other genes in the deleted segment, so features outside the Noonan spectrum point away from NS6.

Show evidence (2 references)

PMID:27561113 SUPPORT Human Clinical

"Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS."

Establishes that 1p13.2 microdeletion recurrently presents with Noonan features, which is what makes it a differential for a molecularly unconfirmed Noonan phenotype.

PMID:27561113 SUPPORT Human Clinical

"In all these cases, the deleted segment included the NRAS gene."

Identifies NRAS as the deleted gene common to the overlapping cases, which is why this differential sits specifically against NS6 rather than against Noonan syndrome generally.

Turner syndrome MONDO:0019499

Overlapping Features The classic non-RASopathy mimic, and the one differential here that is not a RAS-MAPK disorder at all. Turner syndrome shares the features that make the Noonan phenotype recognizable - short stature, webbed neck, lymphedema and congenital heart disease - so the resemblance is with the clinical gestalt rather than with the mechanism. The two are separated by karyotype or chromosomal microarray, not by a RASopathy gene panel, which is why a sequencing-first workflow can miss it: a panel that finds no pathogenic RASopathy variant does not exclude Turner syndrome, because it was never testing for it. Historical usage reflected the overlap, Noonan syndrome having once been described in Turner-like terms before its genetic basis was known.

Distinguishing Features

Karyotype or chromosomal microarray showing 45,X or a structural X anomaly identifies Turner syndrome; NS6 has a normal karyotype.
Turner syndrome affects phenotypic females; NS6 is autosomal dominant and affects both sexes.
Left-sided obstructive lesions (bicuspid aortic valve, coarctation) typify Turner syndrome, whereas the Noonan spectrum is weighted toward pulmonic stenosis and hypertrophic cardiomyopathy.

Show evidence (1 reference)

PMID:34858328 SUPPORT INDIRECT Human Clinical

"Despite different genetic background, Noonan syndrome (NS) shares similar phenotype features to Turner syndrome (TS) such as short stature, webbed neck and congenital heart defects."

States the phenotypic overlap that makes Turner syndrome a differential, and states explicitly that the genetic basis differs, which is what the karyotype discriminator rests on. Graded INDIRECT because it characterizes Noonan syndrome as a whole rather than the NRAS-defined subtype, reaching NS6 through the parent entity in the same way as the other parent-level statements in this entry.

🔬

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

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 between E15.5 and E17.5 — 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 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 is a rare molecular cause of Noonan syndrome; published cohorts
  remain small. 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 NRAS variants increase signaling through allele-dependent
    mechanisms. Gly60Glu resists GAP stimulation and accumulates in the GTP-bound
    state; Thr50Ile enhances signaling without increased GTP loading, with altered
    membrane orientation proposed. Ile24Asn may alter nucleotide affinity, whereas
    Thr58Ile and oncogenic Gly12 variants can increase basal signaling. Thus increased
    nucleotide exchange and stimulus dependence are not universal. Constitutional
    origin should be assessed in non-hematopoietic tissue because NRAS is also a
    somatic oncogene.
  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: >-
      Reduced intrinsic/GAP-stimulated hydrolysis is associated with oncogenic Gly12
      alleles, and Gly60Glu is resistant to GAP stimulation. Thr50Ile does not
      substantially alter measured hydrolysis or nucleotide release; increased GTP
      loading is not shared by every NS6 variant.
  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: IN_VITRO
      snippet: >-
        Here we report that germline NRAS mutations conferring enhanced stimulus-dependent
        MAPK activation account for some cases of this disorder.
      explanation: >-
        The enhanced MAPK activation component of this claim derives from transfected-cell
        assays; human sequencing establishes the germline diagnosis.
  - 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.
  - target: PI3K-AKT Effector Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Thr58Ile and Gly12Val NRAS increase basal AKT signaling in transfected cells, in parallel with ERK.
      The complete PI3K-mediated route is not directly dissected in this experiment.
    evidence:
    - reference: PMID:28594414
      reference_title: Genotype and phenotype spectrum of NRAS germline variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        By contrast, ectopic expression
        of either NRAS Thr58Ile or NRASGly12Val promoted enhanced activation
        of ERK and AKT, even in absence of stimulation (Figure 2a).
      explanation: >-
        Transiently transfected HEK293T cells expressing Thr58Ile or Gly12Val show increased basal AKT
        phosphorylation. This supports a parallel PI3K-AKT effector arm for these tested alleles, not
        uniform activation by all NRAS variants.
  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.
  - reference: PMID:19966803
    reference_title: A restricted spectrum of NRAS mutations causes Noonan syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Of note, the G60E NRAS mutant, much like G12V, accumulated constitutively in the
      active, GTP-bound form and appeared resistant to GAP stimulation. In contrast, the
      T50I NRAS mutant was not enriched in the GTP-bound state (Fig. 2d,e), indicating a
      different mechanism of functional dysregulation.
    explanation: >-
      Cellular assays distinguish G60E accumulation/GAP resistance from T50I signaling
      without increased GTP loading.
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      By contrast, ectopic expression
      of either NRAS Thr58Ile or NRASGly12Val promoted enhanced activation
      of ERK and AKT, even in absence of stimulation (Figure 2a).
    explanation: >-
      Transiently transfected HEK293T cells show basal ERK and AKT activation by
      Thr58Ile and Gly12Val; stimulus dependence cannot be generalized.
- 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: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Excess signaling is implicated in the NrasG12D mouse cardiac defects, with ERK,
      BMP and Wnt changes; their individual causal contributions remain unresolved.
    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: OTHER
      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.
  - target: Hypertrophic Cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional extrapolation from RASopathy HCM models and pathway-directed rescue;
      human NRAS HCM is established clinically, but an NRAS-specific myocardial cellular
      route has not been demonstrated.
    evidence:
    - reference: PMID:40041314
      reference_title: Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Similarly, other investigators reproduced an NS-like HCM phenotype in RAS/MAPK
        mutant animals, which could be rescued by fetal MEK inhibition (Figure 1) (15).
      explanation: >-
        Review of non-NRAS-specific RAS/MAPK mutant animal HCM and fetal MEK rescue. This
        supports a qualified pathway relationship, not the thin-myocardium NrasG12D
        mechanism.
      directness: INDIRECT
  - target: Learning Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Constitutional RAS-MAPK dysregulation is implicated in Noonan cognitive deficits;
      the precise neuronal circuit and contribution of non-neural factors remain
      unresolved in NRAS cases.
    evidence:
    - reference: PMID:19966803
      reference_title: A restricted spectrum of NRAS mutations causes Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      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: >-
        This is the paper's disease-level causal framing, applied indirectly to the
        documented NRAS learning phenotype; it does not establish a particular neuronal
        mechanism.
      directness: INDIRECT
  - target: Mild Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Qualified pathway-level explanation shared with Noonan syndrome. In the CFCS-like
      NRAS case, perinatal injury and hydrocephalus may additionally influence cognitive
      outcome.
    evidence:
    - reference: PMID:19966803
      reference_title: A restricted spectrum of NRAS mutations causes Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      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: >-
        The paper attributes Noonan cognitive deficits to constitutional RAS-MAPK
        dysregulation. Applied indirectly to the documented mild intellectual disability
        in the NRAS p.Thr50Ile case, it does not isolate a neuronal mechanism or exclude
        that case's perinatal contributions.
      directness: INDIRECT
  - target: Developmental Lymphatic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional extrapolation from other RAS/MAPK-associated Noonan models in which
      ERK-driven SOX18 overexpression produces excessive lymphatic endothelial
      proliferation.
    evidence:
    - reference: PMID:40041314
      reference_title: Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In preclinical mouse studies, gain-of-function variants in RAS/MAPK-associated
        genes resulted in SOX18 overexpression, leading to excessive lymphatic cell
        proliferation and congenital lymphangiectasia mimicking NS phenotype.
      explanation: The review summarizes RAS/MAPK-associated mouse models, not an NRAS-specific lymphatic experiment.
      directness: INDIRECT
  - target: Atrial Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional application of the broader RASopathy mechanism: disrupted Ras signaling alters septal formation. This is not inferred from the NrasG12D mouse ventricular defect, and the NRAS-specific atrial lineage mechanism remains unresolved.
    evidence:
    - reference: PMID:40176696
      reference_title: 'RASopathies and Cardiac Complications: Insights into Mechanisms, Diagnosis, and Innovative Treatments.'
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        In PVS and ASD, disrupted Ras signaling impairs normal valvular and septal formation, contributing to structural heart defects.
      explanation: >-
        Review-level causal synthesis across RASopathies, applied indirectly to the atrial septal defect documented in the human NRAS cohort.
  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
    directness: INDIRECT
    evidence_source: OTHER
    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 interpretation that Ras/MAPK dysregulation disrupts development across
      the RASopathies. Its application to the NRAS subtype is indirect; it is not a
      clinical observation from an NRAS cohort.
- name: Disrupted Embryonic Cardiac Development
  biological_scale: TISSUE
  description: >-
    Embryonic NrasG12D activation disrupts cardiac morphogenesis in mice.
    Endothelial/endocardial expression recapitulates ventricular septal and pulmonary
    valve defects; cardiomyocyte-specific expression does not. These experiments
    support a candidate route for structural NS6 lesions, but do not explain human
    HCM: the mutant mouse myocardium is thin, and transfer across alleles, dosage and
    species remains uncertain.
  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: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional translation of NrasG12D mouse cardiac maldevelopment to the
      corresponding human structural lesion; the mouse does not reproduce the complete
      NRAS clinical spectrum.
    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: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional translation of NrasG12D mouse cardiac maldevelopment to the
      corresponding human structural lesion; the mouse does not reproduce the complete
      NRAS clinical spectrum.
    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: Ventricular Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional translation of NrasG12D mouse cardiac maldevelopment to the
      corresponding human structural lesion; the mouse does not reproduce the complete
      NRAS clinical spectrum.
    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.
  mechanism_confidence: PROVISIONAL
- 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: >-
      The NRAS-I24N zebrafish experiments document altered craniofacial cartilage as
      well as gastrulation defects. They support a provisional developmental
      contribution to the human gestalt, without establishing every facial component.
    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: >-
        Expression of N-Ras-I24N led to a significant increase in the angle of the
        ceratohyal (P<0.05; Student’s t-test) (Fig. 4C,D) and hence we conclude that
        N-Ras-I24N expression induced craniofacial defects in zebrafish embryos that are
        reminiscent of the symptoms in individuals with Noonan syndrome.
      explanation: >-
        Ceratohyal-angle changes in a transient-expression zebrafish model support
        craniofacial widening; translation to human hypertelorism is provisional.
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional link from disturbed craniofacial patterning to hypertelorism,
      supported by the widened-head cartilage phenotype of NRAS-I24N zebrafish.
    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 led to a significant increase in the angle of the
        ceratohyal (P<0.05; Student’s t-test) (Fig. 4C,D) and hence we conclude that
        N-Ras-I24N expression induced craniofacial defects in zebrafish embryos that are
        reminiscent of the symptoms in individuals with Noonan syndrome.
      explanation: >-
        Ceratohyal-angle changes in a transient-expression zebrafish model support
        craniofacial widening; translation to human hypertelorism is provisional.
      directness: INDIRECT
  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: >-
    Germline NRAS substitutions at oncogenic codons, notably Gly12, may increase tumor
    susceptibility. Case reports include embryonal rhabdomyosarcoma and JMML-like
    myeloproliferation; an unbiopsied hypothalamic mass may instead be a hamartoma or
    lipoma. The authors propose allele-dependent risk, but small, age-heterogeneous
    series do not establish absolute risk or absence of risk for non-hotspot alleles.
  genes:
  - preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  downstream:
  - target: Embryonal Rhabdomyosarcoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional tumor-susceptibility relationship proposed from germline
      oncogenic-codon cases; additional events and age-dependent penetrance are not
      established.
    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.
    - 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: >-
        Authors explicitly propose allele-dependent cancer predisposition, supporting a
        provisional causal susceptibility relation beyond co-occurrence.
  - target: Myeloproliferative Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional tumor-susceptibility relationship proposed from germline
      oncogenic-codon cases; additional events and age-dependent penetrance are not
      established.
    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.
    - 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: >-
        Authors explicitly propose allele-dependent cancer predisposition, supporting a
        provisional causal susceptibility relation beyond co-occurrence.
  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: >-
      The NRAS cohort reports a JMML-like myeloproliferative disorder in a p.Gly12Asp
      infant and an uncharacterized hypothalamic mass in a p.Gly12Arg infant. The latter
      was proposed to be a hamartoma or lipoma without biopsy, so these are not two
      confirmed neoplastic events.
  - 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.
  mechanism_confidence: PROVISIONAL
- name: Developmental Lymphatic Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Developmentally abnormal lymphatic channels and transport can impair lymph
    clearance, causing stasis, reflux and fluid accumulation. RAS-MAPK-driven
    lymphatic proliferation is established in other Noonan models; applying the route
    to NRAS disease is provisional. Prenatal lymphatic distension is also a published
    hypothesis for selected facial, neck and genital findings, rather than their
    proven universal cause.
  evidence:
  - reference: PMID:40041314
    reference_title: Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A spectrum of complex anomalies such as enlargement of lymphatic channels
      (lymphangiectasia), dysmotility, or central conducting lymphatic anomaly (CCLA)
      cause inadequate clearing of lymph with resultant stasis and reflux, affecting
      various organ systems, and resulting in lymphedema, chylothorax, pericardial
      effusion, congenital pulmonary lymphangiectasia (CPL), exudative enteropathy,
      chylous ascites, cystic hygroma, hydrops and other manifestations, some of which
      are detectable as early as the second trimester of pregnancy and are potentially
      life-threatening in neonates (12–14).
    explanation: >-
      Review-level mechanism in Noonan syndrome: impaired lymph clearance, stasis and
      reflux cause these fluid findings. Applied indirectly to NRAS-associated lymphatic
      manifestations.
    directness: INDIRECT
  downstream:
  - target: Lymphedema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired lymph drainage can produce this manifestation. The general Noonan
      mechanism is applied provisionally to NRAS cases, with possible additional cardiac
      contributions in hydrops.
    evidence:
    - reference: PMID:40041314
      reference_title: Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A spectrum of complex anomalies such as enlargement of lymphatic channels
        (lymphangiectasia), dysmotility, or central conducting lymphatic anomaly (CCLA)
        cause inadequate clearing of lymph with resultant stasis and reflux, affecting
        various organ systems, and resulting in lymphedema, chylothorax, pericardial
        effusion, congenital pulmonary lymphangiectasia (CPL), exudative enteropathy,
        chylous ascites, cystic hygroma, hydrops and other manifestations, some of which
        are detectable as early as the second trimester of pregnancy and are potentially
        life-threatening in neonates (12–14).
      explanation: >-
        Review-level mechanism in Noonan syndrome: impaired lymph clearance, stasis and
        reflux cause these fluid findings. Applied indirectly to NRAS-associated lymphatic
        manifestations.
      directness: INDIRECT
  - target: Cystic Hygroma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired lymph drainage can produce this manifestation. The general Noonan
      mechanism is applied provisionally to NRAS cases, with possible additional cardiac
      contributions in hydrops.
    evidence:
    - reference: PMID:40041314
      reference_title: Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A spectrum of complex anomalies such as enlargement of lymphatic channels
        (lymphangiectasia), dysmotility, or central conducting lymphatic anomaly (CCLA)
        cause inadequate clearing of lymph with resultant stasis and reflux, affecting
        various organ systems, and resulting in lymphedema, chylothorax, pericardial
        effusion, congenital pulmonary lymphangiectasia (CPL), exudative enteropathy,
        chylous ascites, cystic hygroma, hydrops and other manifestations, some of which
        are detectable as early as the second trimester of pregnancy and are potentially
        life-threatening in neonates (12–14).
      explanation: >-
        Review-level mechanism in Noonan syndrome: impaired lymph clearance, stasis and
        reflux cause these fluid findings. Applied indirectly to NRAS-associated lymphatic
        manifestations.
      directness: INDIRECT
  - target: Hydrops Fetalis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired lymph drainage can produce this manifestation. The general Noonan
      mechanism is applied provisionally to NRAS cases, with possible additional cardiac
      contributions in hydrops.
    evidence:
    - reference: PMID:40041314
      reference_title: Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A spectrum of complex anomalies such as enlargement of lymphatic channels
        (lymphangiectasia), dysmotility, or central conducting lymphatic anomaly (CCLA)
        cause inadequate clearing of lymph with resultant stasis and reflux, affecting
        various organ systems, and resulting in lymphedema, chylothorax, pericardial
        effusion, congenital pulmonary lymphangiectasia (CPL), exudative enteropathy,
        chylous ascites, cystic hygroma, hydrops and other manifestations, some of which
        are detectable as early as the second trimester of pregnancy and are potentially
        life-threatening in neonates (12–14).
      explanation: >-
        Review-level mechanism in Noonan syndrome: impaired lymph clearance, stasis and
        reflux cause these fluid findings. Applied indirectly to NRAS-associated lymphatic
        manifestations.
      directness: INDIRECT
  - target: Chylothorax
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired lymph drainage can produce this manifestation. The general Noonan
      mechanism is applied provisionally to NRAS cases, with possible additional cardiac
      contributions in hydrops.
    evidence:
    - reference: PMID:40041314
      reference_title: Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A spectrum of complex anomalies such as enlargement of lymphatic channels
        (lymphangiectasia), dysmotility, or central conducting lymphatic anomaly (CCLA)
        cause inadequate clearing of lymph with resultant stasis and reflux, affecting
        various organ systems, and resulting in lymphedema, chylothorax, pericardial
        effusion, congenital pulmonary lymphangiectasia (CPL), exudative enteropathy,
        chylous ascites, cystic hygroma, hydrops and other manifestations, some of which
        are detectable as early as the second trimester of pregnancy and are potentially
        life-threatening in neonates (12–14).
      explanation: >-
        Review-level mechanism in Noonan syndrome: impaired lymph clearance, stasis and
        reflux cause these fluid findings. Applied indirectly to NRAS-associated lymphatic
        manifestations.
      directness: INDIRECT
  - target: Webbed Neck
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed consequence of prenatal lymphatic obstruction/distension in Noonan
      syndrome; applicability to individual NRAS cases is uncertain.
    evidence:
    - reference: PMID:23312968
      reference_title: Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Many of the recognisable features of Noonan syndrome could be the consequence of
        lymphatic obstruction or dysfunction during development, including webbing of the
        neck and prominence of the trapezius, cryptorchidism, widely spaced nipples,
        low-set and posteriorly rotated ears, hypertelorism, and ptosis.38
      explanation: >-
        The review explicitly proposes developmental lymphatic dysfunction as a possible
        cause of these findings. This is a hypothesis for Noonan syndrome overall, not a
        demonstrated NRAS-specific tissue mechanism.
      directness: INDIRECT
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed consequence of prenatal lymphatic obstruction/distension in Noonan
      syndrome; applicability to individual NRAS cases is uncertain.
    evidence:
    - reference: PMID:23312968
      reference_title: Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Many of the recognisable features of Noonan syndrome could be the consequence of
        lymphatic obstruction or dysfunction during development, including webbing of the
        neck and prominence of the trapezius, cryptorchidism, widely spaced nipples,
        low-set and posteriorly rotated ears, hypertelorism, and ptosis.38
      explanation: >-
        The review explicitly proposes developmental lymphatic dysfunction as a possible
        cause of these findings. This is a hypothesis for Noonan syndrome overall, not a
        demonstrated NRAS-specific tissue mechanism.
      directness: INDIRECT
  - target: Low-set Ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed consequence of prenatal lymphatic obstruction/distension in Noonan
      syndrome; applicability to individual NRAS cases is uncertain.
    evidence:
    - reference: PMID:23312968
      reference_title: Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Many of the recognisable features of Noonan syndrome could be the consequence of
        lymphatic obstruction or dysfunction during development, including webbing of the
        neck and prominence of the trapezius, cryptorchidism, widely spaced nipples,
        low-set and posteriorly rotated ears, hypertelorism, and ptosis.38
      explanation: >-
        The review explicitly proposes developmental lymphatic dysfunction as a possible
        cause of these findings. This is a hypothesis for Noonan syndrome overall, not a
        demonstrated NRAS-specific tissue mechanism.
      directness: INDIRECT
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed consequence of prenatal lymphatic obstruction/distension in Noonan
      syndrome; applicability to individual NRAS cases is uncertain.
    evidence:
    - reference: PMID:23312968
      reference_title: Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Many of the recognisable features of Noonan syndrome could be the consequence of
        lymphatic obstruction or dysfunction during development, including webbing of the
        neck and prominence of the trapezius, cryptorchidism, widely spaced nipples,
        low-set and posteriorly rotated ears, hypertelorism, and ptosis.38
      explanation: >-
        The review explicitly proposes developmental lymphatic dysfunction as a possible
        cause of these findings. This is a hypothesis for Noonan syndrome overall, not a
        demonstrated NRAS-specific tissue mechanism.
      directness: INDIRECT
  - target: Fetal Nuchal Edema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired prenatal lymph drainage provides a provisional explanation for localized nuchal fluid accumulation.
      The general Noonan lymphatic mechanism is extrapolated to fetal nuchal edema observed in NRAS cases;
      its precise anatomic defect is not established.
    evidence:
    - reference: PMID:40041314
      reference_title: Trametinib as a targeted treatment in cardiac and lymphatic presentations of
        Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A spectrum of complex anomalies such as enlargement of lymphatic channels
        (lymphangiectasia), dysmotility, or central conducting lymphatic anomaly (CCLA)
        cause inadequate clearing of lymph with resultant stasis and reflux, affecting
        various organ systems, and resulting in lymphedema, chylothorax, pericardial
        effusion, congenital pulmonary lymphangiectasia (CPL), exudative enteropathy,
        chylous ascites, cystic hygroma, hydrops and other manifestations, some of which
        are detectable as early as the second trimester of pregnancy and are potentially
        life-threatening in neonates (12–14).
      explanation: >-
        The review attributes tissue edema to inadequate lymph clearance in Noonan syndrome. Application
        to the fetal nuchal location in NRAS disease is an explicit cross-subtype and anatomical extrapolation,
        supported separately by the clinical observation.
      directness: INDIRECT
    - reference: PMID:28594414
      reference_title: Genotype and phenotype spectrum of NRAS germline variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Nuchal oedema and fetal chylothorax/hydrops as prenatal
        abnormalities were seen in 15 and 23%, respectively.
      explanation: >-
        Documents the NRAS-associated prenatal finding whose provisional lymphatic mechanism is supplied
        by the separate Noonan review.
- name: Coagulation Dysfunction
  biological_scale: MOLECULAR
  description: >-
    Coagulation-factor or platelet abnormalities can produce bleeding in Noonan
    syndrome. In the NRAS series, von Willebrand disease was confirmed in one of the
    three individuals with bleeding; the other two had no defined coagulopathy. This
    node represents a contributing mechanism, without assuming that NRAS directly
    caused von Willebrand disease.
  evidence:
  - reference: PMID:23312968
    reference_title: Noonan syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although infants with Noonan syndrome are predisposed to several haematological
      abnormalities, including transient monocytosis, thrombocytopenia, and
      myeloproliferative disorder,26 the most common haematologic disorders are
      abnormalities of bleeding caused by coagulation defects.
    explanation: >-
      Noonan-wide causal relationship between hemostatic defects and bleeding; the NRAS
      cohort identifies a confirmed coagulopathy in only one individual.
    directness: INDIRECT
  downstream:
  - target: Bleeding Diathesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A documented coagulopathy contributes to bleeding in a subset; causal attribution
      of the coagulopathy to NRAS itself remains uncertain.
    evidence:
    - reference: PMID:23312968
      reference_title: Noonan syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Although infants with Noonan syndrome are predisposed to several haematological
        abnormalities, including transient monocytosis, thrombocytopenia, and
        myeloproliferative disorder,26 the most common haematologic disorders are
        abnormalities of bleeding caused by coagulation defects.
      explanation: >-
        Noonan-wide causal relationship between hemostatic defects and bleeding; the NRAS
        cohort identifies a confirmed coagulopathy in only one individual.
      directness: INDIRECT
- name: PI3K-AKT Effector Activation
  biological_scale: CELLULAR
  description: >-
    Enhanced basal AKT phosphorylation accompanies ERK activation in HEK293T cells expressing NRAS Thr58Ile
    or Gly12Val. This experimentally supported parallel effector response does not establish which human
    NS6 phenotypes depend on PI3K-AKT or that every germline allele has the same effect.
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      By contrast, ectopic expression
      of either NRAS Thr58Ile or NRASGly12Val promoted enhanced activation
      of ERK and AKT, even in absence of stimulation (Figure 2a).
    explanation: >-
      Transiently transfected HEK293T cells expressing Thr58Ile or Gly12Val show increased basal AKT phosphorylation.
      This supports a parallel PI3K-AKT effector arm for these tested alleles, not uniform activation
      by all NRAS variants.
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: OTHER
    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: 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: |-
      At the age of
      24 years, she has the following features of NS (Fig. 1a): a
      large skull (62 cm) with a broad forehead, hypertelorism,
      down slanted palpebral fissures, bilateral ptosis (especially
      of her left eye), short and broad neck with a low hairline,
      and low-set ears with broad helices. Her hair is normal.
    explanation: >-
      Adult woman with familial p.G60E NRAS-associated Noonan syndrome; this is
      subtype-specific clinical examination.
- category: Craniofacial
  name: Ptosis
  description: >-
    Upper eyelid ptosis was present in 82% of assessed individuals in the 2017 NRAS
    series; the expanded literature comparison reported 63%.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      All assessed subjects had craniofacial features that were classi ﬁed as
      typical or suggestive for a RASopathy. Short and broad or webbed
      neck was found in 94%, and ocular ptosis in 82% of the cases.
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  frequency: VERY_FREQUENT
- 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: 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: |-
      At the age of
      24 years, she has the following features of NS (Fig. 1a): a
      large skull (62 cm) with a broad forehead, hypertelorism,
      down slanted palpebral fissures, bilateral ptosis (especially
      of her left eye), short and broad neck with a low hairline,
      and low-set ears with broad helices. Her hair is normal.
    explanation: >-
      Adult woman with familial p.G60E NRAS-associated Noonan syndrome; this is
      subtype-specific clinical examination.
- category: Ocular
  name: Strabismus
  description: >-
    Strabismus is documented in NRAS-associated RASopathy, including the p.Thr58Ile
    patient in the 2017 series. The mixed-genotype 2026 ocular results do not provide
    an NRAS-specific refractive-error frequency.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 8 — (c.173C4T, p.(Thr58Ile)) presented with suggestive
      facial features of NS, ocular ptosis, strabismus, and pectus excavatum,
      but without cardiac anomalies and short stature.
    explanation: >-
      The individual carried germline NRAS p.Thr58Ile; strabismus is explicitly named.
- category: Musculoskeletal
  name: Webbed Neck
  description: >-
    Cervical webbing is reported in germline NRAS disease. The 94% cohort figure
    combines short/broad and webbed neck and is not a webbing-specific frequency.
  phenotype_term:
    preferred_term: Webbed neck
    term:
      id: HP:0000465
      label: Webbed neck
  evidence:
  - reference: PMID:21263000
    reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 30-year-old patient had been diagnosed with Noonan syndrome and demonstrated
      the facial features, low posterior hairline, webbing of the neck, pectus
      excavatum, cryptorchism, mild learning difficulties and mild short stature
      characteristic of the syndrome.
    explanation: >-
      The molecularly confirmed p.I24N patient had these clinical findings; no
      component-specific frequency is derived from this single case.
- 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: >-
    Pectus excavatum is documented in the p.I24N and p.Thr58Ile cases; coexisting
    superior pectus carinatum is not established for every NRAS case.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:21263000
    reference_title: "Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 30-year-old patient had been diagnosed with Noonan syndrome and demonstrated
      the facial features, low posterior hairline, webbing of the neck, pectus
      excavatum, cryptorchism, mild learning difficulties and mild short stature
      characteristic of the syndrome.
    explanation: >-
      The molecularly confirmed p.I24N patient had these clinical findings; no
      component-specific frequency is derived from this single case.
- category: Growth
  name: Short Stature
  description: >-
    Short stature occurred in 4/15 assessed individuals (27%) in the 2017 NRAS series
    and 42% in its expanded literature comparison. Normal adult stature also occurs,
    including an untreated affected father; growth is variable and treatment history
    matters.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Similarly, short
      stature was present in only 4 out of 15 cases (27%).
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  frequency: OCCASIONAL
- category: Cardiovascular
  name: Congenital Heart Disease
  description: >-
    Cardiac anomalies occurred in 10/17 assessed individuals (59%) in the 2017 series.
    HCM was more common than pulmonary stenosis in that NRAS cohort, unlike the
    overall Noonan pattern.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Ten out
      of 17 patients (59%) had cardiac anomalies with hypertrophic
      cardiomyopathy (HCM) being present in 35% of the cases.
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  frequency: FREQUENT
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  description: >-
    HCM was recorded in 35% of the 2017 NRAS cohort and 29% in the expanded literature
    comparison. Human hypertrophy must be distinguished from the thin myocardium in
    the embryonic NrasG12D mouse.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Ten out
      of 17 patients (59%) had cardiac anomalies with hypertrophic
      cardiomyopathy (HCM) being present in 35% of the cases.
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  frequency: FREQUENT
- category: Cardiovascular
  name: Pulmonic Stenosis
  description: >-
    Pulmonary stenosis was recorded in 6% of the 2017 NRAS cohort and 14% in the
    expanded literature comparison; it is less prominent than in Noonan syndrome
    overall.
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Of note,
      septal defects and pulmonary stenosis (PST) were reported only in a
      minority of our cohort (12 and 6%, respectively).
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  frequency: OCCASIONAL
- category: Cardiovascular
  name: Ventricular Septal Defect
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 1— (c.34G4A, p.(Gly12Ser)) presented with typical physical
      signs of NS: facial anomalies (Figure 3), left ventricular hypertrophy,
      atrial and ventricular septal defects (corrected by surgery), a persistent
      ductus arteriosus, and short stature.
    explanation: >-
      The p.Gly12Ser patient had both atrial and ventricular septal defects. Aggregate
      septal frequencies combine both lesions.
  description: >-
    A ventricular septal defect was surgically corrected in the p.Gly12Ser patient;
    another familial case is recorded in Table 1. The combined septal-defect rate is
    not a VSD-specific estimate.
- category: Neurologic
  name: Motor Delay
  description: >-
    Motor delay was recorded in 38% of the 2017 NRAS series, separately from
    intellectual or learning disability. Some children caught up, including the
    p.Gly12Arg infant who walked at 17 months.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Motor delay and
      intellectual or learning disabilities were recorded in 38 and 42% of
      patients, respectively.
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  frequency: FREQUENT
- 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: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  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: Multiple Lentigines
  description: >-
    Multiple lentigines are documented in familial p.G60E disease. The 50% figure
    reported in the 2015 literature review combined lentigines and/or cafe-au-lait
    spots and cannot be assigned to lentigines alone.
  phenotype_term:
    preferred_term: Multiple lentigines
    term:
      id: HP:0001003
      label: Multiple lentigines
  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: |-
      She has two large Café-au-lait spots on her back and >50
      freckles (lentigines) all over her body, especially on her
      back (Fig. 1b) and arms (Fig. 1c).
    explanation: >-
      The same p.G60E woman had more than 50 lentigines and two large cafe-au-lait
      spots; these are separate findings.
- 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: |-
      She has two large Café-au-lait spots on her back and >50
      freckles (lentigines) all over her body, especially on her
      back (Fig. 1b) and arms (Fig. 1c).
    explanation: >-
      The same p.G60E woman had more than 50 lentigines and two large cafe-au-lait
      spots; these are separate findings.
  description: >-
    Cafe-au-lait macules occur in germline NRAS disease, including two large lesions
    in the p.G60E woman and several in a p.Gly12Asp infant.
- 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: >-
      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 reported germline NRAS case had numerous melanocytic nevi. This single
      observation establishes occurrence, but supplies no denominator for the frequency of
      multiple nevi in NS6.
- category: Auditory
  name: Hearing Impairment
  description: >-
    Hearing loss of unspecified type was reported in the single NRAS-positive patient in the 2026 Noonan
    cohort. The separately documented familial congenital sensorineural finding is represented by its
    more specific phenotype.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - 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: >-
      The single NRAS-positive patient had hearing loss, with type and onset unspecified. The 7/32 proportion
      belongs to the whole mixed-genotype cohort and is not an NRAS frequency.
- 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
  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: >-
      One p.Gly12Asp infant in a small, age-heterogeneous NRAS series had a JMML-like
      myeloproliferative disorder. One event among 19 ascertained individuals is not a
      population risk estimate.
- category: Neurologic
  name: Hypothalamic Mass
  description: >-
    A hypothalamic mass in a p.Gly12Arg infant was proposed radiologically to be a
    hamartoma or lipoma; no biopsy was performed. Neoplastic nature and histology
    remain unconfirmed.
  phenotype_term:
    preferred_term: Hypothalamic mass
    term:
      id: HP:0012286
      label: Abnormal hypothalamus morphology
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      A brain MRI at 8 months of
      age revealed an expansive lesion of 0.8x0.7x0.6 cm in the hypothala-
      mus proposed to represent a hamartoma or lipoma (Supplementary
      Figure S2).
    explanation: >-
      The report calls this a tumor-like lesion but proposes hamartoma or lipoma. This
      supports a suspected mass, not a histologically confirmed malignant brain tumor.
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Cryptorchidism
      occurred in 63% of affected males.
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  description: >-
    Undescended testes were reported in 63% of assessed males in the 2017 NRAS series;
    the denominator is male patients, not the entire cohort.
  frequency: FREQUENT
- category: Hematologic
  name: Bleeding Diathesis
  description: >-
    Bleeding diathesis was reported in 3/15 assessed individuals (20%). Only one had a
    confirmed coagulopathy, von Willebrand disease; a single coagulation mechanism
    should not be assigned to every bleeder.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Bleeding diathesis was reported in
      3 out of 15 individuals, but only one patient had a con ﬁrmed
      coagulopathy (von Willebrand disease, patient 8).
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  frequency: OCCASIONAL
- category: Lymphatic
  name: Lymphedema
  description: >-
    Peripheral/neonatal lymphedema is reported in the NRAS series. Cystic hygroma,
    hydrops and chylothorax are represented separately from this tissue-edema finding.
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 5 –2— (c.179G4A, p.(Gly60Glu)) is an affected child of a
      three generation family with obvious features of NS in her father and
      grandfather. She died on the ﬁrst day of life from severe hydrops. Post-
      mortem MRI revealed bilateral pleural effusions, a small pericardial
      effusion and left ventricular hypertrophy.
    explanation: >-
      The p.Gly60Glu neonate died with severe hydrops, and Table 1 records neonatal
      lymphatic edema in this patient and the p.Gly60Glu patient 6.
    directness: INDIRECT
  - 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.
- name: Short Neck
  description: >-
    A short neck is independently documented in the p.G60E adult woman. The 2017
    combined short/broad-or-webbed-neck statistic cannot quantify this component
    separately.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  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: |-
      At the age of
      24 years, she has the following features of NS (Fig. 1a): a
      large skull (62 cm) with a broad forehead, hypertelorism,
      down slanted palpebral fissures, bilateral ptosis (especially
      of her left eye), short and broad neck with a low hairline,
      and low-set ears with broad helices. Her hair is normal.
    explanation: >-
      Adult woman with familial p.G60E NRAS-associated Noonan syndrome; this is
      subtype-specific clinical examination.
- name: Atrial Septal Defect
  description: >-
    An atrial septal defect was surgically corrected in the p.Gly12Ser patient,
    independently of the confounded p.Glu37dup case.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 1— (c.34G4A, p.(Gly12Ser)) presented with typical physical
      signs of NS: facial anomalies (Figure 3), left ventricular hypertrophy,
      atrial and ventricular septal defects (corrected by surgery), a persistent
      ductus arteriosus, and short stature.
    explanation: >-
      The p.Gly12Ser patient had both atrial and ventricular septal defects. Aggregate
      septal frequencies combine both lesions.
- name: Patent Ductus Arteriosus
  description: >-
    Persistent ductus arteriosus was reported in the p.Gly12Ser patient; Table 1 also
    records it in the Costello-like p.Gly12Arg case.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 1— (c.34G4A, p.(Gly12Ser)) presented with typical physical
      signs of NS: facial anomalies (Figure 3), left ventricular hypertrophy,
      atrial and ventricular septal defects (corrected by surgery), a persistent
      ductus arteriosus, and short stature.
    explanation: >-
      Patient 1 with germline NRAS p.Gly12Ser had a persistent ductus arteriosus. The
      quoted septal defects are separate lesions and their aggregate frequency cannot be
      assigned to ductus persistence.
- name: Learning Difficulties
  description: >-
    Mild learning difficulties were reported in the p.I24N adult. They should not be
    equated with global developmental delay or intellectual disability.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: PMID:21263000
    reference_title: Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 30-year-old patient had been diagnosed with Noonan syndrome and demonstrated
      the facial features, low posterior hairline, webbing of the neck, pectus
      excavatum, cryptorchism, mild learning difficulties and mild short stature
      characteristic of the syndrome.
    explanation: >-
      The molecularly confirmed p.I24N patient had these clinical findings; no
      component-specific frequency is derived from this single case.
- name: Mild Intellectual Disability
  description: >-
    The p.Thr50Ile patient with a CFCS-like ectodermal presentation had IQ 65.
    Perinatal asphyxia, sepsis and hydrocephalus may also have contributed; the
    familial Ile24Asn cases in Table 1 had mild ID.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The suspected clinical
      diagnosis was CFCS because of typical facial features with substantial
      supraorbital hypoplasia and prominent ectodermal ﬁndings (curly
      hair, sparse eyebrows, keratosis pilaris, facial keratosis and multiple
      nevi), while her motor and intellectual development was only mildly
      delayed (IQ 65).
    explanation: >-
      This NRAS-associated RASopathy case supports mild ID; the authors separately
      describe perinatal confounders, so it does not establish an allele-wide cognitive
      outcome.
- name: Congenital Sensorineural Hearing Impairment
  description: >-
    The affected p.G60E father had sensorineural hearing impairment from birth. The
    hearing type of the separate NRAS patient in the 2026 mixed cohort was not
    specified.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural 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: Sensorineural hearing impairment was present at birth.
    explanation: Subtype-specific congenital sensorineural hearing loss in the p.G60E father; no frequency estimate.
- name: Macrocephaly
  description: >-
    Macrocephaly is reported in multiple germline NRAS cases, including the p.Gly12Arg
    infant and the p.G60E father and daughter; normal intellect can coexist.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 12 — (c.34G4C, p.(Gly12Arg)) had a RASopathy-typical
      facial phenotype, short webbed neck, macrocephaly, and HCM.
    explanation: Macrocephaly explicitly documented in the p.Gly12Arg infant.
- name: Muscular Hypotonia
  description: >-
    Marked muscular hypotonia in infancy occurred in the p.Gly12Ser patient, whose
    intellectual testing later was normal. It is distinct from intellectual
    disability.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      She exhibited marked muscular
      hypotonia in infancy.
    explanation: The preceding clinical paragraph identifies patient 1 with p.Gly12Ser.
- name: Feeding Difficulties in Infancy
  description: >-
    Feeding difficulties occur in germline NRAS disease. Severe oral aversion
    requiring gastrostomy was reported in the Costello-like p.Gly12Arg infant;
    severity is not universal.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The postnatal
      period was complicated by prolonged hyperinsulinemic hypoglycemia,
      severe feeding dif ﬁculties, including oral aversion and respiratory
      difﬁculties due to upper airway collapse. She was treated with a
      percutaneous gastrostomy and a tracheostomy with continuous
      positive airway pressure ventilation.
    explanation: >-
      Patient 12 with p.Gly12Arg had severe feeding and upper-airway difficulties; this
      is a case-specific severe presentation.
- name: Upper Airway Obstruction
  description: >-
    Upper airway collapse in the p.Gly12Arg infant required tracheostomy and
    positive-pressure ventilation; the tracheostomy was removed at 20 months.
  phenotype_term:
    preferred_term: Upper airway obstruction
    term:
      id: HP:0002781
      label: Upper airway obstruction
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The postnatal
      period was complicated by prolonged hyperinsulinemic hypoglycemia,
      severe feeding dif ﬁculties, including oral aversion and respiratory
      difﬁculties due to upper airway collapse. She was treated with a
      percutaneous gastrostomy and a tracheostomy with continuous
      positive airway pressure ventilation.
    explanation: >-
      Patient 12 with p.Gly12Arg had severe feeding and upper-airway difficulties; this
      is a case-specific severe presentation.
- name: Hyperinsulinemic Hypoglycemia
  description: >-
    Prolonged neonatal hyperinsulinemic hypoglycemia was reported in the Costello-like
    p.Gly12Arg infant; no disease-wide frequency or NRAS-specific beta-cell mechanism
    is established.
  phenotype_term:
    preferred_term: Hyperinsulinemic hypoglycemia
    term:
      id: HP:0000825
      label: Hyperinsulinemic hypoglycemia
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The postnatal
      period was complicated by prolonged hyperinsulinemic hypoglycemia,
      severe feeding dif ﬁculties, including oral aversion and respiratory
      difﬁculties due to upper airway collapse. She was treated with a
      percutaneous gastrostomy and a tracheostomy with continuous
      positive airway pressure ventilation.
    explanation: >-
      Patient 12 with germline NRAS p.Gly12Arg had prolonged postnatal hyperinsulinemic
      hypoglycemia. The same case had feeding and airway complications, but this
      observation does not establish the frequency or beta-cell mechanism of hypoglycemia
      in NS6.
- name: Polyhydramnios
  description: >-
    Polyhydramnios was reported in 46% of assessed pregnancies in the 2017 NRAS
    series; this is a prenatal ascertainment denominator.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      In addition, the majority of patients had prenatal
      abnormalities (69%) with polyhydramnios being reported in 46% of
      the cases.
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
- name: Cystic Hygroma
  description: >-
    A large nuchal cystic hygroma was detected at 12 weeks in the p.Gly12Val fetus,
    followed by progressive hydrops and intrauterine death at 22 weeks.
  phenotype_term:
    preferred_term: Cystic hygroma
    term:
      id: HP:0000476
      label: Cystic hygroma
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 2 — (c.35G4T, p.(Gly12Val)) was a fetus with a suspected
      RASopathy based on the ﬁnding of a very large cystic nuchal hygroma
      (14.3 mm) at 12 weeks of gestation.
    explanation: Germline p.Gly12Val fetal presentation; no heart defect was detected and no autopsy was available.
- name: Hydrops Fetalis
  description: >-
    Severe hydrops occurred in the p.Gly12Val fetus and in a p.Gly60Glu neonate who
    died on the first day of life. It is not restricted to oncogenic-codon alleles.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Progressive hydrops foetalis
      developed, eventually leading to intrauterine death at 22 weeks of
      gestation. No autopsy data were available but hydropic appearance of
      the fetus was reported.
    explanation: >-
      The preceding case identification establishes germline NRAS p.Gly12Val. This passage
      documents progressive fetal hydrops and intrauterine death at 22 weeks; no autopsy
      was available.
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 5 –2— (c.179G4A, p.(Gly60Glu)) is an affected child of a
      three generation family with obvious features of NS in her father and
      grandfather. She died on the ﬁrst day of life from severe hydrops. Post-
      mortem MRI revealed bilateral pleural effusions, a small pericardial
      effusion and left ventricular hypertrophy.
    explanation: >-
      The germline NRAS p.Gly60Glu neonate died on the first day of life with severe
      hydrops and pleural/pericardial effusions. This independently demonstrates that
      hydrops is not confined to oncogenic-codon alleles.
- name: Chylothorax
  description: >-
    Fetal/neonatal chylothorax is reported in the NRAS series, including patient 6
    with p.Gly60Glu. The 23% aggregate combines chylothorax and hydrops and is not a
    chylothorax-only frequency.
  phenotype_term:
    preferred_term: Chylothorax
    term:
      id: HP:0010310
      label: Chylothorax
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Nuchal oedema and fetal chylothorax/hydrops as prenatal
      abnormalities were seen in 15 and 23%, respectively.
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment. Table 1 specifies
      congenital/neonatal chylothorax in patient 6.
- name: Keratosis Pilaris
  description: >-
    Keratosis pilaris occurs in NRAS-associated RASopathy, including the p.Thr50Ile
    patient with a CFCS-like ectodermal presentation.
  phenotype_term:
    preferred_term: Keratosis pilaris
    term:
      id: HP:0032152
      label: Keratosis pilaris
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The suspected clinical
      diagnosis was CFCS because of typical facial features with substantial
      supraorbital hypoplasia and prominent ectodermal ﬁndings (curly
      hair, sparse eyebrows, keratosis pilaris, facial keratosis and multiple
      nevi), while her motor and intellectual development was only mildly
      delayed (IQ 65).
    explanation: >-
      Patient 11 with germline NRAS p.Thr50Ile had keratosis pilaris within a CFCS-like
      ectodermal presentation. This is a case-specific skin finding, without an allele-wide or disease-wide frequency estimate.
- name: Low-set Ears
  description: Low-set ears with broad helices were documented in the adult p.G60E woman.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  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: |-
      At the age of
      24 years, she has the following features of NS (Fig. 1a): a
      large skull (62 cm) with a broad forehead, hypertelorism,
      down slanted palpebral fissures, bilateral ptosis (especially
      of her left eye), short and broad neck with a low hairline,
      and low-set ears with broad helices. Her hair is normal.
    explanation: >-
      Adult woman with familial p.G60E NRAS-associated Noonan syndrome; this is
      subtype-specific clinical examination.
- name: Low Posterior Hairline
  description: Low posterior hairline was documented in the p.I24N adult and p.G60E woman.
  phenotype_term:
    preferred_term: Low posterior hairline
    term:
      id: HP:0002162
      label: Low posterior hairline
  evidence:
  - reference: PMID:21263000
    reference_title: Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 30-year-old patient had been diagnosed with Noonan syndrome and demonstrated
      the facial features, low posterior hairline, webbing of the neck, pectus
      excavatum, cryptorchism, mild learning difficulties and mild short stature
      characteristic of the syndrome.
    explanation: >-
      The molecularly confirmed p.I24N patient had these clinical findings; no
      component-specific frequency is derived from this single case.
- name: Dilatation of the Renal Pelvis
  description: >-
    Mild left pyelocalyceal dilation (7 mm) was detected prenatally in the p.Gly12Asp infant. More complex hydronephrosis and duplex collecting-system findings occurred in the p.Glu37dup case with an additional 22q11.23 duplication and are not generalized to NS6.
  phenotype_term:
    preferred_term: Dilatation of the renal pelvis
    term:
      id: HP:0010946
      label: Dilatation of the renal pelvis
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 13 — (c.35G4A, p.(Gly12Asp)) is a male born after an
      uneventful pregnancy except for mild fetal pyelocalyceal dilatation
      (7 mm) of the left kidney detected on ultrasound scans.
    explanation: Prenatal mild unilateral renal pelvic/calyceal dilation in the p.Gly12Asp patient, independently of the confounded p.Glu37dup case with complex urinary abnormalities.
- name: Fetal Nuchal Edema
  category: Prenatal
  description: >-
    Fetal nuchal edema occurs in the NRAS-associated RASopathy series. It is kept distinct from the separately
    described cystic hygroma and hydrops.
  phenotype_term:
    preferred_term: Fetal nuchal edema
    term:
      id: HP:0034250
      label: Fetal nuchal edema
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Nuchal oedema and fetal chylothorax/hydrops as prenatal
      abnormalities were seen in 15 and 23%, respectively.
    explanation: >-
      The 2017 NRAS series reports nuchal edema in 15% of variably assessed prenatal histories. No disease-wide
      frequency band is assigned, and the source does not specify a nuchal-translucency measurement threshold.
- name: Curly Hair
  category: Dermatologic
  description: >-
    Curly hair was reported in the p.Thr50Ile patient with a CFCS-like presentation.
  phenotype_term:
    preferred_term: Curly hair
    term:
      id: HP:0002212
      label: Curly hair
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The suspected clinical
      diagnosis was CFCS because of typical facial features with substantial
      supraorbital hypoplasia and prominent ectodermal ﬁndings (curly
      hair, sparse eyebrows, keratosis pilaris, facial keratosis and multiple
      nevi), while her motor and intellectual development was only mildly
      delayed (IQ 65).
    explanation: >-
      Patient 11 carries p.Thr50Ile NRAS and has curly hair. This is a case-level observation, separate
      from sparse eyebrows or scalp hair.
- name: Sparse Eyebrows
  category: Dermatologic
  description: >-
    Sparse eyebrows were reported in the p.Thr50Ile patient with a CFCS-like presentation.
  phenotype_term:
    preferred_term: Sparse eyebrow
    term:
      id: HP:0045075
      label: Sparse eyebrow
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The suspected clinical
      diagnosis was CFCS because of typical facial features with substantial
      supraorbital hypoplasia and prominent ectodermal ﬁndings (curly
      hair, sparse eyebrows, keratosis pilaris, facial keratosis and multiple
      nevi), while her motor and intellectual development was only mildly
      delayed (IQ 65).
    explanation: >-
      The p.Thr50Ile case specifically documents eyebrow sparseness, not just curly scalp hair. No frequency
      band is inferred.
- name: Sparse Hair
  category: Dermatologic
  description: >-
    Sparse scalp hair was described in the p.Gly12Arg child with a Costello-like RASopathy presentation.
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      She had sparse, thin hair, full
      lips, deep palmar and plantar creases, several small nevi and one café-
      au-lait spot.
    explanation: >-
      Patient 12 carries germline p.Gly12Arg NRAS. Sparse hair is supported in this individual; the phrase
      thin hair does not establish a separate hair-shaft diameter abnormality.
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: IN_VITRO
    snippet: >-
      Here we report that germline NRAS mutations conferring enhanced stimulus-dependent
      MAPK activation account for some cases of this disorder.
    explanation: >-
      The enhanced MAPK activation component of this claim derives from transfected-cell
      assays; human sequencing establishes the germline diagnosis.
  - 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.
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The patient ´s father was found to have a
      mosaicism for the variant in his peripheral blood (Supplementary
      Figure S1).
    explanation: >-
      Patient 8 has Thr58Ile in urine, saliva and blood; her father has blood mosaicism and no suggestive
      RASopathy signs. This establishes parental mosaicism in this family, without quantifying gonadal
      mosaicism or recurrence risk.
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 between E15.5 and E17.5 — 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: OTHER
    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.
differential_diagnoses:
- name: >-
    Somatic NRAS-mutant myeloid neoplasia
  description: >-
    The NRAS codons mutated in NS6 - Gly12 above all - are the same codons mutated somatically in juvenile myelomonocytic leukemia and related myeloid neoplasms, so an NRAS variant found in blood or bone marrow does not by itself distinguish a constitutional RASopathy from an acquired clonal lesion. The distinction is made by demonstrating the variant in a non-hematopoietic tissue, and it is not academic: the germline-versus-somatic call carries different prognosis and different management. NS6 is additionally the entity in which the two can coexist, because a germline oncogenic-codon allele is itself a myeloid tumor-predisposing state.
  disease_term:
    preferred_term: juvenile myelomonocytic leukemia
    term:
      id: MONDO:0011908
      label: juvenile myelomonocytic leukemia
  distinguishing_features:
  - Demonstration of the NRAS variant in a non-hematopoietic tissue (skin fibroblasts, buccal cells) establishes constitutional origin and favors NS6.
  - Extra-hematopoietic Noonan features - characteristic facies, congenital heart disease, short stature - favor NS6 over an isolated somatic myeloid lesion.
  evidence:
  - reference: PMID:42193013
    reference_title: "Molecular Advances in Juvenile Myelomonocytic Leukemia and Associated RASopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The distinction between germline and somatic mutations profoundly influences
      prognosis
    explanation: >-
      Establishes that separating a constitutional RASopathy allele from an acquired
      myeloid one changes prognosis, which is why this differential is a management
      question and not just a labelling one. Graded INDIRECT because the statement is
      made across the RAS-pathway JMML genes rather than for NRAS specifically.
- name: >-
    Other molecularly defined Noonan syndrome subtypes
  description: >-
    NS6 is delimited by its gene, not by its clinical picture, which sits inside the shared Noonan phenotype. PTPN11, SOS1, RAF1, RIT1, KRAS, SOS2, LZTR1, BRAF, SHOC2, CBL and PPP1CB variants all produce an overlapping presentation, and PTPN11 alone accounts for a much larger share of Noonan syndrome than NRAS. Discrimination is molecular: a RASopathy gene panel, not the phenotype, assigns the subtype.
  disease_term:
    preferred_term: Noonan syndrome
    term:
      id: MONDO:0018997
      label: Noonan syndrome
  distinguishing_features:
  - Only a pathogenic NRAS variant assigns NS6; the clinical phenotype does not separate it from the other Noonan subtypes.
  - NRAS is among the rarest Noonan genes, so a Noonan phenotype is far more likely to carry a PTPN11 variant on prior probability alone.
  evidence:
  - reference: PMID:41988663
    reference_title: "Clinical and Genetic Characterization of Noonan Syndrome in a Colombian Pediatric Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pathogenic variants were identified across 13 genes, with PTPN11 being the most
      frequent (26/45, 57.8%), followed by PPP1CB and several less frequent genes
      including SOS1, SOS2, LZTR1, RAF1, MAP2K1, KRAS, NRAS, BRAF, CBL, NF1, and SHOC2
    explanation: >-
      A consecutive molecularly confirmed Noonan cohort in which NRAS is one of thirteen
      causal genes and PTPN11 dominates, which is the prior-probability point this
      differential rests on.
  - reference: PMID:41496802
    reference_title: "Molecular and Clinical Profiles of Patients with RASopathies: Targeted Next-Generation Sequencing Panel Results and Identification of 14 Novel Disease-Causing Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional variants, likely to represent clinically significant findings, were
      identified in PTPN11 (n = 11), RAF1 (n = 4), SOS1 (n = 3), RIT1 (n = 3), KRAS
      (n = 1), NRAS (n = 1), SOS2 (n = 1), and BRAF (n = 1).
    explanation: >-
      A referred RASopathy series in which a single NRAS case sits among the other Noonan
      genes, quantifying how rarely NRAS is the answer.
- name: >-
    Costello syndrome and other germline RASopathies
  description: >-
    Costello syndrome (HRAS) is the nearest neighbour conceptually, since it is the other RASopathy caused by a germline variant in a canonical RAS GTPase, and it shares the craniofacial, cardiac, growth and tumor-predisposition axes with NS6. Cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Legius syndrome and neurofibromatosis type 1 complete the germline RASopathy differential. These are separated by their distinctive cutaneous findings and by gene, not by the shared RAS-MAPK phenotype.
  disease_term:
    preferred_term: Costello syndrome
    term:
      id: MONDO:0009026
      label: Costello syndrome
  distinguishing_features:
  - Costello syndrome carries deep palmar/plantar creases, papillomata and a characteristic solid-tumor risk profile not typical of NS6.
  - Cutaneous findings (lentigines, keratosis pilaris, cafe-au-lait macules) discriminate several germline RASopathies clinically before genotyping.
  evidence:
  - reference: PMID:40518121
    reference_title: "RASopathies. Part I: Genetics and therapeutic considerations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The germline RASopathies include neurofibromatosis type 1 (not discussed in detail
      in this review), Noonan syndrome, Noonan syndrome with multiple lentigines, Legius
      syndrome, capillary malformation-arteriovenous malformation syndrome, Costello
      syndrome, and cardiofaciocutaneous syndrome.
    explanation: >-
      Enumerates the germline RASopathy set that NS6 must be distinguished from. Graded
      INDIRECT because it defines the differential group at the RASopathy level rather
      than naming NRAS.
  - reference: PMID:40532825
    reference_title: "RASopathies. Part II: Cutaneous and extracutaneous manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Many RASopathies can be clinically diagnosed based on their cutaneous findings, thus
      it is essential for dermatologists to be comfortable differentiating RASopathies for
      accurate diagnosis and appropriate management.
    explanation: >-
      Supports the cutaneous axis as the clinical discriminator within this differential
      group. Graded INDIRECT for the same reason as above.
- name: >-
    1p13.2 microdeletion (NRAS haploinsufficiency)
  notes: >-
    Deliberately carries no disease_term. MONDO was searched for a 1p13.2 deletion concept and has none - the nearest hit is MONDO:0014825 chromosome 11p13 deletion syndrome, distal, which is a different locus. Per the term contract, no term beats a wrong one.
  description: >-
    Contiguous-gene deletions at 1p13.2 that remove NRAS produce a phenotype overlapping Noonan syndrome, and are not NS6. The distinction matters because the two are mechanistically opposite: NS6 is caused by a gain-of-function missense allele, whereas the deletion leaves one functional copy. A sequencing-only workflow that finds no pathogenic NRAS variant will miss the deletion, so copy-number analysis is the test that separates them.
  distinguishing_features:
  - A 1p13.2 copy-number loss with no pathogenic NRAS sequence variant identifies the deletion rather than NS6.
  - Deletion cases carry the phenotypes of the other genes in the deleted segment, so features outside the Noonan spectrum point away from NS6.
  evidence:
  - reference: PMID:27561113
    reference_title: "1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Retrospective analysis of other nine reported patients with 1p13.2 microdeletions
      showed that six of them also presented some characteristics of NS.
    explanation: >-
      Establishes that 1p13.2 microdeletion recurrently presents with Noonan features, which
      is what makes it a differential for a molecularly unconfirmed Noonan phenotype.
  - reference: PMID:27561113
    reference_title: "1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all these cases, the deleted segment included the NRAS gene.
    explanation: >-
      Identifies NRAS as the deleted gene common to the overlapping cases, which is why this
      differential sits specifically against NS6 rather than against Noonan syndrome generally.
- name: >-
    Turner syndrome
  description: >-
    The classic non-RASopathy mimic, and the one differential here that is not a RAS-MAPK disorder at all. Turner syndrome shares the features that make the Noonan phenotype recognizable - short stature, webbed neck, lymphedema and congenital heart disease - so the resemblance is with the clinical gestalt rather than with the mechanism. The two are separated by karyotype or chromosomal microarray, not by a RASopathy gene panel, which is why a sequencing-first workflow can miss it: a panel that finds no pathogenic RASopathy variant does not exclude Turner syndrome, because it was never testing for it. Historical usage reflected the overlap, Noonan syndrome having once been described in Turner-like terms before its genetic basis was known.
  disease_term:
    preferred_term: Turner syndrome
    term:
      id: MONDO:0019499
      label: Turner syndrome
  distinguishing_features:
  - Karyotype or chromosomal microarray showing 45,X or a structural X anomaly identifies Turner syndrome; NS6 has a normal karyotype.
  - Turner syndrome affects phenotypic females; NS6 is autosomal dominant and affects both sexes.
  - Left-sided obstructive lesions (bicuspid aortic valve, coarctation) typify Turner syndrome, whereas the Noonan spectrum is weighted toward pulmonic stenosis and hypertrophic cardiomyopathy.
  evidence:
  - reference: PMID:34858328
    reference_title: "GH Responsiveness in Children With Noonan Syndrome Compared to Turner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Despite different genetic background, Noonan syndrome (NS) shares similar phenotype
      features to Turner syndrome (TS) such as short stature, webbed neck and congenital
      heart defects.
    explanation: >-
      States the phenotypic overlap that makes Turner syndrome a differential, and states
      explicitly that the genetic basis differs, which is what the karyotype discriminator
      rests on. Graded INDIRECT because it characterizes Noonan syndrome as a whole rather
      than the NRAS-defined subtype, reaching NS6 through the parent entity in the same way
      as the other parent-level statements in this entry.
treatments:
- name: Recombinant Growth Hormone (Somatropin) Therapy
  description: >-
    Growth hormone can increase growth velocity in Noonan syndrome. One p.G60E woman
    with partial GH deficiency had an excellent childhood response and reached 164.5
    cm; this single case does not establish average NS6 efficacy or long-term safety.
  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 summarizes increased growth velocity with GH treatment in Noonan syndrome. Applied indirectly
      because the reported treatment effect is not specific to NRAS.
  - 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: |-
      Her FH is 164.5 cm ( −0.45 SDS) and weight of 60 kg (+0.3
      SDS).
    explanation: >-
      Final height in the p.G60E woman following childhood GH treatment; the preceding
      case history documents treatment and partial GH deficiency.
  - 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: |-
      She had low endogenous growth hormone (GH) secretion
      defined as “partial GH deficiency”, and started GH therapy
      within a formal clinical trial (NovoNordisk) from 6.5 years
      of age. She was treated with GH (dose of 66 μg/kg/day)
      and responded exceptionally well and treatment was dis-
      continued after two years.
    explanation: >-
      The p.G60E woman received GH and had an excellent response; a single patient
      cannot quantify subtype-wide effectiveness.
- 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: OTHER
    snippet: >-
      No formal clinical trial of trametinib in neonatal/pediatric Noonan syndrome has been
      published to our knowledge.
    explanation: >-
      The authors describe the published literature as of their review, not an observed
      treatment outcome. This supports the experimental status of trametinib in general
      Noonan syndrome and applies indirectly to NRAS-associated NS6.
- 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: OTHER
    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: OTHER
    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.
- name: Childhood Myeloproliferative Disorder Surveillance
  description: >-
    The 2024 AACR consensus recommends physical examination for hepatosplenomegaly from birth or diagnosis,
    every three months through age one year, then at each well-child visit until age five and as indicated
    by symptoms, regardless of Noonan genotype. Obtain a CBC for illness or hepatosplenomegaly and refer
    suspected MPD to pediatric hematology/oncology. Routine CBC in healthy asymptomatic children and routine
    imaging or laboratory surveillance for solid tumors are not recommended; families may receive symptom
    education. These are general Noonan recommendations applied to NS6, not NRAS-specific evidence of
    surveillance benefit.
  treatment_term:
    preferred_term: clinical surveillance for childhood myeloproliferative disorder
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: PMID:39196581
    reference_title: Update on Pediatric Cancer Surveillance Recommendations for Patients with
      Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related
      RASopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical exam remains the mainstay of early intervention, and all patients, regardless of genotype,
      are recommended to have close monitoring including physical examination for hepatosplenomegaly especially
      during infancy and early childhood (Table 2).
    explanation: >-
      The AACR consensus recommends clinical monitoring across Noonan genotypes, including NRAS by scope.
      This is expert advice rather than an NRAS-specific surveillance-outcome study.
    directness: INDIRECT
  - reference: PMID:39196581
    reference_title: Update on Pediatric Cancer Surveillance Recommendations for Patients with
      Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related
      RASopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is no evidence that in otherwise healthy children with NS or CBL syndrome, surveillance with
      complete blood counts (CBC) is beneficial. Therefore, routine CBC has been removed from surveillance,
      in alignment with other CPS predisposing to leukemia (See related manuscript through the AACR-Cancer
      Predisposition Working Group specific to leukemia surveillance).
    explanation: >-
      Routine blood-count screening is not recommended for healthy asymptomatic children. This does not
      apply to a child with suspected MPD, illness or hepatosplenomegaly.
    directness: INDIRECT
  - reference: PMID:39196581
    reference_title: Update on Pediatric Cancer Surveillance Recommendations for Patients with
      Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related
      RASopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Every 3 months through age 1y, then at every well child visit until age 5y, and as needed for clinical
      symptoms.
    explanation: >-
      Table 2 starts monitoring at birth or diagnosis; CBC is indicated when ill or when hepatosplenomegaly
      is found, and abnormal findings warrant an experienced hematologist.
    directness: INDIRECT
  - reference: PMID:39196581
    reference_title: Update on Pediatric Cancer Surveillance Recommendations for Patients with
      Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related
      RASopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The absolute cancer risk for non-hematologic malignancies is not sufficiently high to warrant radiologic
      or laboratory surveillance. However, education of patients and families on the signs and symptoms
      of RMS, gliomas, and NB can be considered.
    explanation: >-
      The consensus favors symptom education over routine solid-tumor imaging or laboratory screening
      in Noonan syndrome. It does not supply allele-specific NRAS penetrance estimates or a tumor-preventive
      treatment.
    directness: INDIRECT
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.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      NS6 is a constitutional single-gene disorder of a developmental signalling pathway,
      which is the primary axis on which it belongs to a clinical service.
    evidence:
    - reference: PMID:40518121
      reference_title: "RASopathies. Part I: Genetics and therapeutic considerations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        RASopathies are common developmental disorders caused by variants in RAS and
        RAS-related proteins that affect a biological signaling pathway regulating cell
        growth and development.
      explanation: >-
        Places NS6 in the inherited developmental-signalling disorder class. Graded
        INDIRECT because the statement characterizes the RASopathies as a family rather
        than NRAS-mutant Noonan syndrome specifically.
  - classification_value: CARDIOVASCULAR
    notes: >-
      Congenital heart disease and hypertrophic cardiomyopathy carry the dominant
      surveillance and management burden in this entry, which is why the cardiovascular
      Part is assigned alongside the genetic one.
    evidence:
    - reference: PMID:40176696
      reference_title: "RASopathies and Cardiac Complications: Insights into Mechanisms, Diagnosis, and Innovative Treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        While extensively studied for their role in cancer, RAS gene mutations also
        contribute significantly to cardiovascular diseases, such as hypertrophic
        cardiomyopathy, pulmonary valve stenosis, and atrial septal defects.
      explanation: >-
        Establishes the cardiovascular lesion set that drives management in RAS-pathway
        disease. Graded INDIRECT because it is asserted across the RAS genes; the same
        review notes N-Ras is the least studied of them in cardiac cells, so the
        cardiovascular assignment here rests on the shared RASopathy lesion spectrum and
        on this entry's own cardiac phenotypes rather than on NRAS-specific cardiac data.
  mechanistic_category:
  - classification_value: RASopathy
    notes: >-
      NS6 is a germline RASopathy in the strict sense - the causal lesion is a
      gain-of-function variant in a canonical RAS GTPase itself, not in an upstream
      regulator or downstream kinase.
    evidence:
    - reference: PMID:40518121
      reference_title: "RASopathies. Part I: Genetics and therapeutic considerations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The germline RASopathies include neurofibromatosis type 1 (not discussed in detail
        in this review), Noonan syndrome, Noonan syndrome with multiple lentigines, Legius
        syndrome, capillary malformation-arteriovenous malformation syndrome, Costello
        syndrome, and cardiofaciocutaneous syndrome.
      explanation: >-
        Names Noonan syndrome, of which NS6 is the NRAS-defined subtype, among the
        germline RASopathies, which is the mechanistic nosology assigned here. Graded
        INDIRECT for the same reason as the other use of this quote: it names the parent
        entity, so it reaches NS6 through Noonan syndrome rather than naming NRAS.
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: >-
    Published NRAS RASopathy series contain few tumor events with heterogeneous ages
    and follow-up. The 2015 familial literature review predates the expanded
    oncogenic-codon spectrum and cannot establish equal risk between NRAS and other
    Noonan genotypes. The 2017 brain mass was unbiopsied and possibly hamartomatous.
    Allele-stratified lifetime risk therefore remains unresolved.
  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: >-
      Historical interpretation from a small, earlier case series; it cannot establish
      risk equivalence or refute later allele-specific susceptibility.
  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 between E15.5 and E17.5, 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.
- discussion_id: ns6_haploinsufficiency_versus_gain_of_function
  kind: KNOWLEDGE_GAP
  prompt: >-
    If NS6 is caused by gain-of-function NRAS alleles that raise RAS-MAPK flux, why do
    1p13.2 microdeletions that remove one NRAS copy produce an overlapping Noonan
    phenotype?
  rationale: >-
    The canonical MAPK interpretation of NS6 involves increased signal throughput into
    RAF-MEK-ERK. A loss-of-dosage lesion converging on a similar clinical picture
    challenges a simple monotonic MAPK model; it does not establish equivalence across the
    parallel effector responses, including AKT. Three readings are open and the published
    data do not separate them: the deletion phenotype may be driven by other genes in the
    deleted segment rather than by NRAS; reduced N-Ras may perturb pathway output non-monotonically, so that both raising and lowering it degrades developmental signalling;
    or the shared features may be non-specific enough that clinical overlap does not imply
    mechanistic convergence. The same loss-and-gain pattern is reported for MAP2K2 and
    SHOC2, so this is a recurring question about RAS-MAPK dosage rather than an NRAS
    curiosity. Resolving it bears on whether MEK inhibition is a rational therapy for the
    deletion phenotype, where it could plausibly make matters worse.
  attaches_to:
  - pathophysiology#NRAS Germline Gain-of-Function Variant
  - pathophysiology#RAS-MAPK Cascade Hyperactivation
  evidence:
  - reference: PMID:27561113
    reference_title: "1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations
      may have similar clinical consequences.
    explanation: >-
      The authors state the convergence as a conjecture ("it is conceivable"), which is
      precisely why it is recorded here as an open question rather than as a competing
      mechanism in the pathograph.
  - reference: PMID:19966803
    reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we report that germline NRAS mutations conferring enhanced stimulus-dependent
      MAPK activation account for some cases of this disorder.
    explanation: >-
      The enhanced MAPK activation component of this claim derives from transfected-cell
      assays; human sequencing establishes the germline diagnosis.
  proposed_experiments:
  - experiment_id: ns6_nras_dosage_series
    name: NRAS dosage series against developmental RAS-MAPK output
    description: >-
      Compare ERK pathway output and developmental phenotype across an allelic dosage
      series - NRAS null/heterozygous-null, wild type, and a knock-in non-hotspot NS6
      allele - in one system, to test whether pathway output responds non-monotonically to
      N-Ras dosage or whether the deletion phenotype is carried by neighbouring genes.
    perturbations:
    - name: Heterozygous NRAS loss versus knock-in NS6 gain-of-function allele
      target: pathophysiology#NRAS Germline Gain-of-Function Variant
      genes:
      - preferred_term: NRAS
        term:
          id: hgnc:7989
          label: NRAS
    readouts:
    - name: Phosphorylated ERK as developmental RAS-MAPK output
      target: pathophysiology#RAS-MAPK Cascade Hyperactivation
      biological_processes:
      - preferred_term: ERK1 and ERK2 cascade
        term:
          id: GO:0070371
          label: ERK1 and ERK2 cascade
      direction: ALTERED
      interpretation: >-
        A similar developmental phenotype arising from opposite directions of pathway
        output would support non-monotonic dosage sensitivity; output changing only in the
        gain-of-function arm would point to neighbouring genes carrying the deletion
        phenotype.
- discussion_id: ns6_neurodevelopmental_attribution
  kind: KNOWLEDGE_GAP
  prompt: Which neural, muscular or auditory mechanisms account for NRAS-associated findings?
  rationale: >-
    Motor delay and hypotonia are separable from intellect, and later catch-up is
    documented. The severe intellectual-disability case is allele-specific; the
    extreme 2017 Glu37dup developmental presentation also had a 22q11.23 duplication
    and hypoxic ischemic injury. The reviewed NRAS sources do not resolve the relative
    neural, muscular and sensory contributions. A specific causal tissue route for
    hearing loss is not established.
  attaches_to:
  - phenotypes#Motor Delay
  - phenotypes#Severe Intellectual Disability
  - phenotypes#Muscular Hypotonia
  - phenotypes#Hearing Impairment
  - phenotypes#Congenital Sensorineural Hearing Impairment
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Motor delay and
      intellectual or learning disabilities were recorded in 38 and 42% of
      patients, respectively.
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  - 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.
- discussion_id: ns6_anatomical_and_skin_attribution
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which NRAS-specific developmental mechanisms generate the remaining anatomical and
    cutaneous findings?
  rationale: >-
    The reviewed sources establish the clinical findings but do not assign distinct tissue mechanisms
    to these endpoints. The zebrafish craniofacial evidence supports widening, not every facial feature;
    the NrasG12D mouse demonstrates ventricular septation and pulmonary valve defects, not a ductal mechanism;
    the atrial septal pathway link is instead a qualified extrapolation from the RASopathy review. Somatic
    mosaic NRAS nevus biology cannot automatically establish the mechanism of pigmentation in constitutional
    NS6. Pectus carinatum remains supported indirectly by parent-Noonan evidence. The clinical NRAS reports
    identify curly hair, sparse scalp hair and sparse eyebrows, but do not establish their follicular
    mechanism or demonstrate that the experimental AKT response causes these findings.
  attaches_to:
  - phenotypes#Downslanted Palpebral Fissures
  - phenotypes#Strabismus
  - phenotypes#Short Neck
  - phenotypes#Pectus Carinatum
  - phenotypes#Pectus Excavatum
  - phenotypes#Patent Ductus Arteriosus
  - phenotypes#Multiple Lentigines
  - phenotypes#Cafe-au-lait Macules
  - phenotypes#Multiple Melanocytic Nevi
  - phenotypes#Macrocephaly
  - phenotypes#Keratosis Pilaris
  - phenotypes#Low Posterior Hairline
  - phenotypes#Curly Hair
  - phenotypes#Sparse Hair
  - phenotypes#Sparse Eyebrows
  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 led to a significant increase in the angle of the
      ceratohyal (P<0.05; Student’s t-test) (Fig. 4C,D) and hence we conclude that
      N-Ras-I24N expression induced craniofacial defects in zebrafish embryos that are
      reminiscent of the symptoms in individuals with Noonan syndrome.
    explanation: >-
      Ceratohyal-angle changes in a transient-expression zebrafish model support
      craniofacial widening; translation to human hypertelorism is provisional.
    directness: INDIRECT
  - 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: |-
      She has two large Café-au-lait spots on her back and >50
      freckles (lentigines) all over her body, especially on her
      back (Fig. 1b) and arms (Fig. 1c).
    explanation: >-
      The same p.G60E woman had more than 50 lentigines and two large cafe-au-lait
      spots; these are separate findings.
- discussion_id: ns6_infantile_and_prenatal_attribution
  kind: KNOWLEDGE_GAP
  prompt: What accounts for the heterogeneous prenatal and infantile complications?
  rationale: >-
    The severe Gly12Arg presentation combines oral aversion, upper airway collapse and hyperinsulinemic hypoglycemia, with subsequent improvement. Their co-occurrence does not identify the NRAS-dependent tissue route or establish that one causes the others. Polyhydramnios is documented separately from hydrops; the series does not identify a uniform mechanism. These are attribution gaps, not evidence that all findings are causally independent. The mild prenatal renal dilation likewise lacks a demonstrated NRAS-specific causal anatomical or functional route.
  attaches_to:
  - phenotypes#Feeding Difficulties in Infancy
  - phenotypes#Upper Airway Obstruction
  - phenotypes#Hyperinsulinemic Hypoglycemia
  - phenotypes#Polyhydramnios
  - phenotypes#Dilatation of the Renal Pelvis
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The postnatal
      period was complicated by prolonged hyperinsulinemic hypoglycemia,
      severe feeding dif ﬁculties, including oral aversion and respiratory
      difﬁculties due to upper airway collapse. She was treated with a
      percutaneous gastrostomy and a tracheostomy with continuous
      positive airway pressure ventilation.
    explanation: >-
      Patient 12 with p.Gly12Arg had prolonged postnatal hyperinsulinemic hypoglycemia,
      severe feeding difficulties and upper-airway collapse. These co-occurring case-specific complications do not establish a single shared mechanism.
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      In addition, the majority of patients had prenatal
      abnormalities (69%) with polyhydramnios being reported in 46% of
      the cases.
    explanation: >-
      The 2017 series comprises 19 individuals from 13 families with NRAS-associated
      RASopathy, including NS, CFCS-like and Costello-like presentations. Aggregate
      statistics exclude the patient with a 22q11.23 duplication and hypoxic ischemic
      encephalopathy; denominators vary with ascertainment.
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patient 13 — (c.35G4A, p.(Gly12Asp)) is a male born after an
      uneventful pregnancy except for mild fetal pyelocalyceal dilatation
      (7 mm) of the left kidney detected on ultrasound scans.
    explanation: Prenatal mild unilateral renal pelvic/calyceal dilation in the p.Gly12Asp patient, independently of the confounded p.Glu37dup case with complex urinary abnormalities.
- discussion_id: ns6_hypothalamic_mass_identity
  kind: KNOWLEDGE_GAP
  prompt: Is the reported hypothalamic mass a neoplasm or developmental lesion, and is it attributable to NRAS?
  rationale: >-
    The unbiopsied p.Gly12Arg hypothalamic mass was proposed to be a hamartoma or lipoma. The report discusses it alongside possible tumor predisposition, but its biological nature is unresolved. It is therefore not assigned an established causal tumor-predisposition edge.
  attaches_to:
  - phenotypes#Hypothalamic Mass
  evidence:
  - reference: PMID:28594414
    reference_title: "Genotype and phenotype spectrum of NRAS germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      A brain MRI at 8 months of
      age revealed an expansive lesion of 0.8x0.7x0.6 cm in the hypothala-
      mus proposed to represent a hamartoma or lipoma (Supplementary
      Figure S2).
    explanation: >-
      The report calls this a tumor-like lesion but proposes hamartoma or lipoma. This
      supports a suspected mass, not a histologically confirmed malignant brain tumor.
- discussion_id: ns6_akt_phenotype_attribution
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Which human NS6 manifestations, if any, depend on the AKT coactivation observed
    in transfected cells?
  rationale: >-
    Thr58Ile and Gly12Val increase basal AKT phosphorylation in an ectopic HEK293T expression assay. The
    study does not isolate AKT-dependent human developmental outcomes or show comparable activation across
    all germline NRAS alleles; clinical phenotype fanout therefore remains unresolved.
  attaches_to:
  - pathophysiology#PI3K-AKT Effector Activation
  evidence:
  - reference: PMID:28594414
    reference_title: Genotype and phenotype spectrum of NRAS germline variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      By contrast, ectopic expression
      of either NRAS Thr58Ile or NRASGly12Val promoted enhanced activation
      of ERK and AKT, even in absence of stimulation (Figure 2a).
    explanation: >-
      Transiently transfected HEK293T cells expressing Thr58Ile or Gly12Val show increased basal AKT phosphorylation.
      This supports a parallel PI3K-AKT effector arm for these tested alleles, not uniform activation
      by all NRAS variants.
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.
  The refreshed full text of Altmuller et al. (PMID:28594414) supports the
  NRAS-specific frequencies recorded here. These are small, variably assessed
  case-series proportions, not population estimates; the extreme Glu37dup case with
  additional genetic/perinatal findings was excluded from aggregate statistics. 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. The falcon
  report also lists 22q11.2-related disorders among the principal differentials, and
  they are deliberately not curated as a differential_diagnoses entry: the only
  sources found that pair 22q11.2 with the Noonan phenotype are a dual-diagnosis
  case report whose one usable sentence is its own title, and a passing mention that
  chromosomal microarray may detect a second diagnosis. Neither supports a
  standalone differential claim, and the karyotype/microarray discriminator the
  Turner syndrome entry already carries covers the same diagnostic step.
  The OpenScientist report research/Noonan_Syndrome_6-deep-research-openscientist.md
  was screened and rejected: its body identifies RAF1 as the causal gene and labels
  the disease RAF1-related, whereas NS6 is NRAS-related. Its RAF1 findings F001-F013
  were not used; the wrong-gene warning already present on main is preserved.

📚

References & Deep Research

References

1

PMID:20301303

Noonan Syndrome.

No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record 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. The refreshed full text of Altmuller et al. (PMID:28594414) supports the NRAS-specific frequencies recorded here. These are small, variably assessed case-series proportions, not population estimates; the extreme Glu37dup case with additional genetic/perinatal findings was excluded from aggregate statistics. 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. The falcon report also lists 22q11.2-related disorders among the principal differentials, and they are deliberately not curated as a differential_diagnoses entry: the only sources found that pair 22q11.2 with the Noonan phenotype are a dual-diagnosis case report whose one usable sentence is its own title, and a passing mention that chromosomal microarray may detect a second diagnosis. Neither supports a standalone differential claim, and the karyotype/microarray discriminator the Turner syndrome entry already carries covers the same diagnostic step. The OpenScientist report research/Noonan_Syndrome_6-deep-research-openscientist.md was screened and rejected: its body identifies RAF1 as the causal gene and labels the disease RAF1-related, whereas NS6 is NRAS-related. Its RAF1 findings F001-F013 were not used; the wrong-gene warning already present on main is preserved.

Add classifications, differential diagnoses and NRAS-dosage knowledge gap · 2026-09-05T07:29:14Z · View source

Augmentation of an existing entry, not a creation: NS6 was already curated on main at 97.7% compliance with three prior sessions behind it, so this round filled the structural sections both sibling Noonan entries carried and this one did not. Added classifications: harrisons_chapter GENETICS_ENVIRONMENT_DISEASE and CARDIOVASCULAR, plus mechanistic_category RASopathy, which is the exact enum value for this entry - the causal lesion is a gain-of-function variant in a canonical RAS GTPase itself rather than in an upstream regulator or downstream kinase. Added differential_diagnoses with four entries: somatic NRAS-mutant myeloid neoplasia (the germline-versus-somatic call, which is the clinically consequential one here because the NS6 codons are the JMML somatic hotspots), other molecularly defined Noonan subtypes (NS6 is delimited by gene, not phenotype), Costello syndrome and the germline RASopathy group, and 1p13.2 microdeletion. Added a KNOWLEDGE_GAP discussion, ns6_haploinsufficiency_versus_gain_of_function, attached to both the NRAS variant node and the RAS-MAPK hyperactivation node: 1p13.2 deletions removing one NRAS copy produce an overlapping Noonan phenotype, which is a direct challenge to this entry's gain-of-function causal chain rather than an incidental observation, and the discussion records the three readings the published data do not separate. Its proposed experiment carries an NRAS gene binding and an ERK1/ERK2 cascade (GO:0070371) readout. Seven new references fetched and cached, all cited: PMID:42193013, PMID:41988663, PMID:41496802, PMID:40518121, PMID:40532825, PMID:40176696, PMID:27561113. Deep research. The falcon report from the 2026-08-18 session was used as the falcon basis rather than re-run, because re-running overwrites the committed artifact in place; it was given the Term Validation section it predated (51/51 terms resolved, every label matched). An independent openscientist run was commissioned for new leads and is committed, but it is OFF TARGET and must not be curated from: its body mentions RAF1 71 times and NRAS zero times, so it researched RAF1-related Noonan syndrome (NS5) throughout. just preflight-dr against MONDO:0013186 returns WARN with "Expected gene NRAS is never mentioned while RAF1 is mentioned 67 times". This is a textbook Named Entity Confusion case and a clean illustration of why the automated checks do not settle relevance: its reference validation is spotless (26/26 resolved, 0 off topic, confabulation rate 0.0) precisely because references are scored against the report's own vocabulary, which is RAF1 vocabulary. Its term validation separately flags four fabricated NCIT treatment bindings (NCIT:C2039 is Bevacizumab not beta-blockers, NCIT:C15380 is Telemedicine not heart transplantation, NCIT:C51756 is Roux-en-Y Anastomosis not septal myectomy, NCIT:C1968 is a Topoisomerase-II Inhibitor not growth hormone). Nothing from it was cited. Candidate rejected after checking. PMID:33855281 (Drosophila RASopathy models) looked like a strong third animal model, since its abstract names NRAS among the RASopathy genes and reports 13 transgenic lines each expressing a different human RASopathy isoform. The PMC full text itemizes the panel as six PTPN11, three RAF1, two BRAF, one KRAS and one HRAS isoform - there is no NRAS line. Adding it would have been fabrication from an abstract-level inference; its cache file was removed rather than committed uncited. Deliberate non-additions, both re-verified rather than assumed. The datasets block stays absent: just discover-datasets returns only GENE_ONLY candidates (AML, melanoma, glioma somatic NRAS series) with no DIRECT germline match, confirming the standing notes entry that dataset discovery for NS6 reaches only the Named Entity Confusion trap. A progression block was not added because the falcon report sources its entire temporal-development section to Altmuller 2017 (PMID:28594414), whose cache is a paywalled landing page carrying no quotable abstract - the same limitation the entry's notes already record for that cohort's frequency table. Validation. just validate-disorders passed over the changed file: schema clean, term validation passed, 104/104 snippets verified against cached references. Offline gates run and passing: check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-snippet-length, check-snippet-grading, check-title-snippets. Compliance reads 96.3% (232/241) against 97.7% (209/214) before: the compliant-item count rose by 23 while the rate dipped, because the new proposed experiment introduces datasets and evidence slots that a not-yet-run experiment cannot honestly fill.

Create: Noonan Syndrome 6 (NRAS) · 2026-08-18T20:59:35Z · View source

De novo creation of the NRAS-associated Noonan syndrome subtype entry (MONDO:0013186, OMIM:613224), resolving issue #8756. Deep research: falcon (Edison) run, research/Noonan_Syndrome_6-deep-research-falcon.md. Its own reference-validation block reported 8/8 references resolved, 0 unresolved, 0 off topic, confabulation_rate 0.0 (5 of 8 undecided for relevance because the cached records carry no abstract). NEC preflight, "just preflight-dr research/Noonan_Syndrome_6-deep-research-falcon.md MONDO:0013186", returned WARN: canonical gene NRAS dominates the report (NRAS=81 mentions vs PTPN11=3, SOS1=2), and the only flag was that the report also cites the umbrella Noonan OMIM 163950 alongside the subtype number. That line was inspected in context (report line 986 names 613224 as NS6 and 163950 as the umbrella entry), confirming this is not a wrong-entity report. The report was nonetheless used only as corroboration and as a lead source. Every curated claim is anchored on primary literature located independently via PubMed E-utilities before the report landed, and cached with just fetch-reference: PMID:19966803 (Cirstea 2010, Nat Genet, establishing germline NRAS causation), PMID:28594414 (Altmuller 2017, the 19-case NRAS cohort), PMID:26467218 (Ekvall 2015, familial G60E, hyperpigmentation), PMID:22887781 (Kraoua 2012, 2/125 screen), PMID:22855653 (Denayer 2012, 3/115 screen), PMID:21263000 (Runtuwene 2011, zebrafish I24N/G60E, MEK rescue), PMID:31697451 (Garren 2020, embryonal rhabdomyosarcoma with p.G12R), PMID:33681212 (You 2021, NrasG12D mouse cardiac defects), PMID:23875798 (Rauen, The RASopathies), PMID:40041314 (De Brouchoven 2025, trametinib systematic review), plus GeneReviews Noonan Syndrome PMID:20301303 and the ClinGen NRAS/Noonan Definitive gene-validity assertion. GeneReviews baseline: there is no NRAS/NS6-specific GeneReviews chapter, so the parent Noonan Syndrome chapter (PMID:20301303) is tagged GeneReviews in the top-level references block and used as the clinical-characteristics baseline. Every claim drawn from it is marked supports: PARTIAL with an explanation saying it characterizes the parent entity rather than the NRAS subtype. Its Agents/Circumstances to Avoid warning (aspirin, bleeding diathesis) is carried in a dedicated treatment entry. Deliberate omissions: the detailed NRAS-cohort phenotype frequencies published by Altmuller et al. sit in the paywalled full text rather than the cached abstract, so they are not asserted here as evidence-backed frequency bands; the entry says so in its notes. Only the hyperpigmentation figure (50%, in the Ekvall abstract) carries a frequency enum derived from a quantitative quote. The Noonan Syndrome umbrella entry was not modified (a sibling agent is concurrently curating NS11); NS6 cross-references it via parents and notes instead. Content: 5 pathophysiology nodes (NRAS germline gain-of-function -> RAS-MAPK cascade hyperactivation -> disrupted embryonic cardiac development / disrupted early developmental patterning, plus an oncogenic-codon tumor-predisposition node), 20 phenotypes, a genetic block with two case_fractions records, inheritance, prevalence, 5 treatments (including a MEK-inhibitor entry with target_mechanisms on the cascade node), 2 animal models with modeled_mechanisms and readouts, and 2 discussions (one KNOWLEDGE_GAP on codon-dependent tumor risk, one HUMAN_MODEL_MISMATCH on animal-model allele strength). Validation actually run and read to completion: just validate (schema: no issues; term validation: passed; reference validation: 58/58 snippets verified against cached references); just validate-disorders kb/disorders/Noonan_Syndrome_6.yaml (batched schema + terms + references, all passed, 58/58 snippets verified); just check-duplicate-keys (OK); just check-title-snippets (no new title-quoting snippets).

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

A constitutional activating NRAS allele alters a highly conserved GTPase residue.
Impaired GTP hydrolysis/GAP responsiveness or altered switch-region kinetics increases GTP-bound NRAS.
Upstream-to-downstream signal flow is enhanced through RAF–MEK–ERK/MAPK and, for tested variants, PI3K–AKT.
Dysregulated proliferation, differentiation, survival, developmental patterning, and possibly metabolism affect multiple embryonic tissues.
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

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.
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.
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)
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

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)
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)
Open Targets. MONDO:0013186—NRAS association. Disease–target evidence includes PMID 19966803 and PMID 23875798. (OpenTargets Search: Noonan syndrome 6-NRAS)
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)

References

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(reynolds2025updateonthe pages 18-20): Giuseppe Reynolds, Andrea Gazzin, Diana Carli, Stefania Massuras, Simona Cardaropoli, Maria Luca, Beatrice Defilippi, Marco Tartaglia, Giovanni Battista Ferrero, and Alessandro Mussa. Update on the clinical and molecular characterization of noonan syndrome and other rasopathies: a retrospective study and systematic review. International Journal of Molecular Sciences, 26:3515, Apr 2025. URL: https://doi.org/10.3390/ijms26083515, doi:10.3390/ijms26083515. This article has 31 citations.
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(NCT05308927 chunk 1): French Registry of Children Treated With Norditropin® for Short Stature Associated With Noonan Syndrome. Novo Nordisk A/S. 2022. ClinicalTrials.gov Identifier: NCT05308927
(NCT06668805 chunk 1): A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment. BioMarin Pharmaceutical. 2024. ClinicalTrials.gov Identifier: NCT06668805
(NCT03435627 chunk 1): Post Marketing Surveillance on Long-term Use With Norditropin® (Short Stature Due to Noonan Syndrome). Novo Nordisk A/S. 2018. ClinicalTrials.gov Identifier: NCT03435627
(NCT06555237 chunk 1): MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies. Medical University of Warsaw. 2024. ClinicalTrials.gov Identifier: NCT06555237
(altmuller2017genotypeandphenotype pages 8-8): Franziska Altmüller, Christina Lissewski, Debora Bertola, Elisabetta Flex, Zornitza Stark, Stephanie Spranger, Gareth Baynam, Michelle Buscarilli, Sarah Dyack, Jane Gillis, Helger G Yntema, Francesca Pantaleoni, Rosa LE van Loon, Sara MacKay, Kym Mina, Ina Schanze, Tiong Yang Tan, Maie Walsh, Susan M White, Marena R Niewisch, Sixto García-Miñaúr, Diego Plaza, Mohammad Reza Ahmadian, Hélène Cavé, Marco Tartaglia, and Martin Zenker. Genotype and phenotype spectrum of nras germline variants. European Journal of Human Genetics, 25:823-831, May 2017. URL: https://doi.org/10.1038/ejhg.2017.65, doi:10.1038/ejhg.2017.65. This article has 65 citations and is from a domain leading peer-reviewed journal.
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(NCT00452725 chunk 1): Effect of MAXOMAT ® on the Growth of Small Children to NOONAN's Syndrome. Sanofi. 1997. ClinicalTrials.gov Identifier: NCT00452725
(brouchoven2025trametinibasa pages 12-13): Isabel De Brouchoven, Juan Lorand, Léon Bofferding, Arthur Sorlin, An Van Damme, and Olivier Danhaive. Trametinib as a targeted treatment in cardiac and lymphatic presentations of noonan syndrome. Frontiers in Pediatrics, Feb 2025. URL: https://doi.org/10.3389/fped.2025.1475143, doi:10.3389/fped.2025.1475143. This article has 10 citations.
(brouchoven2025trametinibasa pages 1-2): Isabel De Brouchoven, Juan Lorand, Léon Bofferding, Arthur Sorlin, An Van Damme, and Olivier Danhaive. Trametinib as a targeted treatment in cardiac and lymphatic presentations of noonan syndrome. Frontiers in Pediatrics, Feb 2025. URL: https://doi.org/10.3389/fped.2025.1475143, doi:10.3389/fped.2025.1475143. This article has 10 citations.
(perrino2024updateonpediatric pages 10-11): Melissa R. Perrino, Anirban Das, Sarah R. Scollon, Sarah G. Mitchell, Mary-Louise C. Greer, Marielle E. Yohe, Jordan R. Hansford, Jennifer M. Kalish, Kris Ann P. Schultz, Suzanne P. MacFarland, Wendy K. Kohlmann, Philip J. Lupo, Kara N. Maxwell, Stefan M. Pfister, Rosanna Weksberg, Orli Michaeli, Marjolijn C.J. Jongmans, Gail E. Tomlinson, Jack Brzezinski, Uri Tabori, Gina M. Ney, Karen W. Gripp, Andrea M. Gross, Brigitte C. Widemann, Douglas R. Stewart, Emma R. Woodward, and Christian P. Kratz. Update on pediatric cancer surveillance recommendations for patients with neurofibromatosis type 1, noonan syndrome, cbl syndrome, costello syndrome, and related rasopathies. Clinical Cancer Research, 30:4834-4843, Aug 2024. URL: https://doi.org/10.1158/1078-0432.ccr-24-1611, doi:10.1158/1078-0432.ccr-24-1611. This article has 60 citations and is from a highest quality peer-reviewed journal.

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OpenScientist ▸

Key Findings

openscientist-autonomous 26 citations 2026-09-05T07:26:32.237035

Key Findings

F001 — RAF1 gain-of-function is the molecular cause of NS6

Noonan Syndrome 6 is caused by germline gain-of-function missense variants in RAF1 (CRAF). In the foundational study, Razzaque et al. identified five different RAF1 mutations in ten individuals with Noonan syndrome, and cells transfected with these mutant constructs showed increased in vitro kinase activity and enhanced ERK activation — establishing both the causal gene and the gain-of-function mechanism (PMID: 17603482: "We have identified five different mutations in RAF1 in ten individuals with Noonan syndrome" and "Cells transfected with constructs containing Noonan syndrome-associated RAF1 mutations showed increased in vitro kinase and ERK activation"). RAF1 accounts for approximately 5% of NS cases (PMID: 41507607: "Pathogenic variants in RAF1 are a common cause of Noonan syndrome (NS), accounting for approximately 5% of cases"). Inheritance is autosomal dominant, with most cases arising de novo. Key identifiers: OMIM #613224; gene RAF1 (HGNC:9829), chromosome 3p25.2.

F002 — Domain-specific genotype–phenotype correlation: CR2 variants drive HCM

There is a strong domain-specific correlation within RAF1. Razzaque et al. observed that individuals with CR2-domain mutations had HCM, whereas those with CR3-domain mutations did not (PMID: 17603482: "those with any of four mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy (HCM), whereas affected individuals with mutations leading to changes in the CR3 domain did not"). A large modern cohort of 203 cases confirmed and quantified this: CR2 variants accounted for 83% of cases, with p.Ser257Leu alone representing 53%; HCM occurred in 80.1% overall, in 89.4% of CR2 variant carriers, and 94.2% of p.Ser257Leu heterozygotes, versus only 37.1% for non-CR2 variants (PMID: 41507607: "HCM was markedly more frequently associated with CR2 variants (89.4%) and in subjects heterozygous for the p.Ser257Leu change (94.2%) compared with non-CR2 variants (37.1%)"). Neurodevelopmental features were more common in non-CR2 carriers (69.2%) than CR2 carriers.

F005 — Mutations cluster at Ser259 and disrupt 14-3-3–mediated autoinhibition

The molecular basis of RAF1 gain-of-function is loss of autoinhibition. Pandit et al. found RAF1 missense mutations in 18 of 231 (3%) mutation-negative NS individuals, with most altering a motif flanking Ser259 — a residue critical for autoinhibition of RAF1 through 14-3-3 binding (PMID: 17603483: "Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding"). Of 19 subjects with a mutation in the two hotspots, 18 (95%) had HCM versus the 18% prevalence in general NS ("Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general"). Critically, HCM-hotspot mutants had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase-impaired ("Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired"). RAF1 mutations also cause LEOPARD/NS-with-multiple-lentigines phenotypes.

F013 — Opposing conformational effects explain the HCM-vs-DCM dichotomy

Molecular dynamics analysis of C-terminal CRAF kinase-domain variants revealed a structural basis for divergent cardiac outcomes. The HCM-associated variants S612T and L613V adopt an active conformation (open activation loop, "αC-helix in," assembled hydrophobic spine → enhanced kinase activity), whereas the DCM-associated L603P transitions the kinase to an inactive state (closed activation loop, "αC-helix out," distorted spine → impaired activity) (PMID: 36927384: "genetic alternation at position 603 impairs, while those at positions 612/613 enhance the CRAF kinase activity"; "two HCM-associated variants (S612T and L613V) show features of an active conformation, such as an open activation loop conformation, 'αC-helix in', the assembly of the hydrophobic spine"; "the substitution of Leucine 603 for proline transits the kinase domain to a state that exhibits the molecular hallmarks of an inactive kinase"). This aligns with Pandit 2007's observation that non-HCM RAF1 mutants are kinase-impaired.

F003 — MEK-ERK hyperactivation is causal and druggable

The Raf1(L613V/+) knock-in mouse recapitulates NS (short stature, craniofacial dysmorphia, hematologic abnormalities, eccentric cardiac hypertrophy with aberrant fetal gene expression), and agonist-evoked MEK-ERK activation is enhanced across cell types. Postnatal MEK inhibition normalized growth, facial, and cardiac defects (PMID: 21339642: "postnatal MEK inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice"; "enhanced MEK-ERK activity is critical for causing HCM and other RAF1-mutant NS phenotypes"). Human patient-derived iPSC-cardiomyocytes (RAF1 p.Ser257Leu) further show concurrent activation of MEK1/2–ERK1/2 and an ERK5–Cyclin D1 branch driving hypertrophy (PMID: 42667574: "RAF1-mutant iPSC-CMs exhibited concurrent activation of the MEK1/2-ERK1/2 and ERK5-Cyclin D1 signaling pathways").

F004 — Model organisms recapitulate NS6 and identify candidate therapies

Multiple model systems validate the disease and nominate therapeutics. The Raf1(L613V) knock-in mouse is the validated in-vivo model (PMID: 21339642: "we generated knockin mice expressing the NS-associated Raf1(L613V) mutation"). Rigosertib, a dual RAS/MAPK and PI3K/AKT inhibitor, normalized and reversed RASopathy-associated HCM across transgenic Drosophila and RAF1 models (PMID: 42610277: "our findings suggest that rigosertib normalizes and reverses RASopathy-associated HCM and other NS-associated syndromic features"). Berberine attenuated the hypertrophic phenotype in RAF1 p.Ser257Leu iPSC-cardiomyocytes by suppressing ERK5–Cyclin D1 signaling (PMID: 42667574: "BBR attenuated the hypertrophic phenotype while reducing ERK5 phosphorylation and Cyclin D1 expression").

F006 — Clinical phenotype spectrum

RAF1-NS shares the core Noonan phenotype with a distinctive cardiac profile. In the RAF1 cohort (n=203): HCM in 80.1%, neurodevelopmental features in 44.5% (PMID: 41507607: "HCM was observed in 80.1% of affected individuals, confirming its role as the predominant cardiac manifestation in RAF1-related NS; neurodevelopmental features were reported in 44.5% of patients"). General NS features include characteristic evolving facies, broad/webbed neck, increased bleeding tendency, congenital heart disease, failure to thrive, short stature, feeding difficulties, sternal (pectus) deformity, renal malformation, pubertal delay, cryptorchidism, developmental/behavioral problems, vision problems, hearing loss, and lymphedema (PMID: 24444506). RAF1 carriers are enriched for pulmonary hypertension (PMID: 41863590: "variants in RAF1 (p = 0.013) and KRAS (p = 0.015) were more common among PH patients").

F007 — Prognosis dominated by early-onset HCM

Noonan/RASopathies are the leading genetic cause of HCM presenting in infancy, and HCM is a major cause of morbidity and mortality especially in the first year of life (PMID: 31259454: "HCM is a major cause of morbidity and mortality in children with Noonan spectrum disorders, especially in the first year of life"). RAF1 confers among the highest HCM risk of NS genotypes and enrichment for pulmonary hypertension (transplant-free survival lower in the PH group, p=0.004; PMID: 41863590). In a RAS-HCM cohort, increased end-diastolic interventricular septal thickness (IVSd) was associated with higher mortality (PMID: 42448910: "increased IVSd was associated with higher mortality (p = 0.013)"). Neurocognitive prognosis is generally favorable — "Most patients with Noonan syndrome are intellectually normal as adults" (PMID: 24444506).

F008 — MEK inhibition (trametinib) as emerging targeted therapy

The MEK1/2 inhibitor trametinib reverses/attenuates severe early-onset NS-HCM in off-label case reports, including a RAF1 p.Ser257Leu infant with HCM and pulmonary hypertension (PMID: 42256976). Trametinib enabled ASD surgical closure after cardiac stabilization (PMID: 41718520: "Trametinib, an MEK inhibitor that attenuates abnormal signaling in the RAS/MAPK pathway, has been shown to improve NS-HCM outcomes") and resolved chylothorax/pulmonary lymphangiectasia (PMID: 40041314: "a five-week trametinib course, maximum dose 0.025 mg/kg/day, led to chylothorax resolution and gradual pulmonary function improvement"). A prospective trial is registered (NCT06555237). Standard care remains supportive.

F009 — Diagnosis via targeted RASopathy NGS panels with ACMG classification

Molecular diagnosis is achieved primarily by targeted multigene NGS panels covering RAS/MAPK genes (including RAF1), with reported detection rates of ~78% (PMID: 41078618: "Targeted NGS panels improve diagnosis of RASopathies, with a variant detection rate of 78%"), followed by confirmatory Sanger sequencing and MLPA for deletions, with variants classified per ACMG/AMP guidelines (PMID: 41496802: "A targeted multigene next-generation sequencing panel test was performed, followed by Sanger sequencing for both confirmation and segregation analysis"). Overall NS molecular confirmation is ~70% (PMID: 24444506). Panels also detect NS prenatally in sonographically normal fetuses (PMID: 41588629).

F010 — Modestly elevated childhood cancer risk

In a cohort of 735 individuals with germline RAS-pathway mutations, 12 cancers were observed versus 1.12 expected — a 10.5-fold increased risk of childhood cancer (SIR=10.5, 95% CI 5.4–18.3); the Noonan-syndrome subgroup SIR was 8.1 (PMID: 25742478: "This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3)" and "The childhood cancer SIR in Noonan syndrome patients was 8.1"). JMML/myeloproliferative predisposition is chiefly PTPN11-associated (PMID: 25097206). Growth-hormone therapy requires genetic confirmation and cancer-risk counseling (PMID: 39974721: "Families should be informed about possible cancer risk and in cases predisposing to juvenile myelomonocytic leukemia, early initiation of growth hormone therapy should be avoided").

F011 — Modest growth-hormone efficacy with RAS/MAPK-linked GH insensitivity

Recombinant GH yields small overall height gains (~5–10 cm) in NS, with treatment typically starting ~age 10 at ~−3.0 height SDS (PMID: 20029235: "The NS studies have shown that the overall height gain of patients is small (5-10 cm)"). The modest response partly reflects that "impaired sensitivity to GH is common in NS" — mechanistically, RAS/MAPK hyperactivation blunts GH/IGF-1 signaling, and PTPN11 and RAF1 genotypes tend to respond less well.

F012 — Neurodevelopmental phenotype

NS shows intelligence scores spanning a wide range with a mildly lowered average; language and motor development are often delayed but "no longer dysfunctional in adulthood" (PMID: 20029232: "Cognitive and behavioral findings in NS show intelligence scores across a wide range, with a mildly lowered average level"). Language impairments are more frequent than in the general population and confer higher risk for reading/spelling difficulties (PMID: 20543023: "Language impairments were more frequent in NS than in the general population and were associated with higher risk for reading and spelling difficulties"). In RAF1-NS, neurodevelopmental features occur in 44.5% and are more frequent with non-CR2 variants (69.2%) (PMID: 41507607).

Report by Disease-Characteristic Section

1. Disease Information

Noonan Syndrome 6 is a Mendelian, autosomal dominant subtype of Noonan syndrome — a multisystem RASopathy — defined molecularly by pathogenic variants in RAF1. Noonan syndrome broadly is characterized by "characteristic facial features that evolve with age; a broad, webbed neck; increased bleeding tendency; and a high incidence of congenital heart disease, failure to thrive, short stature, feeding difficulties, sternal deformity, renal malformation, pubertal delay, cryptorchidism, developmental or behavioral problems, vision problems, hearing loss, and lymphedema" (PMID: 24444506).

Key identifiers: | Resource | ID | |---|---| | MONDO | MONDO:0013186 | | OMIM | #613224 (NOONAN SYNDROME 6; NS6) | | Gene | RAF1 / CRAF (HGNC:9829) | | Locus | 3p25.2 | | Orphanet | Noonan syndrome (ORPHA:648, subtype level) | | MeSH | Noonan Syndrome (D009634) |

Synonyms: RAF1-related Noonan syndrome; NS6. Note RAF1 variants also cause Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome). Information is derived primarily from aggregated disease-level resources (OMIM, Orphanet) and cohort/case-report literature rather than individual EHR data.

2. Etiology

Causal factor: Purely genetic — germline gain-of-function missense variants in RAF1. Most cases are de novo; autosomal dominant transmission occurs. Genetic risk factors: the pathogenic RAF1 variant itself is causal; there is a domain-level modifier effect whereby CR2-domain variants strongly predispose to HCM (F002, F005). Environmental risk/protective factors: none established — this is a monogenic condition. Gene–environment interactions: no well-characterized GxE interactions; the principal environmental consideration is iatrogenic (growth-hormone therapy and its cancer-risk implications, F010). No protective alleles are established; the only clinically relevant genetic modifier is the position of the variant within RAF1 (kinase-activating vs kinase-impairing; F013).

3. Phenotypes

Phenotype	Type	HPO (suggested)	Frequency in RAF1-NS	Onset	Severity
Hypertrophic cardiomyopathy	Physical/clinical sign	HP:0001639	~80% overall; 89–95% CR2/S257L	Congenital/infantile	Moderate–severe; leading mortality driver
Short stature	Physical	HP:0004322	Common	Childhood	Variable; modest GH response
Pulmonary valve stenosis	Clinical sign	HP:0001642	Less dominant than in PTPN11	Congenital	Variable
Characteristic facies	Physical	HP:0001999	Common	Evolves with age	—
Webbed/broad neck	Physical	HP:0000465	Common	Congenital	—
Bleeding tendency	Lab/clinical	HP:0001892	Common	Lifelong	Mild–moderate
Pectus deformity	Physical	HP:0000766	Common	Childhood	—
Cryptorchidism (males)	Clinical sign	HP:0000028	Common	Congenital	—
Neurodevelopmental/language delay	Behavioral	HP:0012759 / HP:0000750	44.5% (69.2% non-CR2)	Childhood	Mild; usually normal adult IQ
Pulmonary hypertension	Clinical sign	HP:0002092	Enriched in RAF1	Variable	Severe when present
Lymphatic dysplasia / lymphedema	Physical	HP:0000112	Subset	Congenital/variable	Variable
Sensorineural hearing loss	Clinical sign	HP:0000407	Subset (RAF1 ~11% of NS-SNHL cases)	Congenital	Severe-profound when present

Quality of life: dominated by cardiac disease (HCM/PH), short stature, and learning difficulties requiring special education support; adult cognitive outcomes are generally favorable (PMID: 20029232; PMID: 24444506).

4. Genetic/Molecular Information

Causal gene: RAF1 (CRAF), HGNC:9829, 3p25.2, OMIM 164760; encodes a serine/threonine-protein kinase in the RAS–MAPK cascade. Variant type: predominantly missense. Recurrent alleles: p.Ser257Leu (most common, ~53% of RAF1-NS), clustering around Ser259 and within CR2. Classification: pathogenic/likely pathogenic per ACMG/AMP. Allele frequency: absent from population databases (private/de novo). Origin: germline (de novo or inherited). Functional consequence: gain-of-function — increased kinase activity and enhanced ERK activation for HCM-associated variants (F001, F005); a distinct subset (e.g., L603P) is kinase-impaired/loss-of-function and associates with dilated cardiomyopathy (F013). Modifier "genes":* the intragenic domain/position of the variant is the dominant modifier of cardiac phenotype. No specific epigenetic or chromosomal abnormality defines NS6 (it is a single-gene missense disorder).

5. Environmental Information

Not applicable as a cause — NS6 is monogenic. No environmental toxins, lifestyle factors, or infectious agents are implicated in disease causation. The relevant non-genetic consideration is treatment-related (growth hormone and cancer-risk counseling; F010).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

A germline missense variant in RAF1, typically at/near Ser259 in the CR2 domain, disrupts the 14-3-3–binding motif that normally holds CRAF in an autoinhibited conformation (PMID: 17603483).
Loss of autoinhibition releases constitutive CRAF kinase activity (gain of function) (PMID: 17603482). (Branch: C-terminal variants at 612/613 lock the kinase in an active conformation → GOF → HCM; the variant at 603 locks it inactive → LOF → DCM; F013.)
Increased CRAF activity hyperactivates the downstream MEK1/2–ERK1/2 cascade (and an ERK5–Cyclin D1 branch), with enhanced agonist-evoked signaling across cell types (PMID: 21339642; PMID: 42667574).
In cardiomyocytes, sustained MEK–ERK/ERK5–Cyclin D1 signaling drives pathological hypertrophy with aberrant fetal gene reactivation → hypertrophic cardiomyopathy (PMID: 21339642; PMID: 42667574).
During development, dysregulated MAPK signaling in multiple lineages produces the systemic Noonan phenotype — craniofacial dysmorphism, short stature, hematologic changes (inferred from mouse recapitulation; PMID: 21339642).
MAPK hyperactivation also blunts GH/IGF-1 responsiveness, contributing to GH-insensitive short stature (inferred mechanistic link; PMID: 20029235).
Therapeutic node: MEK inhibition reverses steps 3–5 — postnatal MEK inhibition normalized growth, facial, and cardiac defects in mice, and trametinib reverses HCM/lymphatic disease in patients (PMID: 21339642; PMID: 42256976).

Molecular pathway: RAS–RAF–MEK–ERK (MAPK) — GO:0000165 (MAPK cascade), GO:0007265 (Ras protein signal transduction). Cellular process: cardiomyocyte hypertrophy (GO:0003300), cardiac muscle cell proliferation. Protein dysfunction: gain-of-function via loss of 14-3-3 autoinhibition (F005). Cell types: cardiomyocytes (CL:0000746), craniofacial neural crest derivatives, hematopoietic cells. Upstream: RAF1 GOF; downstream: MEK/ERK/ERK5–Cyclin D1 → hypertrophy.

7. Anatomical Structures Affected

Primary organ: heart (UBERON:0000948) — cardiac ventricle/interventricular septum (HCM), pulmonary valve (stenosis).
Secondary/systemic: pulmonary vasculature (pulmonary hypertension), lymphatic system (UBERON:0006558; lymphangiectasia/chylothorax), skeletal system (pectus, short stature), craniofacial structures, gonads (cryptorchidism), kidney (malformation), inner ear/cochlea (SNHL), CNS (neurodevelopment).
Body systems: cardiovascular (predominant), lymphatic, endocrine/growth, nervous, musculoskeletal, genitourinary.
Cell/subcellular: cardiomyocytes (CL:0000746); signaling occurs at the plasma membrane/cytoplasm (GO:0005829 cytosol), with kinase relocalization governed by 14-3-3.
Lateralization: cardiac hypertrophy is typically asymmetric septal.

8. Temporal Development

Onset: congenital to infantile. HCM often presents in the first months of life; facial features evolve with age.
Progression: HCM can be progressive and, in infancy, rapidly decompensating; increased IVSd predicts worse outcome (PMID: 42448910).
Course: chronic, lifelong. Infancy is the critical window of vulnerability (highest HCM mortality; PMID: 31259454) and also the window of therapeutic opportunity for MEK inhibition.
Remission: HCM regression has been documented under trametinib (treatment-induced; F008).

9. Inheritance and Population

Inheritance: autosomal dominant; most NS6 cases de novo.
Prevalence: Noonan syndrome overall ~1 in 1,000–2,500 live births; RAF1 accounts for ~3–5% of NS (PMID: 41507607).
Penetrance/expressivity: high penetrance with variable expressivity; HCM penetrance is strongly variant-dependent (89–95% for CR2/S257L vs 37% non-CR2).
Sex ratio: roughly equal (males noted for cryptorchidism-related features).
Founder effects/consanguinity: not applicable (dominant, mostly de novo). Recurrent p.Ser257Leu reflects a mutational hotspot, not a founder haplotype.

10. Diagnostics

Genetic testing (first-line): targeted multigene RASopathy NGS panels including RAF1; ~78% detection rate (PMID: 41078618); confirmatory Sanger + MLPA; ACMG/AMP classification (PMID: 41496802). WES/WGS reserved for panel-negative cases. Prenatal panels can detect NS in sonographically normal fetuses (PMID: 41588629).
Cardiac evaluation: echocardiography and cardiac MRI for HCM/septal thickness; ECG; assessment for pulmonary stenosis and pulmonary hypertension (cardiac catheterization; PMID: 41863590).
Other labs: coagulation studies (bleeding tendency); audiology (SNHL).
Differential diagnosis: other RASopathies (PTPN11-NS, SOS1, RIT1, LZTR1) and NS-mimics (SETD5, GATA4, etc.) — resolved by genotype-driven panels/ES (PMID: 41137536).

11. Outcome / Prognosis

Prognosis is dominated by HCM, particularly infantile-onset disease, which is a leading cause of morbidity and mortality (PMID: 31259454). RAF1 confers among the highest HCM burden of NS genotypes and is enriched for pulmonary hypertension (lower transplant-free survival, p=0.004; PMID: 41863590). Increased IVSd is a quantitative predictor of heart failure (p=0.006) and mortality (p=0.013) (PMID: 42448910). Heart-transplant series in NS report ~33% mortality. Neurocognitive prognosis is generally good — most patients are intellectually normal as adults (PMID: 24444506). A modestly elevated childhood cancer risk (NS SIR = 8.1) requires surveillance (PMID: 25742478).

12. Treatment

Modality	Intervention	NCIT (suggested)	Evidence
Targeted (emerging)	Trametinib (MEK1/2 inhibitor)	NCIT:C77908	Reverses severe NS-HCM incl. RAF1 S257L; resolves chylothorax; trial NCT06555237 (PMID: 42256976; PMID: 40041314)
Supportive (HCM)	Beta-blockers / non-dihydropyridine CCBs	NCIT:C2039	Standard; caution re: LVOT obstruction
Supportive (HCM)	Ivabradine (refractory neonatal HCM)	—	Rate control without negative inotropy (PMID: 42213003)
Surgical	Septal myectomy / modified Konno	NCIT:C51756	For obstructive HCM (PMID: 30104063)
Interventional	Balloon valvuloplasty / RVOT stenting	—	For pulmonary stenosis
Advanced	Heart transplantation	NCIT:C15380	Refractory heart failure (~33% mortality)
Endocrine	Recombinant growth hormone	NCIT:C1968	Modest height gain (~5–10 cm); confirm genotype, counsel cancer risk (PMID: 20029235; PMID: 39974721)
Preclinical	Rigosertib; berberine	—	HCM reversal in models (PMID: 42610277; PMID: 42667574)

Personalized medicine: genotype-guided — the shift toward MEK inhibition is directly rationalized by the RAF1→MEK-ERK mechanism (F003, F008).

13. Prevention

Primary prevention is not possible (mostly de novo dominant mutation). Prevention centers on secondary/tertiary measures: early molecular diagnosis, cardiac surveillance (serial echocardiography), and early intervention for HCM/PH. Genetic counseling is essential — 50% recurrence risk for an affected parent; prenatal/preimplantation testing available; cancer-risk and GH-timing counseling (PMID: 39974721). Prenatal NGS panels can identify NS in structurally normal fetuses (PMID: 41588629).

14. Other Species / Natural Disease

RAF1/CRAF is deeply conserved. Orthologs: mouse Raf1 (NCBI Gene 110157). No specific naturally occurring companion-animal NS6 disease is established; comparative relevance is chiefly through engineered models. Evolutionary conservation of the RAS-MAPK pathway underpins model-organism validity.

15. Model Organisms

Mouse: Raf1(L613V/+) knock-in recapitulates short stature, craniofacial dysmorphia, hematologic abnormalities, and eccentric cardiac hypertrophy; MEK inhibition rescues (PMID: 21339642). Type: knock-in; strong phenotype recapitulation.
Drosophila: transgenic RASopathy models used for rigosertib HCM-reversal studies (PMID: 42610277).
Human iPSC-cardiomyocytes: RAF1 p.Ser257Leu iPSC-CMs model NS-HCM and reveal ERK5–Cyclin D1 signaling; used for berberine testing (PMID: 42667574).
Limitations: models capture cardiac and growth phenotypes well; neurodevelopmental and lymphatic features are less fully recapitulated.

Mechanistic Model / Interpretation

RAF1 missense variant (CR2, ~Ser259; e.g., p.Ser257Leu)
│  disrupts 14-3-3 binding motif
▼
Loss of CRAF autoinhibition  ──────────────┐
│  (GAIN of function)              │  BRANCH by C-terminal position:
▼                                  │   • 612/613 → active conformation → GOF → HCM
Constitutive CRAF kinase activity          │   • 603     → inactive conformation → LOF → DCM
│
▼
Hyperactivated MEK1/2–ERK1/2  (+ ERK5–Cyclin D1 branch)
│
├──► Cardiomyocyte hypertrophy + fetal gene program ──► HYPERTROPHIC CARDIOMYOPATHY (~80–95%)
├──► Developmental MAPK dysregulation ──► facies, short stature, hematologic changes
├──► Blunted GH/IGF-1 signaling ──► GH-insensitive short stature
└──► Lymphatic/vascular dysregulation ──► lymphangiectasia, pulmonary hypertension
│
▼
   [ MEK INHIBITION (trametinib) reverses HCM & lymphatic disease ]

The unifying theme is dose of MAPK signal output: variants that raise CRAF kinase activity produce hypertrophic cardiomyopathy and the classic Noonan gestalt, while the rare kinase-impairing variant produces dilated cardiomyopathy — a rare instance where opposite biochemical effects at neighboring residues yield opposite clinical cardiomyopathies (F013). Because the entire phenotype funnels through MEK-ERK, pharmacologic MEK inhibition is a mechanistically precise therapy, validated from mouse to bedside.

Evidence Base

PMID	Role	Contribution
17603482	Foundational	Identifies RAF1 GOF as cause of NS; CR2-HCM correlation
17603483	Foundational	Ser259/14-3-3 autoinhibition mechanism; 95% HCM in hotspots
41507607	Large cohort (n=203)	Quantifies HCM/neurodevelopmental frequencies by domain
21339642	Mouse model	Proves MEK-ERK causality; rescue by MEK inhibition
36927384	Computational/MD	Structural basis of HCM-vs-DCM dichotomy
42667574	iPSC model	ERK5–Cyclin D1 branch; berberine candidate
42610277	Preclinical	Rigosertib reverses RASopathy HCM
42256976	Case report	Trametinib in genetically confirmed RAF1 NS6
40041314	Case series	Trametinib for cardiac + lymphatic NS
31259454	Clinical	HCM as principal mortality driver in infancy
42448910	Cohort	IVSd as prognostic factor
41863590	Cohort	RAF1 enrichment for pulmonary hypertension
41078618	Diagnostic	78% NGS panel yield
25742478	Registry	Childhood cancer risk (NS SIR=8.1)
20029235	Observational	GH efficacy and insensitivity
20029232 / 20543023	Clinical	Neurodevelopmental/language phenotype
24444506	Review	Core NS clinical features; adult cognition

Limitations and Knowledge Gaps

Therapy evidence is largely anecdotal. MEK-inhibitor benefit in NS6-HCM rests on case reports/small series; the prospective trial (NCT06555237) has not yet reported. Long-term safety in infants (growth, neurodevelopment) is unknown.
Genotype–phenotype granularity beyond the cardiac axis. The molecular basis for the higher neurodevelopmental burden in non-CR2 carriers is undefined.
DCM-causing RAF1 variants (L603P) are rare; the LOF→DCM branch is based primarily on computational modeling plus limited functional data and needs more clinical corroboration.
Epigenetic and multi-omic data specific to NS6 (methylation, proteomics, single-cell) are largely absent; most omic insight is inferred from broader RASopathy/HCM studies.
Population epidemiology for NS6 specifically (incidence, sex ratio, geographic distribution) is extrapolated from Noonan syndrome overall.
Citation caveat: the PMID 42256976 snippet reflects the article title (flagged as a title-level match during verification); the underlying clinical claim (trametinib in RAF1 p.Ser257Leu) remains directly supported by that report.

Proposed Follow-up Experiments / Actions

Await/support NCT06555237 and advocate for genotype-stratified endpoints (CR2 vs non-CR2; RAF1 vs other RASopathy genes) to define which NS6 patients benefit most from MEK inhibition.
Functional characterization of the ERK5–Cyclin D1 branch in RAF1 iPSC-CMs to determine whether ERK5-selective inhibitors (or berberine) add benefit over MEK inhibition alone.
Natural-history registry of RAF1-NS6 capturing IVSd trajectories, PH incidence, and infant mortality to refine prognostic models (building on the IVSd–mortality signal).
Comparative structural/biochemical assays across the RAF1 C-terminus (603 vs 612/613 vs CR2) to map the kinase-activity-to-cardiomyopathy axis and predict phenotypes of novel variants (VUS reclassification).
Single-cell/spatial transcriptomics of NS6 cardiac tissue or iPSC-CM/organoids to resolve cell-type-specific MAPK output and hypertrophy programs.
Cancer-surveillance and GH-timing guidelines tailored to RAF1-NS6, integrating the NS SIR=8.1 estimate with genotype-specific JMML risk (chiefly PTPN11, not RAF1).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	26
Resolved	26
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	26
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	28
Resolved	26
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	21
Terms named correctly	2
Terms named as a different term	15
Terms whose name is worth a second look	4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0013186 (3 mentions) - the report calls it "if available", "MONDO"; MONDO calls it Noonan syndrome 6
HP:0001639 (1 mention) - the report calls it "Physical/clinical sign"; HP calls it Hypertrophic cardiomyopathy
HP:0004322 (1 mention) - the report calls it "Physical"; HP calls it Short stature
HP:0001999 (1 mention) - the report calls it "Physical"; HP calls it Abnormal facial shape
HP:0000465 (1 mention) - the report calls it "Physical"; HP calls it Webbed neck
HP:0001892 (1 mention) - the report calls it "Lab/clinical"; HP calls it Abnormal bleeding
HP:0000766 (1 mention) - the report calls it "Physical"; HP calls it Abnormal sternum morphology
HP:0000028 (1 mention) - the report calls it "Clinical sign"; HP calls it Cryptorchidism
HP:0002092 (1 mention) - the report calls it "Clinical sign"; HP calls it Pulmonary arterial hypertension
HP:0000112 (1 mention) - the report calls it "Physical"; HP calls it Nephropathy
HP:0000407 (1 mention) - the report calls it "Clinical sign"; HP calls it Sensorineural hearing impairment
NCIT:C2039 (1 mention) - the report calls it "Beta-blockers / non-dihydropyridine CCBs"; NCIT calls it Bevacizumab
NCIT:C51756 (1 mention) - the report calls it "Septal myectomy / modified Konno"; NCIT calls it Roux-en-Y Anastomosis
NCIT:C15380 (1 mention) - the report calls it "Heart transplantation"; NCIT calls it Telemedicine
NCIT:C1968 (1 mention) - the report calls it "Recombinant growth hormone"; NCIT calls it Topoisomerase-II Inhibitor

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0001642 (1 mention) - the report calls it "Clinical sign"; HP calls it Pulmonic stenosis, and lists "Pulmonic valve stenosis" among its other names
CL:0000746 (2 mentions) - the report calls it "Cell/subcellular: cardiomyocytes"; CL calls it cardiac muscle cell**, and lists "cardiomyocyte" among its other names
UBERON:0000948 (1 mention) - the report calls it "Primary organ: heart"; UBERON calls it heart**, and lists "branchial heart" among its other names
NCIT:C77908 (1 mention) - the report calls it "Trametinib (MEK1/2 inhibitor)"; NCIT calls it Trametinib

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0013186 - called "if available", "MONDO"
HGNC:9829 - called "RAF1", "RAF1* / CRAF"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Clinical Trials

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

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

Executive summary and evidence boundaries

1. Disease information

Definition and identifiers

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

Causal factor

Genetic risk factors

Environmental and protective factors

3. Phenotypes

NRAS-specific frequencies

Quality of life

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended approach

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current implementation

Targeted/experimental therapies

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Current expert interpretation and critical knowledge gaps

Core references

Artifacts

Reference Validation

Term Validation

Key Findings

F001 — RAF1 gain-of-function is the molecular cause of NS6

F002 — Domain-specific genotype–phenotype correlation: CR2 variants drive HCM

F005 — Mutations cluster at Ser259 and disrupt 14-3-3–mediated autoinhibition

F013 — Opposing conformational effects explain the HCM-vs-DCM dichotomy

F003 — MEK-ERK hyperactivation is causal and druggable

F004 — Model organisms recapitulate NS6 and identify candidate therapies

F006 — Clinical phenotype spectrum