Noonan Syndrome

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0018997 Noonan syndrome

Orphanet lists MONDO:0018997 as an exact cross-reference for Noonan syndrome.

ICD-10-CM

ICD10CM:Q87.1 Congenital malformation syndromes predominantly associated with short stature

Orphanet lists ICD-10 Q87.1 as a narrower cross-reference for Noonan syndrome.

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Definitions

2

Noonan syndrome molecular-clinical case definition

Noonan syndrome is defined as a RASopathy with compatible craniofacial, growth, developmental, and cardiovascular phenotype supported by molecular evidence in a causative RAS-MAPK pathway gene.

CASE_DEFINITION Clinical genetics and pediatric cardiology evaluation for suspected RASopathy

Show evidence (1 reference)

PMID:41675685 SUPPORT Human clinical

"RASopathies are a heterogeneous group of conditions of the RAS/mitogen-activated protein kinase pathway presenting with overlapping features such as growth deficiency, neurodevelopmental disorders, cardiac defects, craniofacial dysmorphisms, cutaneous and ocular abnormalities, and increased cancer risk."

Cohort evidence supports a combined phenotype-plus-genotype approach for Noonan syndrome case definition in modern practice.

Orphanet disease definition

Orphanet defines Noonan syndrome as a rare, highly variable, multisystemic disorder mainly characterized by short stature, distinctive facial features, congenital heart defects, cardiomyopathy and an increased risk to develop tumors in childhood.

CASE_DEFINITION

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"A rare, highly variable, multisystemic disorder mainly characterized by short stature, distinctive facial features, congenital heart defects, cardiomyopathy and an increased risk to develop tumors in childhood."

Orphanet's definition supports the multisystem characterization of this entry.

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Inheritance

2

Autosomal Dominant

Most cases follow autosomal dominant inheritance with variable expressivity. Approximately 30-75% of cases are de novo mutations.

Show evidence (2 references)

PMID:11992261 SUPPORT Human clinical

"Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS."

Supports autosomal dominant inheritance with both familial transmission and de novo/sporadic occurrence.

ORPHA:648 SUPPORT Other

"Autosomal dominant"

Orphanet records autosomal dominant inheritance for Noonan syndrome.

Autosomal Recessive

A subset of Noonan syndrome is inherited in an autosomal recessive manner, particularly in LZTR1-associated disease. SPRED2 is the other recessive locus: homozygosity for three different loss-of-function variants was reported in four subjects from three families, and the authors describe it as the second recessive form of Noonan syndrome.

Show evidence (4 references)

PMID:34626534 SUPPORT Human clinical

"Homozygosity for three different variants-c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95)-were identified in four subjects from three families."

The recessive segregation evidence behind adding SPRED2 to this block.

PMID:34626534 SUPPORT Human clinical

"Our findings identify the second recessive form of Noonan syndrome"

The authors' own framing, which is what this description asserts.

PMID:20301303 SUPPORT Human clinical

"NS caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner."

Supports autosomal recessive inheritance in LZTR1-associated Noonan syndrome.

+ 1 more reference

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Subtypes

15

General

Noonan syndrome 1 (PTPN11-related) MONDO:0008104

PTPN11 hgnc:9644

Most common form caused by PTPN11 mutations, accounting for approximately 50% of cases.

Show evidence (1 reference)

PMID:41675685 SUPPORT Human clinical

"Final diagnoses included 15 individuals with Noonan syndrome (nine with variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS...)"

This cohort confirms PTPN11-positive Noonan syndrome as the predominant molecular subtype.

Noonan Syndrome with Multiple Lentigines MONDO:0007893

PTPN11 hgnc:9644

Formerly known as LEOPARD syndrome, characterized by lentigines and hypertrophic cardiomyopathy. Only PTPN11 is bound here: the cohort cited below found PTPN11 variants in both of its lentigines cases, and RAF1 and BRAF, which MONDO also records against MONDO:0007893, are not attested for this subtype by a source this entry cites.

Show evidence (1 reference)

PMID:41675685 SUPPORT Human clinical

"two with Noonan syndrome with multiple lentigines (both with variants in PTPN11)"

Confirms Noonan syndrome with multiple lentigines as a related and clinically relevant subtype in modern RASopathy cohorts.

molecular

Noonan syndrome 2 (biallelic LZTR1) MONDO:0011531

LZTR1 hgnc:6742

The autosomal recessive LZTR1 form. MONDO carries "autosomal recessive Noonan syndrome" as a synonym of this class, and ClinGen curates a separate autosomal recessive LZTR1-Noonan syndrome assertion alongside the dominant one. Distinguished from NS10 by zygosity rather than by gene.

Show evidence (2 references)

CGGV:assertion_7aa1e103-4f77-4c50-99c5-621a6a837b95-2020-08-27T160000.000Z SUPPORT Other

ClinGen curates a definitive autosomal recessive LZTR1-Noonan syndrome relationship, which is the relationship this subtype names.

PMID:20301303 SUPPORT Human clinical

"The parents of an individual with autosomal recessive NS are typically heterozygotes (i.e., have one LZTR1 pathogenic variant), and may either be asymptomatic or have mild features of NS."

The GeneReviews chapter states that the recessive form of Noonan syndrome is the biallelic LZTR1 form, which is what separates this subtype from NS10.

Noonan syndrome 3 (KRAS-related) MONDO:0012371

KRAS hgnc:6407

The KRAS form. MONDO defines this class as "Any Noonan syndrome in which the cause of the disease is a mutation in the KRAS gene."

Show evidence (2 references)

PMID:17143285 SUPPORT Human clinical

"KRAS mutations account for <5% of cases of Noonan syndrome"

Establishes KRAS as a rare molecular cause of Noonan syndrome, which is the relationship this subtype names.

CGGV:assertion_6476a5fd-8f66-462b-b17a-43540dad3c1f-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the KRAS-Noonan syndrome relationship as definitive with autosomal dominant inheritance.

Noonan syndrome 4 (SOS1-related) MONDO:0012547

SOS1 hgnc:11187

The SOS1 form, which the founding report identifies as a major cause of Noonan syndrome in patients without a PTPN11 mutation. MONDO defines this class as "Any Noonan syndrome in which the cause of the disease is a mutation in the SOS1 gene."

Show evidence (3 references)

PMID:17143285 SUPPORT Human clinical

"We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation."

The founding report establishes SOS1 as a major cause of PTPN11-negative Noonan syndrome, which is the relationship this subtype names.

PMID:17143285 SUPPORT Human clinical

"Our results identify SOS1 mutants as a major cause of Noonan syndrome"

The source for this subtype's description calling SOS1 a major cause.

CGGV:assertion_9781b6bf-9b1e-4a10-a0a9-7e56562a6e3a-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the SOS1-Noonan syndrome relationship as definitive with autosomal dominant inheritance.

Noonan syndrome 5 (RAF1-related) MONDO:0012690

RAF1 hgnc:9829

The RAF1 form, notable for its association with hypertrophic cardiomyopathy. MONDO defines this class as "Any Noonan syndrome in which the cause of the disease is a mutation in the RAF1 gene."

Show evidence (2 references)

PMID:17603483 SUPPORT Human clinical

"18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals)...have missense mutations in RAF1"

Quantifies the RAF1 share of Noonan syndrome, which is the relationship this subtype names.

CGGV:assertion_85645d27-2056-4ad3-9593-8d7739aa4121-2024-10-23T160000.000Z SUPPORT Other

ClinGen classifies the RAF1-Noonan syndrome relationship as definitive with autosomal dominant inheritance.

Noonan syndrome 6 (NRAS-related) MONDO:0013186

NRAS hgnc:7989

The NRAS form. Curated in full as the standalone entry kb/disorders/Noonan_Syndrome_6.yaml; the row is retained here so the numbered series reads as a complete catalog.

Show evidence (1 reference)

PMID:19966803 SUPPORT Human clinical

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

The founding report establishes NRAS as a molecular cause of Noonan syndrome, which is the relationship this subtype names.

Noonan syndrome 7 (BRAF-related) MONDO:0013379

BRAF hgnc:1097

The BRAF form, which overlaps clinically with cardiofaciocutaneous syndrome. MONDO defines this class as "Any Noonan syndrome in which the cause of the disease is a mutation in the BRAF gene." ClinGen grades the BRAF-Noonan syndrome relationship Moderate rather than Definitive.

Show evidence (2 references)

PMID:19953625 SUPPORT Human clinical

"We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients."

Reports BRAF variants in a Noonan syndrome cohort, which is the relationship this subtype names.

CGGV:assertion_47cf08d5-efc6-4d42-b031-a06619873161-2018-07-24T160000.000Z SUPPORT Other

Records the Moderate ClinGen grade this subtype description states.

Noonan syndrome 8 (RIT1-related) MONDO:0014143

RIT1 hgnc:10023

The RIT1 form. MONDO defines this class as "Any Noonan syndrome in which the cause of the disease is a mutation in the RIT1 gene."

Show evidence (2 references)

PMID:23791108 SUPPORT Human clinical

"we identified a total of nine missense, nonsynonymous mutations in RIT1...in 17 of 180 individuals (9%) with Noonan syndrome"

Quantifies the RIT1 share of Noonan syndrome, which is the relationship this subtype names.

CGGV:assertion_240565fc-61b9-4ff8-9f5a-85938f17cdd9-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the RIT1-Noonan syndrome relationship as definitive with autosomal dominant inheritance.

Noonan syndrome 9 (SOS2-related) MONDO:0014691

SOS2 hgnc:11188

The SOS2 form. MONDO defines this class as "Any Noonan syndrome in which the cause of the disease is a mutation in the SOS2 gene."

Show evidence (2 references)

PMID:25795793 SUPPORT Human clinical

"We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands."

The discovery cohort establishes SOS2 as a cause of Noonan syndrome, which is the relationship this subtype names.

CGGV:assertion_f20a1034-e29d-49bb-aed9-b4ba63dc5968-2020-08-27T160000.000Z SUPPORT Other

ClinGen classifies the SOS2-Noonan syndrome relationship as definitive with autosomal dominant inheritance.

Noonan syndrome 10 (heterozygous LZTR1) MONDO:0014693

LZTR1 hgnc:6742

The autosomal dominant LZTR1 form. MONDO defines this class as "Any Noonan syndrome in which the cause of the disease is a mutation in the LZTR1 gene"; it is separated from NS2 by zygosity, not by gene.

Show evidence (2 references)

PMID:25795793 SUPPORT Human clinical

"We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands."

The discovery cohort establishes LZTR1 as a cause of Noonan syndrome, which is the relationship this subtype names.

CGGV:assertion_6f21db9c-87ea-4095-96ca-4277eaa21232-2020-04-23T170000.000Z SUPPORT Other

ClinGen classifies the dominant LZTR1-Noonan syndrome relationship as definitive, which is the relationship that separates this subtype from NS2.

Noonan syndrome 11 (MRAS-related) MONDO:0032786

MRAS hgnc:7227

The MRAS form. Curated in full as the standalone entry kb/disorders/Noonan_Syndrome_11.yaml; the row is retained here so the numbered series reads as a complete catalog.

Show evidence (1 reference)

PMID:41675685 SUPPORT Human clinical

"Final diagnoses included 15 individuals with Noonan syndrome (nine with variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS...)"

Reports an MRAS-positive Noonan syndrome diagnosis in a contemporary molecular cohort, which is the relationship this subtype names.

Noonan syndrome 12 (RRAS2-related) MONDO:0032839

RRAS2 hgnc:17271

The RRAS2 form. MONDO carries no text definition for this class; the gene assignment rests on the founding report and the ClinGen assertion cited here.

Show evidence (2 references)

PMID:31130282 SUPPORT Human clinical

"By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families."

The founding report establishes RRAS2 as a cause of Noonan syndrome, which is the relationship this subtype names.

CGGV:assertion_c5742615-3820-41dd-a523-e660a498f9e8-2022-12-14T170000.000Z SUPPORT Other

ClinGen classifies the RRAS2-Noonan syndrome relationship as definitive with autosomal dominant inheritance.

Noonan syndrome 13 (MAPK1-related) MONDO:0033669

MAPK1 hgnc:6871

The MAPK1 form, in which the mutated gene encodes ERK2, the terminal kinase of the cascade every other subtype in this series acts upstream of. The attribution is weaker than for the rest of the series and the row records that: the founding report describes the phenotype as a neurodevelopmental disorder within the RASopathy spectrum that is Noonan-like in only some subjects, the 2025 GeneReviews chapter does not list MAPK1 among the genes whose variants establish a Noonan syndrome diagnosis, and the committed ClinGen Gene-Disease Validity snapshot carries no MAPK1 assertion for any disease.

Show evidence (3 references)

PMID:32721402 SUPPORT Human clinical

"Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects."

The founding report states both the gene-disease relationship and the hedge on its Noonan attribution that this subtype description records.

PMID:32721402 SUPPORT Human clinical

"After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies."

Source for this subtype's description placing MAPK1 at the terminal tier of the cascade the rest of the series acts upstream of.

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..."

The GeneReviews diagnostic gene list, quoted here because MAPK1 is absent from it; this is the source for the caveat in this subtype's description.

Noonan syndrome 14 (biallelic SPRED2) MONDO:0030679

SPRED2 hgnc:17722

The SPRED2 form, which its founding report identifies as the second recessive form of Noonan syndrome. SPRED2 negatively modulates EGF-promoted RAF1, MEK and ERK phosphorylation, so the entry point is loss of a brake rather than gain of a signal. As with NS13, the attribution is weaker than for the rest of the series: the 2025 GeneReviews chapter does not list SPRED2 among the diagnostic genes, and the committed ClinGen Gene-Disease Validity snapshot carries no SPRED2 assertion.

Show evidence (3 references)

PMID:34626534 SUPPORT Human clinical

"Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome."

The founding report states the gene-disease relationship and the recessive mode this subtype names.

PMID:34626534 SUPPORT In vitro / ex vivo

"When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation"

Source for the negative-regulator role this subtype's description gives SPRED2, and for calling the entry point loss of a brake.

ORPHA:648 SUPPORT Other

"SPRED2 | sprouty related EVH1 domain containing 2 | hgnc:17722 | Disease-causing germline mutation(s) in"

Orphanet records SPRED2 as disease-causing for Noonan syndrome, the second attestation this subtype rests on.

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Discussions and Knowledge Gaps

3

Does the magnitude of ERK activation produced by a PTPN11 variant predict its neural crest phenotype and clinical severity, or can a variant perturb neural crest development without measurably raising ERK phosphorylation?

OPEN QUESTION OPEN noonan_erk_magnitude_vs_neural_crest_phenotype

Attached to

pathophysiology#SHP2 Gain-of-Function Activation pathophysiology#ERK Cascade Hyperactivation pathophysiology#Neural Crest Cell Developmental Dysregulation

The entry models Noonan syndrome as convergent RAS-MAPK hyperactivation, and for the craniofacial arm that model is well supported: neural-crest-restricted SHP2 Q79R causes the defects and MEK inhibition prevents them. But ERK magnitude is not obviously the whole story, and this matters practically because "how much does it raise pERK" is the assay a functional lab would reach for when classifying a variant of uncertain significance. Two independent lines argue the assay is incomplete. Peer-reviewed zebrafish work already showed SHP2 has a phosphatase- and Erk-independent function in neural crest, mediated through its SH2 domains, which is what reconciles catalytically impaired NSML alleles with catalytically enhanced Noonan alleles causing overlapping disease. A recent preprint then reported a Noonan-spectrum variant of uncertain significance, c.1282G>A (V428M), that did not raise ERK phosphorylation in cells yet drove excessive neural crest migration in chick embryos, and reported that ERK activation did not track clinical severity across an 18-patient cohort. This is deliberately recorded as an open question rather than curated as a mechanism. The V428M observation is preprint-only, from an overexpression assay, and is not sole support for anything in this entry. What would settle it is whether the ERK-independent arm is the same SH2-domain function the zebrafish work identified, and whether it operates in human cranial neural crest rather than avian trunk neural crest.

Proposed experiments

Test whether the ERK-independent neural crest effect requires the SHP2 SH2 domains

noonan_sh2_domain_requirement_for_erk_independent_ncc_effect

Assay the paradoxical variant class alongside SH2-domain mutants in the same neural crest system, to determine whether the ERK-independent migration effect is the SH2-mediated function already identified in zebrafish or a distinct one.

Replicate the migration phenotype at endogenous expression levels in human neural crest

noonan_endogenous_level_human_ncc_replication

Knock the variant in at the endogenous locus in human iPSC-derived neural crest cells rather than overexpressing it in avian trunk neural crest, which would separate allele-specific effects from SHP2 dosage effects and test the human cranial lineage that generates the Noonan facial skeleton.

Correlate pERK with phenotype in a cohort powered for it

noonan_perk_vs_phenotype_powered_cohort

A variant-stratified cohort large enough to test whether ERK activation magnitude predicts craniofacial, cardiac, and neurodevelopmental outcome, rather than the 18-patient exploratory series the question arose from.

Raised from monarch-initiative/dismech#6513 (preprint scan). Preprint findings are recorded here as an open question, not curated as mechanism.

Show evidence (4 references)

PMID:20493809 SUPPORT Model organism

"We also identify an unexpected phosphatase- and Erk-independent function, mediated through its SH2 domains, which is evolutionarily conserved and prevents p53-mediated apoptosis in the brain and neural crest."

Peer-reviewed precedent that SHP2 has a neural crest function which an ERK-phosphorylation readout cannot see — this is what makes the question well-posed rather than speculative.

PPR:PPR1278294 Preprint · not peer-reviewed SUPPORT In vitro / ex vivo

"variants stratify beyond simple gain/loss-of-function dichotomies into strong ERK-dependent hyperactivation, moderate ERK activation with variable protein stability and the paradoxical c.1282G>A variant, which did not increase ERK phosphorylation"

Biochemical profiling in HEK293T cells reporting the variant class that motivates the question. Preprint, not peer reviewed.

PPR:PPR1278294 Preprint · not peer-reviewed SUPPORT Model organism

"In vivo, this variant drove excessive neural crest cell migration in chick embryos, suggesting that its effects on NCC migration may involve ERK-independent mechanisms or context-dependent signaling not captured by steady-state assays."

The in vivo half of the observation, and the reason the migration modifier on the neural crest node is DYSREGULATED rather than directional. Note the authors state it as a suggestion, not a demonstration.

+ 1 more reference

Is ERK1/2 hyperactivation, rather than ERK5 signaling, the correct driver to assert for RAF1-associated cardiomyocyte hypertrophy in Noonan syndrome?

HUMAN MODEL MISMATCH OPEN noonan_erk5_not_erk1_2_drives_raf1_cm_hypertrophy

Attached to

pathophysiology#Cardiomyocyte Hypertrophy pathophysiology#ERK Cascade Hyperactivation experimental_models#Noonan syndrome iPSC-cardiomyocyte model

The entry's ERK Cascade Hyperactivation node asserts a downstream edge to Cardiomyocyte Hypertrophy on the strength of a mouse RIT1 study showing that MAPK-pathway inhibition alleviates cardiac hypertrophy. A RAF1 S257L/+ iPSC-cardiomyocyte model directly tested the ERK1/2 arm of that pathway and found the opposite: MEK1/2 inhibitors that strongly reduced ERK1/2 phosphorylation had no effect on cell size, while a distinct pathway, ERK5, drove the hypertrophic phenotype. ERK5 is not otherwise modeled anywhere in this entry. The mismatch may reflect a genuine genotype-specific difference (RIT1 vs. RAF1) rather than a wrong edge, but the entry currently cannot distinguish those possibilities because it has no ERK5 node to attach the RAF1 finding to.

Proposed experiments

Test ERK5-selective inhibition of RAF1-mutant cardiomyocyte hypertrophy directly

noonan_erk5_selective_inhibition_raf1_icm

Confirm the ERK5 dependence reported for RAF1 S257L/+ iCMs (BIX02189 and dominant-negative ERK5 both reduced cell size) in an independent RAF1 patient line, and test whether the same rescue holds for RIT1 mutant human iPSC-cardiomyocytes to determine whether the RIT1 mouse and RAF1 human results reflect one pathway or two genotype-specific ones.

Raised while adding modeled_mechanisms links for the Noonan iPSC-cardiomyocyte model (monarch-initiative/dismech#10432).

Show evidence (2 references)

PMID:31163979 REFUTE In vitro / ex vivo

"Importantly, although ERK1/2 activation was strongly reduced, there was no significant effect on hypertrophy in RAF1S257L/+ iCMs in response to treatment with either PD98059 or Trametinib (Fig.4C–D), suggesting that MEK1/2-ERK1/2 activation is not the principal driver of hypertrophy in..."

The human-model evidence behind the mismatch.

DOI:10.1126/sciadv.adf4766 SUPPORT Model organism

"Consistent with aberrant RAF/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of RIT1 mutant Noonan syndrome."

The mouse-model evidence the entry's existing edge is built on, which this discussion contrasts against the human iPSC-cardiomyocyte result.

Does the MEK inhibition that reverses RAF1-driven hypertrophic cardiomyopathy also impose the cardiomyocyte injury that MEK inhibition causes in cancer patients, and if so at what dose, duration and age is the net effect still favourable?

KNOWLEDGE GAP OPEN noonan_mek_therapeutic_window_vs_cardiotoxicity

Attached to

treatments#MEK Inhibitor Therapy pathophysiology#ERK Cascade Hyperactivation pathophysiology#Cardiomyocyte Hypertrophy

The same pharmacology appears in this knowledge base twice, in opposite directions. Here, abrogating ERK signalling is the intended benefit. In kb/modules/mek_inhibition_cardiac_mitochondrial_injury.yaml it is the initiating injury: loss of ERK-dependent mitochondrial STAT3 serine-727 phosphorylation, respiratory chain failure and reversible cardiac hypocontractility, curated from oncology cohorts and mouse work. The two bodies of evidence do not overlap in what they measured. Every therapeutic result cited in this entry reads out echocardiographic wall thickness, outflow gradient (the only measure that moved in the adult RAF1 case), cardiac mass or fetal gene expression over weeks to months; none assessed mitochondrial respiration or STAT3 serine-727. The toxicity module is not reported in a RAS-MAPK-variant background. So the directions are unreconciled rather than contradictory, and neither body of work refutes the other. One dataset touches both. In paediatric RASopathy myocardial slices (PMID:39573843) trametinib lowered developed force while improving sarcoplasmic reticulum calcium handling in the same tissue. Reduced force is the direction of the toxicity module's terminal node, measured for once in a Noonan-variant context, and it sits beside a calcium result pointing the other way. That is a single patient's tissue under acute exposure, so it frames the question rather than answering it. This matters for how the treatment is read off the entry. A reader who sees only the case reports will take MEK inhibition to be straightforwardly corrective, and the entry currently gives them no route to the account of what the same drug does to cardiomyocytes. There is no schema slot that would carry that link: Treatment has no adverse-effect or adverse-mechanism field, which is recorded in dismech#12664. It is deliberately not curated as a conforms_to link. Noonan syndrome's own pathophysiology does not instantiate MEK-inhibition injury; the injury is a property of a treatment given for it, and the module's conformer is the drug-toxicity entry MEK_Inhibitor_Induced_Cardiomyopathy.

Proposed experiments

Paired contractile and mitochondrial readout of MEK inhibition in RASopathy myocardium

noonan_mek_force_and_mitochondrial_readout

Extend the myocardial slice protocol that measured force and calcium handling so that it also reports the quantities the cardiotoxicity module is built on, in the same tissue and the same exposure. Measure developed force, force-frequency relationship and post-pause potentiation alongside mitochondrial respiration and STAT3 serine-727 phosphorylation, across a trametinib dose range and a culture duration longer than an acute exposure, in slices or engineered heart tissue from several RASopathy genotypes with non-RASopathy hypertrophic myocardium as comparator.

Would support

pathophysiology#Cardiomyocyte Hypertrophy

Supporting outcome

Developed force falls while mitochondrial respiration and STAT3 serine-727 phosphorylation are preserved, and the hypertrophic transcriptional programme regresses. The force change would then be a consequence of reduced hypertrophic signalling rather than the mitochondrial injury the module describes, and the two directions would be reconciled.

Refuting outcome

Mitochondrial respiration and STAT3 serine-727 phosphorylation fall in RASopathy myocardium as they do in the oncology setting, with the same dose dependence. The toxicity mechanism would then be operating concurrently with the benefit, making the therapeutic window a real constraint rather than a theoretical one, and the dose and duration at which it opens would become the clinical question.

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Pathophysiology

16

SHP2 Gain-of-Function Activation

PTPN11 mutations destabilize the autoinhibitory interaction between the N-SH2 and PTP domains, resulting in constitutively elevated phosphatase activity. SHP2 is a positive regulator of RAS-MAPK signaling and gain-of-function mutations lead to enhanced ERK activation.

PTPN11 hgnc:9644

protein tyrosine phosphatase activity GO:0004725 ⇑ GAIN OF FUNCTION

Computational models

SHP2 N308S Molecular-Dynamics and Interaction-Network Model Represents an allele-specific conformational route from N308S to reduced autoinhibitory stability and a qualitative shift toward an activated open state.

Downstream

ERK Cascade Hyperactivation Enhanced SHP2 phosphatase activity promotes RAS activation and downstream ERK signaling.

Hematologic Dysregulation PTPN11-driven Noonan syndrome can include mutation-associated hematologic abnormalities, including bleeding diathesis and JMML risk.

Show evidence (1 reference)

PMID:11992261 SUPPORT Human clinical

"All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains"

PTPN11 mutations cluster at the N-SH2/PTP interface, disrupting autoinhibition.

SOS-Family-Mediated RAS-GTP Loading

SOS-family gain-of-function mutations encode guanine nucleotide exchange factor variants with enhanced activity, increasing the rate of RAS-GDP to RAS-GTP conversion and amplifying downstream MAPK signaling.

SOS1 hgnc:11187 SOS2 hgnc:11188

guanyl-nucleotide exchange factor activity GO:0005085

Computational models

SOS1 R1131K Transfer-Entropy Signaling Model Python 3.9.7, Jupyter, NumPy, pandas, matplotlib, and seaborn Uses SOS1 and RAF membrane-translocation dynamics to measure how R1131K changes effective information flow through the SOS-RAF signaling system. This is an indirect functional readout of the SOS node; RAS-GTP loading is not measured.

Downstream

ERK Cascade Hyperactivation Enhanced RAS-GTP loading directly amplifies RAF-MEK-ERK cascade activation.

Show evidence (1 reference)

PMID:17143285 SUPPORT In vitro / ex vivo

"Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation."

Cell-based functional assays show SOS1 mutations are gain-of-function, enhancing RAS-GTP loading.

RAF1 Kinase Hyperactivation

RAF1 mutations, particularly those altering Ser259 and flanking residues, disrupt 14-3-3 binding and autoinhibition, resulting in constitutively elevated serine-threonine kinase activity and enhanced MEK phosphorylation.

RAF1 hgnc:9829

protein serine/threonine kinase activity GO:0004674

Animal models

Raf1 L613V knock-in mouse Mouse recapitulates The disease allele is knocked in at the endogenous Raf1 locus, so the model carries the kinase-activating lesion itself rather than a downstream surrogate of it.

Downstream

ERK Cascade Hyperactivation Hyperactive RAF1 directly phosphorylates MEK, amplifying ERK signaling.

Cardiomyocyte Hypertrophy RAF1 kinase hyperactivation is strongly associated with hypertrophic cardiomyopathy development.

Show evidence (1 reference)

PMID:17603483 SUPPORT Human clinical

"Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding."

RAF1 mutations disrupt autoinhibitory 14-3-3 binding.

RIT1-Mediated RAF Recruitment

Pathogenic RIT1 proteins evade LZTR1-mediated degradation and accumulate. When membrane-bound, they directly bind and recruit RAF, increasing its local availability for MAPK signaling. Full RAF-MAPK activation nevertheless remains dependent on classical RAS proteins rather than bypassing them.

RIT1 hgnc:10023

Ras protein signal transduction GO:0007265

Computational models

RIT1 A57G-RAF1 Interface Structural Model STRUCTURAL PREDICTION Represents the RIT1 switch-I contact surface with RAF1 and predicts an allele-specific interface change that was tested by binding assays and interface mutagenesis.

Downstream

ERK Cascade Hyperactivation Aberrant RIT1-mediated RAF recruitment amplifies downstream ERK signaling.

Cardiomyocyte Hypertrophy RIT1 mutations are strongly associated with hypertrophic cardiomyopathy.

Show evidence (2 references)

PMID:23791108 SUPPORT Human clinical

"These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes."

RIT1 gain-of-function mutations drive aberrant MAPK signaling.

PMID:37450595 SUPPORT In vitro / ex vivo

"Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins."

Corrects the former implication that pathogenic RIT1 bypasses classical RAS regulation: direct RAF recruitment is necessary but not sufficient for MAPK activation.

LZTR1-Mediated RAS Proteostasis Defect

Loss of LZTR1-mediated RAS proteostasis through CRL3 E3 ligase increases RAS-family protein levels (including MRAS, RIT1, and KRAS) and MAPK signaling. Dominant LZTR1 mutations act in a dominant-negative manner to disrupt ubiquitination and degradation of RAS proteins.

LZTR1 hgnc:6742

protein ubiquitination GO:0016567 regulation of proteolysis GO:0030162

Computational models

LZTR1-RIT1 Recruitment Docking and Molecular-Dynamics Model MOLECULAR DOCKING MODELLER 9.23, HHpred, Maestro 2019-4, ClusPro, ZDOCK, PatchDock, FRODOCK, FoldX, GROMACS 5.1.5 with Amber03/TIP3P, and VMD Models the LZTR1-RIT1 recognition step that precedes CUL3-mediated ubiquitination and degradation, and tests how three LZTR1 substitutions alter the predicted interface or propagate conformational effects.

LZTR1 L580P AlphaFold-Multimer Polymerization Model STRUCTURAL PREDICTION ColabFold version 02c53 with AlphaFold-Multimer v2; six recycles, no templates, NVIDIA A5000 24 GB, two independent runs Predicts an allele-specific change in LZTR1 self-association that offers a structural explanation for impaired LZTR1 complex function and consequent loss of RAS-family protein turnover.

Downstream

ERK Cascade Hyperactivation Accumulated RAS proteins lead to increased basal MAPK signaling.

Show evidence (1 reference)

PMID:39352760 SUPPORT Model organism

"Cardiomyocyte size and the expression of RAS subfamily members, including MRAS and RIT1, were significantly increased in the left ventricles (LVs) of mutant male mice."

Supports LZTR1 loss-of-function effects on RAS-family proteostasis and downstream tissue-level cardiac phenotypes.

Additional RAS-MAPK Signal-Amplifying Variants

Additional established Noonan genes affecting small GTPases, RAF/MEK kinases, and RasGAP regulation converge on increased RAS-MAPK pathway throughput despite diverse molecular entry points. Two of the genes bound here reach that endpoint by losing a brake rather than by gaining a signal: CBL is an E3 ubiquitin ligase whose mutations impair receptor ubiquitylation, and SPRED2 is a negative modulator of EGF-promoted RAF1, MEK and ERK phosphorylation. SPRED2 is the exception to this entry's dominant pattern - it acts recessively - and is recorded in the autosomal recessive inheritance block alongside LZTR1.

KRAS hgnc:6407 NRAS hgnc:7989 MRAS hgnc:7227 RRAS2 hgnc:17271 BRAF hgnc:1097 MAP2K1 hgnc:6840 RASA2 hgnc:9872 CBL hgnc:1541 SPRED2 hgnc:17722

Downstream

ERK Cascade Hyperactivation Diverse rare Noonan genotypes affecting RAS-MAPK components still converge on excess ERK pathway output.

Show evidence (3 references)

PMID:20619386 SUPPORT Human clinical

"Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS."

Supports the CBL entry point this node's description names: loss of receptor ubiquitylation reaching the same RAS output as the activating genotypes.

PMID:34626534 SUPPORT In vitro / ex vivo

"When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs∗95) documented an increased and prolonged activation of the MAPK cascade in response to..."

Supports the SPRED2 entry point: loss of a negative modulator raising MAPK output, measured in patient fibroblasts as well as by overexpression.

PMID:20301303 SUPPORT Human clinical

"DIAGNOSIS/TESTING: 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..."

GeneReviews enumerates these rare but established Noonan genes that converge mechanistically on the same signaling pathway.

ERK Cascade Hyperactivation

Convergent point where all upstream RAS-MAPK pathway defects lead to sustained ERK1/2 phosphorylation and hyperactivation. This affects cell proliferation, differentiation, and survival during embryonic development and postnatal life. MAPK1 is bound here rather than on an upstream node because it encodes ERK2 itself: the NS13 genotype alters the effector this node names instead of altering an input to it.

MAPK1 hgnc:6871

MAPK cascade GO:0000165 regulation of ERK1 and ERK2 cascade GO:0070372

MAP kinase activity GO:0004707 ↑ INCREASED

Experimental models

Noonan syndrome iPSC-cardiomyocyte model IPSC DERIVED MODEL Pharmacological and genetic perturbation of MEK1/2, ERK1/2, and ERK5 in RAF1 S257L/+ iPSC-cardiomyocytes dissects which arm of RAS-MAPK signaling drives which part of the hypertrophic phenotype.

Paediatric Noonan syndrome myocardial tissue slice model OTHER Trametinib is applied directly to the slices, so the system reports what acute MEK inhibition does to contractile and calcium-handling behaviour in human RASopathy myocardium. The contractile and calcium readouts it produces sit on the MEASURES link below, since neither of them measures ERK activity.

Animal models

Raf1 L613V knock-in mouse Mouse recapitulates Agonist-evoked MEK-ERK signalling is elevated across several cell types in the knock-in, and pharmacological MEK inhibition reverses the organ-level phenotypes it drives.

Tie2-Cre Q79R-Shp2 endocardial cushion mouse Mouse perturbs Mutant Shp2 expression raises ERK1/2 activation in cushion mesenchyme, and the ERK1 deletion cross shows that this activation is necessary for the resulting phenotype.

Downstream

Neural Crest Cell Developmental Dysregulation ERK1/2 hyperactivation within the neural crest lineage itself is sufficient to produce the craniofacial malformations of Noonan syndrome, and suppressing that hyperactivation prevents them.

Cardiac Valve Morphogenesis Defects Perturbed ERK signaling alters endocardial-mesenchymal transition during valve development.

Cardiomyocyte Hypertrophy Sustained ERK signaling promotes hypertrophic growth and fetal gene reprogramming.

Cortical Layer Development Abnormalities Sustained RAS-MAPK signaling perturbs cortical neuronal lineage patterning and synaptic maturation programs in Noonan syndrome models.

Lymphatic Structural Abnormalities RAS-MAPK pathway overactivation contributes to clinically severe lymphatic anomalies in Noonan syndrome.

Growth Plate Chondrocyte Differentiation Defect ERK hyperactivation in growth plate cartilage impairs chondrocyte differentiation and endochondral bone growth.

Congenital Cardiac Structural Defects Dysregulated embryonic cardiac development in Noonan syndrome produces septation defects and additional right-sided outflow lesions beyond pulmonary valve dysplasia.

RASopathy Neoplastic Predisposition Chronic dysregulation of the RAS-MAPK pathway in Noonan syndrome contributes to elevated risk of benign and malignant neoplasms.

Hypertelorism

High Palate

Triangular Face

Downslanted Palpebral Fissures

Ptosis

Strabismus

Low-set Ears

Posteriorly Rotated Ears

Cryptorchidism

Hypogonadotropic Hypogonadism

Hearing Loss

Peripheral Neuropathy

Show evidence (2 references)

PMID:17143285 SUPPORT Model organism

"SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice."

Supports ERK cascade hyperactivation as a convergent signaling consequence of NS-associated upstream mutations.

PMID:32721402 SUPPORT In vitro / ex vivo

"Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling"

States that the MAPK1 genotype raises MAPK signaling output, which is the state this node asserts and the reason MAPK1 is bound here.

Growth Plate Chondrocyte Differentiation Defect

Local RAS-ERK hyperactivation in the growth plate impairs chondrocyte differentiation during endochondral bone growth, contributing to the characteristic postnatal growth impairment of Noonan syndrome.

chondrocyte CL:0000138

chondrocyte differentiation GO:0002062

Downstream

Short Stature Impaired endochondral bone growth reduces linear growth and contributes to short stature.

Pectus Deformity

Pectus Carinatum

Joint Hypermobility

Scoliosis

Delayed Skeletal Maturation

Show evidence (1 reference)

PMID:29659837 SUPPORT Model organism

"Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood."

Frames this growth plate defect as a disease-relevant explanatory branch for the short-stature phenotype in Noonan syndrome.

Cortical Layer Development Abnormalities

NS-derived cortical organoid models show abnormal excitatory-neuron layer specification and reduced synaptic connectivity, consistent with neurodevelopmental pathway disruption.

glutamatergic neuron CL:0000679

cerebral cortex development GO:0021987

cerebral cortex UBERON:0000956

Experimental models

Noonan syndrome cortical organoid model ORGANOID NS iPSC-derived cortical organoids reproduce the excitatory-neuron overrepresentation, aberrant SATB2/CTIP2 co-expressing layer identity, and reduced synaptic connectivity that define this node.

Downstream

Global Developmental Delay Perturbed cortical development and connectivity likely contributes to delayed neurodevelopmental trajectories.

Mild Intellectual Disability Abnormal cortical-layer identity and synaptic organization can contribute to persistent cognitive impairment in a subset of patients.

Hypotonia

Feeding Difficulties in Infancy

Show evidence (1 reference)

GEO:GSE213798 SUPPORT In vitro / ex vivo

"Surprisingly, EN subpopulation co-expressing upper layer marker SATB2 and deep layer maker CTIP2 was enriched in NS-COs during the cortical development."

Provides direct transcriptomic evidence of abnormal cortical layering in NS-derived organoid models.

Lymphatic Structural Abnormalities

Noonan syndrome can include severe central and peripheral lymphatic abnormalities that produce clinically significant fluid and lymphatic-flow complications.

endothelial cell of lymphatic vessel CL:0002138

lymphangiogenesis GO:0001946

Downstream

Increased Nuchal Translucency Prenatal lymphatic dysfunction can manifest as increased nuchal fluid on fetal ultrasound.

Lymphedema Structural and flow abnormalities in lymphatic channels manifest clinically as peripheral or generalized lymphedema.

Chylothorax Central conducting lymphatic dysfunction can produce chylous pleural effusions.

Thickened Nuchal Skin Fold

Cystic Hygroma

Webbed Neck

Show evidence (1 reference)

DOI:10.3389/fped.2025.1475143 SUPPORT Human clinical

"Albeit phenotypically heterogeneous, NS can be associated with severe cardiovascular and lymphatic anomalies, potentially lethal during infancy, neonatal and fetal periods."

Supports the presence of clinically severe lymphatic disease as part of the Noonan syndrome pathophysiologic spectrum.

Hematologic Dysregulation

PTPN11-associated Noonan syndrome can include mutation-associated bleeding diathesis and predisposition to juvenile myelomonocytic leukemia, indicating a distinct hematologic disease branch.

hematopoietic stem cell CL:0000037

Downstream

Bruising Susceptibility Bleeding diathesis and coagulation abnormalities manifest clinically as easy bruising or excessive bleeding.

Juvenile Myelomonocytic Leukemia Myeloid dysregulation in susceptible genotypes can progress to JMML in a small subset of affected individuals.

Abnormal Bleeding

Abnormality of Coagulation

Show evidence (1 reference)

PMID:15240615 SUPPORT Human clinical

"hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007)."

Supports a clinically distinct hematologic branch in PTPN11-positive Noonan syndrome.

Cardiac Valve Morphogenesis Defects

In endocardial and valvular tissues, perturbed ERK signaling alters endocardial-mesenchymal transition and valve morphogenesis, underlying pulmonary valve stenosis, the most common cardiac defect in Noonan syndrome.

endocardial cell CL:0002350

epithelial to mesenchymal transition involved in endocardial cushion formation GO:0003198 heart valve morphogenesis GO:0003179

pulmonary valve UBERON:0002146 heart UBERON:0000948

Animal models

Raf1 L613V knock-in mouse Mouse fails to recapitulate Valvuloseptal development is explicitly normal in this model, so a RAF1 kinase-activating allele sufficient to drive postnatal hypertrophy does not on its own reproduce the valve lesion.

Tie2-Cre Q79R-Shp2 endocardial cushion mouse Mouse recapitulates An embryonic system at the developmental stage the valve node describes, observing the cushion overgrowth that precedes the pulmonary valve lesion. It is the only model linked to this node; the postnatal Raf1 L613V knock-in has normal valvuloseptal development.

Downstream

Pulmonary Valve Stenosis Valve morphogenesis defects in the pulmonary outflow tract manifest as dysplastic pulmonary valve stenosis.

Show evidence (1 reference)

PMID:11992261 SUPPORT Human clinical

"pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01)"

Demonstrates that pulmonary valve stenosis is highly associated with PTPN11 mutations in Noonan syndrome.

Congenital Cardiac Structural Defects

Beyond pulmonary valve dysplasia, disturbed embryonic cardiac morphogenesis in Noonan syndrome can produce septation defects and branch pulmonary artery abnormalities.

Downstream

Atrial Septal Defect Abnormal cardiac septation can manifest as secundum or other atrial septal defects.

Ventricular Septal Defect Abnormal ventricular septation can produce clinically significant ventricular septal defects.

Branch Pulmonary Artery Stenosis Aberrant development of the pulmonary outflow tract can narrow the branch pulmonary arteries.

Show evidence (1 reference)

PMID:20301303 SUPPORT Human clinical

"Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot."

GeneReviews supports a broader congenital structural-heart-disease branch in Noonan syndrome beyond pulmonary valve stenosis alone.

RASopathy Neoplastic Predisposition

Noonan syndrome shares the broader RASopathy tendency toward benign and malignant neoplasia, reflecting chronic developmental dysregulation of the RAS-MAPK pathway.

Downstream

Tumor Predisposition This shared RASopathy cancer-predisposition branch manifests clinically as increased risk of diverse solid and hematologic neoplasms.

Neuroblastoma Neuroblastoma has been reported in people with germline mutations in RAS-pathway (RASopathy) genes, including people with Noonan syndrome, which places it within the reported tumor spectrum of this shared predisposition. The cited consensus reports cases rather than a measured risk, and it gives no neuroblastoma risk figure for Noonan syndrome.

Show evidence (1 reference)

DOI:10.1158/1078-0432.ccr-24-1611 SUPPORT Human clinical

"When compared with the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms."

Supports a pathway-linked neoplastic predisposition branch for Noonan syndrome within the broader RASopathy family.

Cardiomyocyte Hypertrophy

In cardiomyocytes, sustained ERK signaling (and intersecting AKT/mTOR activity) promotes hypertrophic growth and fetal gene reprogramming, leading to hypertrophic cardiomyopathy, particularly in patients with RAF1 and RIT1 mutations.

cardiomyocyte CL:0000746

cardiac muscle hypertrophy GO:0003300

heart UBERON:0000948

Experimental models

Noonan syndrome iPSC-cardiomyocyte model IPSC DERIVED MODEL PTPN11 N308S/+ iPSC-cardiomyocytes reproduce the hypertrophic phenotype but argue it is driven by cell-cycle defects rather than by the ERK/AKT-mTOR hypertrophic-growth program this node describes.

Paediatric Noonan syndrome myocardial tissue slice model OTHER The slices are the patient's own hypertrophic myocardium rather than a system engineered to resemble it, so the human genotype, the multicellular composition and the contractile apparatus are all native.

Paediatric Noonan syndrome myocardial tissue slice model OTHER What the slices actually measure under acute MEK inhibition: developed force and sarcoplasmic reticulum calcium handling in the patient's own hypertrophic myocardium. The two move in opposite directions, which is the only dataset in this entry touching both the therapeutic and the cardiotoxic reading of MEK inhibition at once.

Animal models

Raf1 L613V knock-in mouse Mouse recapitulates The knock-in develops eccentric cardiac hypertrophy with fetal gene reactivation and decompensates under pressure overload. MEK inhibition begun postnatally normalizes the cardiac phenotype, which is the result behind treating MEK as the actionable node for RAF1-driven hypertrophy.

Downstream

Hypertrophic Cardiomyopathy Persistent cardiomyocyte hypertrophic remodeling yields clinical hypertrophic cardiomyopathy.

Abnormal EKG

Arrhythmia

Show evidence (2 references)

PMID:17603483 SUPPORT Human clinical

"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."

Demonstrates strong association between RAF1 mutations and HCM, implicating the kinase pathway in cardiac hypertrophy.

PMID:23791108 SUPPORT Human clinical

"Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome."

RIT1 mutations are strongly associated with hypertrophic cardiomyopathy.

Neural Crest Cell Developmental Dysregulation

The neural crest is the lineage in which the RAS-MAPK lesion reaches the conotruncal and craniofacial features of Noonan syndrome. Neural crest cells populate the cardiac outflow tract and supply a large share of the facial and cranial skeleton, and SHP2 is separately required within them: ablating PTPN11 in premigratory neural crest blocks outflow-tract colonisation and produces persistent truncus arteriosus with pronounced craniofacial deficits, while driving the Noonan SHP2 Q79R allele in neural crest is by itself enough to cause craniofacial malformation. Modelling this as an explicit node makes the neural crest step visible instead of leaving the craniofacial and conotruncal outcomes hanging directly off the ERK node. The `modifier` on neural crest cell migration is deliberately DYSREGULATED rather than INCREASED or DECREASED: the direction is not fixed across lesions. Loss of SHP2 in neural crest impairs migration into the outflow tract, whereas at least one Noonan-spectrum missense variant has been reported to drive excessive migration. Which lesions move it which way, and whether that is ERK-dependent, is captured as an open question in `discussions` (`noonan_erk_magnitude_vs_neural_crest_phenotype`).

migratory neural crest cell CL:0000333

PTPN11 hgnc:9644

neural crest cell migration GO:0001755 ↕ DYSREGULATED neural crest cell development GO:0014032 ⚠ ABNORMAL

Animal models

Chick neural tube electroporation of PTPN11 variants Chicken perturbs Variant-specific perturbation of neural crest allocation and spatial organisation, assayed directly in the migrating lineage.

Downstream

Congenital Cardiac Structural Defects Neural crest cells that fail to colonise the developing outflow tract leave conotruncal and great-vessel malformations.

Hypertelorism Neural-crest-derived frontonasal skeleton is affected, widening the interorbital distance.

Triangular Face Reduced skull length with altered mandibular proportion in neural-crest-targeted models parallels the Noonan facial gestalt.

Show evidence (2 references)

PMID:19541608 SUPPORT Model organism

"The data show that SHP2 activity in the NCC is essential for normal migration and differentiation into the diverse lineages found in the heart and skull"

Establishes the neural crest as a lineage with its own SHP2 requirement for both of the organ systems Noonan syndrome affects most characteristically.

PMID:20493809 SUPPORT Model organism

"we identify a phosphatase- and Erk-dependent role for Shp2 in neural crest specification and migration"

Independent (zebrafish) confirmation that Shp2 acts in neural crest specification and migration, and that this arm of its function is ERK-dependent.

⬡

Pathograph

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Phenotypes

41

Blood 4

Bruising Susceptibility OCCASIONAL HP:0000978

Show evidence (2 references)

PMID:24444506 SUPPORT Human clinical

"Most affected individuals have 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,..."

This clinical review supports bleeding tendency/easy bruising as a recognized hematologic phenotype in Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0000978 | Bruising susceptibility | Occasional (29-5%)"

Orphanet phenotype annotation supports bruising susceptibility as occasional in Noonan syndrome.

Abnormal Bleeding FREQUENT HP:0001892

Show evidence (2 references)

PMID:24444506 SUPPORT Human clinical

"Most affected individuals have 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,..."

Clinical review evidence identifies increased bleeding tendency as part of the Noonan syndrome phenotype spectrum.

ORPHA:648 SUPPORT Other

"HP:0001892 | Abnormal bleeding | Frequent (79-30%)"

Orphanet phenotype annotation supports abnormal bleeding as frequent in Noonan syndrome.

Abnormality of Coagulation FREQUENT HP:0001928

Show evidence (2 references)

PMID:20301303 SUPPORT 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 identifies varied coagulation defects as a recognized Noonan syndrome finding.

ORPHA:648 SUPPORT Other

"HP:0001928 | Abnormality of coagulation | Frequent (79-30%)"

Orphanet phenotype annotation supports abnormality of coagulation as frequent in Noonan syndrome.

Juvenile Myelomonocytic Leukemia HP:0012209

Show evidence (2 references)

PMID:15240615 SUPPORT Human clinical

"hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007)."

OMIM/HPOA-linked cohort data support juvenile myelomonocytic leukemia as a recognized hematologic malignancy in PTPN11-associated Noonan syndrome.

PMID:15723289 SUPPORT Human clinical

"In one patient with NS and mild juvenile myelomonocytic leukemia (JMML) the mutation 218C --> T (Thr73Ile) was found. This confirms previous findings indicating that individuals with NS with specific mutations in PTPN11 are at risk of developing JMML."

Independent cohort-review evidence further supports JMML risk as a rare but important oncologic manifestation of Noonan syndrome.

Cardiovascular 7

Pulmonary Valve Stenosis FREQUENT Pulmonic stenosis HP:0001642

Show evidence (2 references)

PMID:11992261 SUPPORT Human clinical

"pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01)"

Confirms high prevalence of pulmonary stenosis in Noonan syndrome, especially with PTPN11 mutations.

ORPHA:648 SUPPORT Other

"HP:0001641 | Abnormal pulmonary valve morphology | Frequent (79-30%)"

Orphanet phenotype annotation for abnormal pulmonary valve morphology directly supports the pulmonary valve stenosis phenotype in this entry at a frequent classification.

Hypertrophic Cardiomyopathy OCCASIONAL HP:0001639

Show evidence (4 references)

PMID:17603483 SUPPORT Human clinical

"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."

RAF1 mutations are strongly associated with HCM.

PMID:23791108 SUPPORT Human clinical

"Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome."

RIT1 mutations confer high risk of hypertrophic cardiomyopathy.

PMID:11992261 SUPPORT Human clinical

"hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005)"

PTPN11 mutations are associated with lower HCM risk compared to other NS genes.

+ 1 more reference

Abnormal EKG VERY_FREQUENT HP:0003115

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0003115 | Abnormal EKG | Very frequent (99-80%)"

Orphanet phenotype annotation supports abnormal EKG as very frequent in Noonan syndrome.

Arrhythmia FREQUENT HP:0011675

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0011675 | Arrhythmia | Frequent (79-30%)"

Orphanet phenotype annotation supports arrhythmia as frequent in Noonan syndrome.

Atrial Septal Defect OCCASIONAL HP:0001631

Show evidence (2 references)

PMID:41718520 SUPPORT Human clinical

"An infant presented with a large secundum atrial septal defect complicating NS-HCM."

Supports atrial septal defect as a documented structural cardiac manifestation in Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0001631 | Atrial septal defect | Occasional (29-5%)"

Orphanet phenotype annotation supports atrial septal defect as occasional in Noonan syndrome.

Ventricular Septal Defect HP:0001629

Show evidence (1 reference)

PMID:20301303 SUPPORT Human clinical

"Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot."

GeneReviews identifies ventricular septal defect as part of the structural cardiac phenotype spectrum in Noonan syndrome.

Branch Pulmonary Artery Stenosis Peripheral pulmonary artery stenosis HP:0004969

Show evidence (1 reference)

PMID:20301303 SUPPORT Human clinical

"Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot."

GeneReviews identifies branch pulmonary artery stenosis as part of the Noonan congenital heart disease spectrum.

Digestive 1

Feeding Difficulties in Infancy FREQUENT HP:0008872

Show evidence (2 references)

PMID:17222357 SUPPORT Human clinical

"Other associated features are webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding tendency and lymphatic dysplasias."

Supports poor feeding in infancy as a common early-life manifestation in Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0008872 | Feeding difficulties in infancy | Frequent (79-30%)"

Orphanet phenotype annotation supports feeding difficulties in infancy as frequent in Noonan syndrome.

Ear 3

Low-set Ears VERY_FREQUENT HP:0000369

Show evidence (1 reference)

PMID:41517739 SUPPORT Human clinical

"A 22-year-old woman presented with typical dysmorphic features of NS, including short stature, broad forehead, hypertelorism, low-set posteriorly rotated ears, and a broad neck."

Case-based clinical evidence supports low-set/posteriorly rotated ears as a characteristic facial finding in Noonan syndrome.

Posteriorly Rotated Ears VERY_FREQUENT HP:0000358

Show evidence (2 references)

PMID:41517739 SUPPORT Human clinical

"A 22-year-old woman presented with typical dysmorphic features of NS, including short stature, broad forehead, hypertelorism, low-set posteriorly rotated ears, and a broad neck."

Case-based clinical evidence supports posteriorly rotated ears as part of the characteristic Noonan syndrome facial phenotype.

ORPHA:648 SUPPORT Other

"HP:0000358 | Posteriorly rotated ears | Very frequent (99-80%)"

Orphanet phenotype annotation supports posteriorly rotated ears as very frequent in Noonan syndrome.

Hearing Loss Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:24444506 SUPPORT Human clinical

"Most affected individuals have 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,..."

Supports hearing loss as part of the multisystem clinical phenotype in Noonan syndrome.

Endocrine 1

Hypogonadotropic Hypogonadism HP:0000044

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0000044 | Hypogonadotropic hypogonadism | Very frequent (99-80%)"

Orphanet phenotype annotation supports hypogonadotropic hypogonadism as an associated Noonan syndrome phenotype; frequency is not asserted here because the broader literature more consistently supports pubertal delay than 80-99% prevalence of frank hypogonadotropic hypogonadism.

Eye 3

Hypertelorism VERY_FREQUENT HP:0000316

Show evidence (2 references)

PMID:41517739 SUPPORT Human clinical

"A 22-year-old woman presented with typical dysmorphic features of NS, including short stature, broad forehead, hypertelorism, low-set posteriorly rotated ears, and a broad neck."

Supports hypertelorism as part of the characteristic craniofacial phenotype in clinically diagnosed Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0000316 | Hypertelorism | Very frequent (99-80%)"

Orphanet phenotype annotation supports hypertelorism as very frequent in Noonan syndrome.

Ptosis VERY_FREQUENT HP:0000508

Show evidence (2 references)

PMID:17222357 SUPPORT Human clinical

"The main facial features of NS are hypertelorism with down-slanting palpebral fissures, ptosis and low-set posteriorly rotated ears with a thickened helix."

Review evidence explicitly identifies ptosis as a core facial feature in Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0000508 | Ptosis | Very frequent (99-80%)"

Orphanet phenotype annotation supports ptosis as very frequent in Noonan syndrome.

Strabismus FREQUENT HP:0000486

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0000486 | Strabismus | Frequent (79-30%)"

Orphanet phenotype annotation supports strabismus as frequent in Noonan syndrome.

Genitourinary 1

Cryptorchidism FREQUENT HP:0000028

Show evidence (2 references)

PMID:11992261 SUPPORT Human clinical

"The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups."

Cryptorchidism is recognized as a common feature across Noonan syndrome genotypes.

ORPHA:648 SUPPORT Other

"HP:0000028 | Cryptorchidism | Frequent (79-30%)"

Orphanet phenotype annotation supports cryptorchidism as frequent in Noonan syndrome.

Head and Neck 7

Increased Nuchal Translucency HP:0010880

Show evidence (1 reference)

PMID:17222357 SUPPORT Human clinical

"NS should be considered in all foetuses with polyhydramnion, pleural effusions, oedema and increased nuchal fluid with a normal karyotype."

Supports increased nuchal translucency or fluid as a recognizable prenatal Noonan syndrome manifestation.

Thickened Nuchal Skin Fold VERY_FREQUENT HP:0000474

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0000474 | Thickened nuchal skin fold | Very frequent (99-80%)"

Orphanet phenotype annotation supports thickened nuchal skin fold as very frequent in Noonan syndrome.

Cystic Hygroma HP:0000476

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0000476 | Cystic hygroma | Very frequent (99-80%)"

Orphanet phenotype annotation supports cystic hygroma as a Noonan syndrome-associated prenatal lymphatic phenotype; frequency is not asserted here because prenatal ascertainment may inflate the structured frequency band.

High Palate VERY_FREQUENT HP:0000218

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0000218 | High palate | Very frequent (99-80%)"

Orphanet phenotype annotation supports high palate as very frequent in Noonan syndrome.

Triangular Face VERY_FREQUENT HP:0000325

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0000325 | Triangular face | Very frequent (99-80%)"

Orphanet phenotype annotation supports triangular face as very frequent in Noonan syndrome.

Downslanted Palpebral Fissures VERY_FREQUENT HP:0000494

Show evidence (2 references)

PMID:17222357 SUPPORT Human clinical

"The main facial features of NS are hypertelorism with down-slanting palpebral fissures, ptosis and low-set posteriorly rotated ears with a thickened helix."

Review evidence explicitly identifies down-slanting palpebral fissures as a main facial feature in Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0000494 | Downslanted palpebral fissures | Very frequent (99-80%)"

Orphanet phenotype annotation supports downslanted palpebral fissures as very frequent in Noonan syndrome.

Webbed Neck VERY_FREQUENT HP:0000465

Show evidence (2 references)

PMID:17222357 SUPPORT Human clinical

"Other associated features are webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding tendency and lymphatic dysplasias."

Review evidence explicitly identifies webbed neck as a recognized associated feature in Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0000465 | Webbed neck | Very frequent (99-80%)"

Orphanet phenotype annotation supports webbed neck as very frequent in Noonan syndrome.

Metabolism 2

Lymphedema OCCASIONAL HP:0001004

Show evidence (2 references)

PMID:24444506 SUPPORT Human clinical

"Most affected individuals have 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,..."

Supports lymphedema as a recognized clinical manifestation in Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0001004 | Lymphedema | Occasional (29-5%)"

Orphanet phenotype annotation supports lymphedema as occasional in Noonan syndrome.

Chylothorax HP:0010310

Show evidence (1 reference)

DOI:10.3390/children11111342 SUPPORT Human clinical

"The phenotype of Noonan syndrome includes characteristic facial and physical features, congenital cardiac defects, lymphatic and cerebrovascular anomalies, renal malformations, hematological abnormalities, developmental issues, and an increased risk of cancer."

Noonan syndrome case report directly documents chylothorax as part of the lymphatic phenotype and confirms trametinib efficacy for this manifestation.

Musculoskeletal 6

Pectus Deformity VERY_FREQUENT Pectus excavatum HP:0000767

Show evidence (2 references)

PMID:11992261 SUPPORT Human clinical

"The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups."

Pectus deformity is recognized as a common feature across genotypes.

ORPHA:648 SUPPORT Other

"HP:0000767 | Pectus excavatum | Very frequent (99-80%)"

Orphanet phenotype annotation classifies pectus excavatum as very frequent in Noonan syndrome.

Pectus Carinatum VERY_FREQUENT HP:0000768

Show evidence (2 references)

PMID:20301303 SUPPORT Human clinical

"Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum,"

GeneReviews identifies pectus carinatum as part of the characteristic chest-wall phenotype in Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0000768 | Pectus carinatum | Very frequent (99-80%)"

Orphanet phenotype annotation supports pectus carinatum as very frequent in Noonan syndrome.

Joint Hypermobility VERY_FREQUENT HP:0001382

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0001382 | Joint hypermobility | Very frequent (99-80%)"

Orphanet phenotype annotation supports joint hypermobility as very frequent in Noonan syndrome.

Scoliosis FREQUENT HP:0002650

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0002650 | Scoliosis | Frequent (79-30%)"

Orphanet phenotype annotation supports scoliosis as frequent in Noonan syndrome.

Delayed Skeletal Maturation FREQUENT HP:0002750

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0002750 | Delayed skeletal maturation | Frequent (79-30%)"

Orphanet phenotype annotation supports delayed skeletal maturation as frequent in Noonan syndrome.

Hypotonia FREQUENT HP:0001252

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"HP:0001252 | Hypotonia | Frequent (79-30%)"

Orphanet phenotype annotation supports hypotonia as frequent in Noonan syndrome.

Nervous System 3

Peripheral Neuropathy OCCASIONAL HP:0009830

Show evidence (1 reference)

PMID:41560462 SUPPORT Human clinical

"All patients reported somatosensory symptoms consistent with peripheral neuropathy...electrodiagnostic testing was consistent with peroneal neuropathy in one patient."

Supports peripheral neuropathy as a clinically meaningful neurologic manifestation in adults with Noonan-spectrum disorders.

Global Developmental Delay FREQUENT HP:0001263

Show evidence (2 references)

PMID:11992261 SUPPORT Human clinical

"The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups."

Developmental delay is a recognized feature across Noonan syndrome genotypes.

ORPHA:648 SUPPORT Other

"HP:0012758 | Neurodevelopmental delay | Frequent (79-30%)"

Orphanet lists neurodevelopmental delay as frequent, supporting the global developmental delay phenotype in this entry.

Mild Intellectual Disability OCCASIONAL HP:0001256

Show evidence (2 references)

PMID:20301303 SUPPORT Human clinical

"Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population."

GeneReviews reports mild intellectual disability in a substantial minority of individuals with Noonan syndrome.

ORPHA:648 SUPPORT Other

"HP:0001249 | Intellectual disability | Occasional (29-5%)"

Orphanet classifies intellectual disability as occasional in Noonan syndrome, consistent with the mild intellectual disability reported in this entry.

Growth 1

Short Stature VERY_FREQUENT HP:0004322

Show evidence (2 references)

PMID:41577878 SUPPORT Human clinical

"Short stature is a key NSSD feature."

Large multicenter Noonan-spectrum cohort data support short stature as a prevalent and clinically significant growth phenotype.

ORPHA:648 SUPPORT Other

"HP:0004322 | Short stature | Very frequent (99-80%)"

Orphanet phenotype annotation supports short stature as very frequent in Noonan syndrome.

Neoplasm 2

Tumor Predisposition Neoplasm HP:0002664

Coarse binding: pathograph hub

Bound at HP:0002664 deliberately. RASopathy Neoplastic Predisposition is the only node that targets this one. Its one other edge reaches Neuroblastoma, one specific tumour from the reported spectrum, curated as its own phenotype beside this node, so the mechanism converges here rather than this being one arm of a wide fan-out, and the coarseness is a property of the biology: germline RAS/MAPK hyperactivation raises risk across haematopoietic and solid lineages instead of producing one characteristic tumour. The reported tumours differ by genotype, so no narrower HP term is the right binding for the node the mechanism reaches.

Show evidence (1 reference)

PMID:19953625 SUPPORT Human clinical

"Three patients with SOS1 mutations presented with tumors (embryonal rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of the skin). One patient with a RAF1 mutation had a lesion suggestive for a giant cell tumor."

Supports a clinically relevant tumor predisposition phenotype in Noonan syndrome, particularly in SOS1- and RAF1-associated disease.

Neuroblastoma VERY_RARE HP:0003006

Frequency is set to VERY_RARE on the count in Kratz et al. (2015): one neuroblastoma among the 632 people in the study's combined Noonan syndrome group (571 with classic Noonan syndrome, 44 with NSML and 17 with the NS-like disorder with loose anagen hair, per its Table 1) matched against the German Childhood Cancer Registry. The same table row gives 0.093 cases expected and an SIR of 10.8 (95% CI 0.3-59.9). One case, with an interval that includes 1, does not show that neuroblastoma risk is raised in Noonan syndrome. The 2024 update's surveillance table covering Noonan syndrome (its Table 2) has no neuroblastoma row, and its neuroblastoma risk figures belong to Costello syndrome (its Table 3 and its Costello syndrome section), so none is carried over here.

Show evidence (6 references)

PMID:39196581 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"The relative childhood cancer risk in NS is estimated to be increased approximately 8-fold over the general population(5). Due to the low baseline cancer risk in children, the high relative risk leads to a moderate absolute cancer risk(5). The spectrum of cancer types is broad and includes..."

In the Noonan syndrome (NS) section of this 2024 consensus update on pediatric cancer surveillance in the RASopathies, which originated from the 2023 AACR Childhood Cancer Predisposition Workshop, the authors estimate the relative childhood cancer risk in NS at about 8-fold that of the general population, which they describe as a moderate absolute risk, and list neuroblastoma (NB) in the broad NS cancer spectrum alongside myeloid and lymphoblastic leukemia, rhabdomyosarcoma (RMS) and glioma. The 8-fold figure is for all childhood cancers combined, not for NB, and the update gives no risk figure for NB in NS. The passage summarizes, with citations, the cancers reported in people with NS, so it is graded HUMAN_CLINICAL with quote_role REVIEW_SYNTHESIS. The same section notes that the majority of data on cancer incidence in NS is based on PTPN11 cases.

PMID:25742478 SUPPORT DIRECT PRIMARY RESULT Human clinical

"8 (NS) | F | 3 | I282M (1) | NBL (3) | Cosmic database"

Kratz et al. (2015) matched people with a molecularly confirmed RASopathy, identified through German genetic laboratories, against the German Childhood Cancer Registry. Their Table 2 describes each person in the cohort who developed cancer. This row, in the table's PTPN11 section, is patient 8: a girl with Noonan syndrome (NS) carrying the PTPN11 variant I282M, who had neuroblastoma (NBL) at age 3 years. Its last column cites the COSMIC database as having previously associated the variant with cancer. It is the study's own observation that NB occurs in NS, so it is graded HUMAN_CLINICAL with quote_role PRIMARY_RESULT. The row is in the paper's full text, not its abstract.

PMID:25742478 SUPPORT DIRECT PRIMARY RESULT Human clinical

"NBL | 632 | 1 | 0.093 | 6535.6 | 10.8 (0.3-59.9)"

Table 3 of Kratz et al. (2015) gives standardised incidence ratios (SIRs) for selected cancers. In its Noonan syndrome (NS) block, whose 'NS combined' label sits on the block's first row, this row reports neuroblastoma (NBL) among the 632 people with NS, the paper's 'NS, all subtypes combined' group (571 classic NS, 44 NS with multiple lentigines and 17 NS-like disorder with loose anagen hair, per its Table 1): 1 case observed against 0.093 expected over 6535.6 person-years, an SIR of 10.8 with a 95% confidence interval of 0.3 to 59.9. The interval includes 1, so the study does not show a raised NB risk in NS; the authors attribute the cohort's raised overall cancer risk primarily to significant excesses of JMML, embryonal rhabdomyosarcoma and brain tumours. The one case among 632 is the basis for the VERY_RARE frequency. It is the study's own registry-matching result, so it is graded HUMAN_CLINICAL with quote_role PRIMARY_RESULT. The row is in the paper's full text, not its abstract.

+ 3 more references

🧬

Genetic Associations

19

PTPN11 (Pathogenic Variants)

Gene: PTPN11 hgnc:9644 gene page

Show evidence (3 references)

PMID:11992261 SUPPORT Human clinical

"Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS."

Confirms PTPN11 mutations account for approximately half of Noonan syndrome cases.

ORPHA:648 SUPPORT Other

"PTPN11 | protein tyrosine phosphatase non-receptor type 11 | hgnc:9644 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports PTPN11 as causative for Noonan syndrome.

CGGV:assertion_2bb08565-4669-4633-b6ed-c04e2a431cf9-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the PTPN11-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

SOS1 (Pathogenic Variants)

Gene: SOS1 hgnc:11187 gene page

Show evidence (3 references)

PMID:17143285 SUPPORT Human clinical

"We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation."

SOS1 mutations are a significant cause of PTPN11-negative Noonan syndrome.

ORPHA:648 SUPPORT Other

"SOS1 | SOS Ras/Rac guanine nucleotide exchange factor 1 | hgnc:11187 | Disease-causing germline mutation(s) (gain of function) in"

Orphanet gene-disease association supports SOS1 as causative for Noonan syndrome.

CGGV:assertion_9781b6bf-9b1e-4a10-a0a9-7e56562a6e3a-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the SOS1-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

SOS2 (Pathogenic Variants)

Gene: SOS2 hgnc:11188

Show evidence (3 references)

PMID:25795793 SUPPORT Human clinical

"We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands."

Discovery-cohort evidence supports SOS2 as an established rare cause of Noonan syndrome.

ORPHA:648 SUPPORT Other

"SOS2 | SOS Ras/Rho guanine nucleotide exchange factor 2 | hgnc:11188 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports SOS2 as causative for Noonan syndrome.

CGGV:assertion_f20a1034-e29d-49bb-aed9-b4ba63dc5968-2020-08-27T160000.000Z SUPPORT Other

ClinGen classifies the SOS2-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

RAF1 (Pathogenic Variants)

Gene: RAF1 hgnc:9829 gene page

Show evidence (3 references)

PMID:17603483 SUPPORT Human clinical

"18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals)...have missense mutations in RAF1"

RAF1 mutations account for approximately 3% of Noonan syndrome.

ORPHA:648 SUPPORT Other

"RAF1 | Raf-1 proto-oncogene, serine/threonine kinase | hgnc:9829 | Disease-causing germline mutation(s) (gain of function) in"

Orphanet gene-disease association supports RAF1 as causative for Noonan syndrome.

CGGV:assertion_85645d27-2056-4ad3-9593-8d7739aa4121-2024-10-23T160000.000Z SUPPORT Other

ClinGen classifies the RAF1-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

BRAF (Pathogenic Variants)

Gene: BRAF hgnc:1097 gene page

Show evidence (3 references)

PMID:19953625 SUPPORT Human clinical

"We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients."

Supports BRAF as a rare molecular cause within the Noonan syndrome spectrum.

ORPHA:648 SUPPORT Other

"BRAF | B-Raf proto-oncogene, serine/threonine kinase | hgnc:1097 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports BRAF as causative for Noonan syndrome.

CGGV:assertion_47cf08d5-efc6-4d42-b031-a06619873161-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the BRAF-Noonan syndrome gene-disease relationship as moderate with autosomal dominant inheritance.

MAP2K1 (Pathogenic Variants)

Gene: MAP2K1 hgnc:6840 gene page

Show evidence (2 references)

PMID:25049390 SUPPORT Human clinical

"We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1) and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients."

Next-generation sequencing in mutation-negative cases supports MAP2K1 as an established rare cause of Noonan syndrome.

CGGV:assertion_1eafd4b1-29b1-4a17-a7ac-2c555f2e2648-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the MAP2K1-Noonan syndrome gene-disease relationship as limited with autosomal dominant inheritance.

RIT1 (Pathogenic Variants)

Gene: RIT1 hgnc:10023

Show evidence (3 references)

PMID:23791108 SUPPORT Human clinical

"we identified a total of nine missense, nonsynonymous mutations in RIT1...in 17 of 180 individuals (9%) with Noonan syndrome"

RIT1 mutations account for approximately 9% of cases without mutations in other known genes.

ORPHA:648 SUPPORT Other

"RIT1 | Ras like without CAAX 1 | hgnc:10023 | Disease-causing germline mutation(s) (gain of function) in"

Orphanet gene-disease association supports RIT1 as causative for Noonan syndrome.

CGGV:assertion_240565fc-61b9-4ff8-9f5a-85938f17cdd9-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the RIT1-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

RRAS2 (Pathogenic Variants)

Gene: RRAS2 hgnc:17271

Show evidence (3 references)

PMID:31130282 SUPPORT Human clinical

"By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families."

Supports RRAS2 as an established but very rare cause of Noonan syndrome.

ORPHA:648 SUPPORT Other

"RRAS2 | RAS related 2 | hgnc:17271 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports RRAS2 as causative for Noonan syndrome.

CGGV:assertion_c5742615-3820-41dd-a523-e660a498f9e8-2022-12-14T170000.000Z SUPPORT Other

ClinGen classifies the RRAS2-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

KRAS (Pathogenic Variants)

Gene: KRAS hgnc:6407 gene page

Show evidence (3 references)

PMID:17143285 SUPPORT Human clinical

"KRAS mutations account for <5% of cases of Noonan syndrome"

KRAS mutations are a rare cause of Noonan syndrome.

ORPHA:648 SUPPORT Other

"KRAS | KRAS proto-oncogene, GTPase | hgnc:6407 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports KRAS as causative for Noonan syndrome.

CGGV:assertion_6476a5fd-8f66-462b-b17a-43540dad3c1f-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the KRAS-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

NRAS (Pathogenic Variants)

Gene: NRAS hgnc:7989 gene page

Show evidence (3 references)

PMID:19966803 SUPPORT Human clinical

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

Supports NRAS as a rare gain-of-function molecular cause of Noonan syndrome.

ORPHA:648 SUPPORT Other

"NRAS | NRAS proto-oncogene, GTPase | hgnc:7989 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports NRAS as causative for Noonan syndrome.

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

ClinGen classifies the NRAS-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

RASA2 (Pathogenic Variants)

Gene: RASA2 hgnc:9872

Show evidence (3 references)

PMID:25049390 SUPPORT Human clinical

"We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1) and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients."

Supports RASA2 loss of function as a rare molecular mechanism in Noonan syndrome.

ORPHA:648 SUPPORT Other

"RASA2 | RAS p21 protein activator 2 | hgnc:9872 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association supports RASA2 as causative for Noonan syndrome.

CGGV:assertion_9635e391-79b6-4054-824e-1c607a02cd07-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the RASA2-Noonan syndrome gene-disease relationship as limited with autosomal dominant inheritance.

LZTR1 (Pathogenic Variants)

Gene: LZTR1 hgnc:6742 gene page

Show evidence (3 references)

PMID:41675685 SUPPORT Human clinical

"Final diagnoses included 15 individuals with Noonan syndrome...one each in LZTR1, A2ML1, and MRAS..."

Supports LZTR1 as a clinically observed Noonan syndrome genotype in contemporary molecular cohorts.

ORPHA:648 SUPPORT Other

"LZTR1 | leucine zipper like post translational regulator 1 | hgnc:6742 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports LZTR1 as causative for Noonan syndrome.

CGGV:assertion_6f21db9c-87ea-4095-96ca-4277eaa21232-2020-04-23T170000.000Z SUPPORT Other

ClinGen classifies the LZTR1-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

MRAS (Pathogenic Variants)

Gene: MRAS hgnc:7227 gene page

Show evidence (4 references)

PMID:41675685 SUPPORT Human clinical

"Final diagnoses included 15 individuals with Noonan syndrome...one each in LZTR1, A2ML1, and MRAS..."

Supports MRAS as a rare but clinically confirmed contributor to Noonan syndrome.

PMID:41517739 SUPPORT Human clinical

"Whole-exome sequencing identified a heterozygous MRAS c.203C>T (p.Thr68Ile) mutation affecting a highly conserved residue among RASopathy-associated GTPases, supporting the diagnosis of MRAS-associated Noonan syndrome complicated by infective endocarditis."

Case-level molecular confirmation supports pathogenic MRAS-associated Noonan syndrome with cardiac involvement.

ORPHA:648 SUPPORT Other

"MRAS | muscle RAS oncogene homolog | hgnc:7227 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports MRAS as causative for Noonan syndrome.

+ 1 more reference

CBL (Pathogenic Variants)

Gene: CBL hgnc:1541 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

ORPHA:648 SUPPORT Other

"CBL | Cbl proto-oncogene | hgnc:1541 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports CBL as causative for Noonan syndrome.

PMID:20619386 SUPPORT Human clinical

"Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes."

The human genetic evidence behind this record, and the source of the yield stated in the note.

SPRED2 (Pathogenic Variants)

Gene: SPRED2 hgnc:17722 relationship_type: CAUSATIVE

Show evidence (2 references)

ORPHA:648 SUPPORT Other

"SPRED2 | sprouty related EVH1 domain containing 2 | hgnc:17722 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association supports SPRED2 as causative for Noonan syndrome.

PMID:34626534 SUPPORT Human clinical

"Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome."

Primary-literature support for the gene-disease relationship and for the recessive mode this record now states.

MAPK1 (Pathogenic Variants)

Gene: MAPK1 hgnc:6871 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:32721402 SUPPORT Human clinical

"Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects."

The founding report for the gene-disease relationship, and the source for the hedge this record states on its Noonan attribution.

PMID:32721402 SUPPORT In vitro / ex vivo

"Pathogenic variants promote increased phosphorylation of the kinase [MAPK1/ERK2], which enhances translocation to the nucleus and boosts MAPK signaling"

Establishes the gain-of-function mechanism that places MAPK1 on the same convergent ERK output as the rest of this entry's genes. The kinase is ERK2, the MAPK1 product named in the preceding sentence of the abstract.

LZTR1 (biallelic) (Pathogenic Variants)

Gene: LZTR1 hgnc:6742 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

CGGV:assertion_7aa1e103-4f77-4c50-99c5-621a6a837b95-2020-08-27T160000.000Z SUPPORT Other

ClinGen classifies the recessive LZTR1-Noonan syndrome relationship as definitive.

PMID:20301303 SUPPORT Human clinical

"The parents of an individual with autosomal recessive NS are typically heterozygotes (i.e., have one LZTR1 pathogenic variant), and may either be asymptomatic or have mild features of NS."

The GeneReviews chapter states that recessive Noonan syndrome is the biallelic LZTR1 form and describes the carrier state recorded here.

MAP2K2 (Pathogenic Variants)

Gene: MAP2K2 hgnc:6842 gene page

Show evidence (1 reference)

CGGV:assertion_6a0eeefd-9105-435d-9daf-c748e52b0941-2018-06-01T160000.000Z SUPPORT Other

ClinGen classifies the MAP2K2-Noonan syndrome gene-disease relationship as limited with autosomal dominant inheritance.

RRAS (Pathogenic Variants)

Gene: RRAS hgnc:10447

Show evidence (1 reference)

CGGV:assertion_96280a14-d8cd-4c9b-b3e0-d5fcd8bf9ef6-2018-07-24T160000.000Z SUPPORT Other

ClinGen classifies the RRAS-Noonan syndrome gene-disease relationship as limited with autosomal dominant inheritance.

🗃️

External Assertions

1

Orphanet Noonan syndrome record

Orphanet Structured disease record ORPHA:648

Orphanet structured record for Noonan syndrome, including curated cross-references to MONDO, ICD-10, ICD-11, OMIM, MeSH, MedDRA, and UMLS identifiers.

Show evidence (4 references)

ORPHA:648 SUPPORT Other

"MONDO:0018997 | Exact"

The Orphanet cross-reference table exactly maps ORPHA:648 to MONDO:0018997.

ORPHA:648 SUPPORT Other

"ICD-10:Q87.1 | Narrower"

The Orphanet cross-reference table maps ORPHA:648 to ICD-10 Q87.1 (narrower).

ORPHA:648 SUPPORT Other

"ICD-11:LD2F.15 | Exact"

The Orphanet cross-reference table exactly maps ORPHA:648 to ICD-11 LD2F.15.

+ 1 more reference

💊

Medical Actions

6

Growth Hormone Therapy

Action: human growth hormone replacement therapy Ontology label: Hormone Replacement Therapy NCIT:C15599

Recombinant human growth hormone (rhGH) is FDA-approved for treatment of short stature in Noonan syndrome. Can improve final adult height by approximately 1 standard deviation.

Target Phenotypes: Short stature HP:0004322

Show evidence (1 reference)

PMID:41577878 SUPPORT Human clinical

"GH therapy was associated with an increase in height SDS from -2.92 to -1.97 (median) following 5 years, and to -1.68 in those with final height."

Large multicenter cohort evidence supports growth hormone therapy for short stature in Noonan syndrome spectrum disorders.

Cardiac Surgical Intervention

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Percutaneous balloon pulmonary valvuloplasty for valvar pulmonary stenosis, with high reintervention rates in Noonan syndrome and surgery for a subset; septal myectomy for obstructive hypertrophic cardiomyopathy; and surgical closure of associated atrial septal defects.

Target Phenotypes: Pulmonic stenosis HP:0001642 Hypertrophic cardiomyopathy HP:0001639

Show evidence (4 references)

PMID:41718520 SUPPORT Human clinical

"The patient was treated with trametinib to improve cardiac hypertrophy and then underwent successful surgical closure of the atrial septal defect."

Supports the atrial septal defect closure part of the description, and shows surgery staged after medical treatment of severe Noonan-associated hypertrophic cardiomyopathy. It does not bear on pulmonary stenosis or myectomy, which the items below support.

PMID:24534818 SUPPORT Human clinical

"Cardiovascular outcomes that differed specifically in a NS cohort included high re-intervention rates (65%) after percutaneous balloon pulmonary valvuloplasty for valvar pulmonary stenosis."

A 293-patient Noonan registry reports balloon pulmonary valvuloplasty as the intervention for valvar pulmonary stenosis, and its high reintervention rate in Noonan syndrome.

PMID:23312968 SUPPORT REVIEW SYNTHESIS Human clinical

"About a third of patients with pulmonary stenosis needed surgery or a repeat procedure."

Supports surgery or repeat intervention for pulmonary stenosis in a subset of Noonan patients on long-term follow-up.

+ 1 more reference

MEK Inhibitor Therapy

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: trametinib CHEBI:75998

Platform: Small molecule

Trametinib (MEK1/2 inhibitor) has shown promising results in case reports for treatment-refractory hypertrophic cardiomyopathy and lymphatic complications such as chylothorax. Pathway inhibition alleviates cardiac hypertrophy in a RIT1 mutant mouse model.

Mechanism Target:

INHIBITS ERK Cascade Hyperactivation — Trametinib directly reduces MEK-ERK pathway signaling, the convergent pathway node downstream of multiple Noonan genotypes.

Show evidence (1 reference)

PMID:41718520 SUPPORT Human clinical

"Trametinib, an MEK inhibitor that attenuates abnormal signaling in the RAS/MAPK pathway, has been shown to improve NS-HCM outcomes."

Directly supports trametinib as a MEK inhibitor that attenuates abnormal RAS/MAPK signaling in Noonan-associated hypertrophic cardiomyopathy.

INHIBITS Cardiomyocyte Hypertrophy — Off-label MEK inhibition ameliorates the hypertrophy itself, not only the signalling upstream of it, in an infant case report and in the Raf1 L613V knock-in. The adult RAF1 case report responded in outflow-tract obstruction, not in wall thickness or left ventricular mass, so regression of the hypertrophy itself has so far been reported only in the infant case and the mouse model.

Show evidence (3 references)

PMID:35052347 SUPPORT Human clinical

"Trametinib was introduced (0.022 mg/kg/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound."

Reports a hypertrophy outcome directly: the RAF1 p.Ser257Leu infant's hypertrophic cardiomyopathy improved at ultrasound on trametinib.

PMID:21339642 SUPPORT Model organism

"postnatal MEK inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice"

In the Raf1 L613V knock-in, whose cardiac defect is eccentric hypertrophy, postnatal MEK inhibition normalized it.

PMID:38827265 REFUTE Human clinical

"Cardiac magnetic resonance imaging following treatment with trametinib showed no objective differences with respect to maximal wall thickness, global left ventricular mass, left ventricular aneurysm, or myocardial fibrosis"

In the adult RAF1 patient, trametinib did not change wall thickness or left ventricular mass on cardiac MRI; the benefit was a reduction in outflow obstruction. The hypertrophy itself did not regress in this case.

Target Phenotypes: Hypertrophic cardiomyopathy HP:0001639 Chylothorax HP:0010310

Show evidence (6 references)

PMID:41718520 SUPPORT Human clinical

"Trametinib, an MEK inhibitor that attenuates abnormal signaling in the RAS/MAPK pathway, has been shown to improve NS-HCM outcomes."

Supports MEK inhibition as a targeted strategy for severe Noonan-associated hypertrophic cardiomyopathy in early clinical use.

DOI:10.3389/fped.2025.1475143 SUPPORT Human clinical

"In our patient, a five-week trametinib course, maximum dose 0.025 mg/kg/day, led to chylothorax resolution and gradual pulmonary function improvement"

Case report supporting the lymphatic part of the description and the chylothorax target phenotype, in an infant with a PTPN11 Noonan variant.

DOI:10.1126/sciadv.adf4766 SUPPORT Model organism

"Consistent with aberrant RAF/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of RIT1 mutant Noonan syndrome."

Supports the animal-model sentence of the description.

+ 3 more references

Early Intervention Services

Action: early intervention services Ontology label: Early Intervention NCIT:C159524

Developmental support including speech therapy, physical therapy, occupational therapy, and special education services for developmental delays and learning disabilities.

Target Phenotypes: Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:20301303 SUPPORT Human clinical

"Developmental disabilities are addressed by early intervention programs and individualized education strategies."

GeneReviews supports early intervention services as standard management for developmental disability in Noonan syndrome.

Speech Therapy

Action: speech therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech and language therapy for articulation difficulties and language delays.

Target Phenotypes: Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:17222357 SUPPORT Human clinical

"Physiotherapy and/or speech therapy should be offered if indicated."

Supports speech therapy as recommended supportive care in Noonan syndrome management.

Physical Therapy

Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Physical therapy to address motor delays and hypotonia common in Noonan syndrome.

Target Phenotypes: Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:17222357 SUPPORT Human clinical

"Physiotherapy and/or speech therapy should be offered if indicated."

Supports physiotherapy (physical therapy) for motor/developmental support in Noonan syndrome.

🔬

Diagnosis

3

Molecular genetic testing

Multigene RASopathy molecular testing is central to confirming Noonan syndrome and separating it from phenotypically overlapping RASopathies. Current diagnostic gene sets include BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, SOS2, and heterozygous or biallelic LZTR1 variants.

molecular genetic testing NCIT:C19770

Show evidence (2 references)

PMID:41675685 SUPPORT Human clinical

"This retrospective study analyzed...individuals diagnosed with Noonan syndrome and related disorders previously submitted to diagnostic molecular analysis through next-generation sequencing techniques."

Supports molecular testing as a practical diagnostic discriminator in suspected Noonan-spectrum disorders.

PMID:20301303 SUPPORT Human clinical

"DIAGNOSIS/TESTING: 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..."

GeneReviews provides the current established molecular diagnostic gene set for classic Noonan syndrome.

Clinical whole-exome sequencing

Whole-exome sequencing can establish diagnosis in atypical or less common genotypes, including MRAS-associated Noonan syndrome.

clinical whole-exome sequencing NCIT:C101295

Show evidence (1 reference)

PMID:41517739 SUPPORT Human clinical

"Whole-exome sequencing identified a heterozygous MRAS c.203C>T (p.Thr68Ile) mutation affecting a highly conserved residue among RASopathy-associated GTPases, supporting the diagnosis of MRAS-associated Noonan syndrome complicated by infective endocarditis."

Demonstrates diagnostic utility of exome sequencing in genetically heterogeneous Noonan syndrome.

Echocardiography

Echocardiography is a key diagnostic assessment for structural defects and hypertrophic cardiomyopathy in Noonan syndrome.

echocardiography NCIT:C16525

Show evidence (1 reference)

PMID:41517739 SUPPORT Human clinical

"Echocardiography demonstrated obstructive hypertrophic cardiomyopathy with vegetation located in the left ventricular outflow tract."

Supports echocardiography as an essential modality for defining Noonan syndrome cardiac phenotype and complications.

📈

Progression

1

Onset

Age: Antenatal to Childhood

Show evidence (2 references)

ORPHA:648 SUPPORT Other

"Age of onset: Antenatal"

Orphanet records antenatal onset as a recognized age-of-onset category for Noonan syndrome.

ORPHA:648 SUPPORT Other

"Age of onset: Neonatal"

Orphanet records neonatal onset for Noonan syndrome.

📊

Prevalence

3

Live births

Prevalence at birth 40.0–100.0 per 100,000 1–9 per 10,000 (births)

Noonan syndrome is among the more common rare Mendelian syndromes and a leading syndromic cause of congenital heart disease.

Show evidence (2 references)

PMID:18047172 SUPPORT Human clinical

"Noonan syndrome, a genetic condition occurring in around 1 in 2,000 live births, was first described in 1968 by Dr Jacqueline Noonan, an American cardiologist, who noticed that patients attending her clinic often had similar features."

This review provides a commonly cited live-birth frequency estimate for Noonan syndrome.

PMID:10912404 SUPPORT Human clinical

"Background: Noonan syndrome is similar phenotypically to Turner syndrome, accounting for one in 1000-2500 live births."

This paper supports the broader conventional birth-frequency range cited for Noonan syndrome.

United States (Orphanet prevalence at birth)

Prevalence at birth 60.0–90.0 per 100,000 1–9 per 10,000 (births)

Orphanet reports a prevalence-at-birth class of 6-9 per 10,000 in the United States.

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"6-9 / 10 000 | United States | Prevalence at birth | PMID:3895929"

The Orphanet epidemiology table provides a US prevalence-at-birth class for Noonan syndrome.

Worldwide (Orphanet point prevalence)

Point prevalence 10.0–50.0 per 100,000 1–9 per 10,000

Orphanet reports a worldwide point-prevalence class of 1-5 per 10,000.

Show evidence (1 reference)

ORPHA:648 SUPPORT Other

"1-5 / 10 000 | Worldwide | Point prevalence | EXPERT"

The Orphanet epidemiology table provides a worldwide point-prevalence class for Noonan syndrome.

🔀

Differential Diagnoses

4

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

Cardiofaciocutaneous syndrome MONDO:0015280

Overlapping Features Cardiofaciocutaneous syndrome is a RASopathy with substantial overlap in growth, dysmorphology, neurodevelopmental, and cardiac findings.

Distinguishing Features

More often associated with BRAF-pathway variants than classic PTPN11-predominant Noonan syndrome.
Ectodermal/skin and hair abnormalities are often more prominent in CFC.

Show evidence (1 reference)

PMID:41675685 SUPPORT Human clinical

"RASopathies are a heterogeneous group...presenting with overlapping features... Final diagnoses included...two with cardiofaciocutaneous syndrome (BRAF)..."

Demonstrates overlap requiring differential diagnosis, with BRAF genotype pattern helping separate CFC from classic Noonan syndrome.

Costello syndrome MONDO:0009026

Overlapping Features Costello syndrome is an overlapping RASopathy that can resemble Noonan syndrome in early referral contexts.

Distinguishing Features

HRAS pathogenic variants support Costello syndrome rather than classic Noonan syndrome.
Relative burden of coarse facies, deep palmar/plantar creases, and tumor predisposition favors Costello syndrome.

Show evidence (1 reference)

PMID:41675685 SUPPORT Human clinical

"Final diagnoses included...one each with...Costello syndrome (HRAS)..."

Supports Costello syndrome as a practical molecular differential in suspected Noonan-spectrum patients.

Neurofibromatosis type 1 MONDO:0018975

Overlapping Features NF1-related phenotypes can overlap with Noonan syndrome (including Neurofibromatosis-Noonan presentations) and require molecular distinction.

Distinguishing Features

NF1 pathogenic variants and neurofibromatosis features (e.g., neurofibromas, cafe-au-lait patterning) support NF1-spectrum diagnosis.
Shared RAS-MAPK dysregulation can create overlapping craniofacial and growth findings.

Show evidence (1 reference)

PMID:41675685 SUPPORT Human clinical

"Final diagnoses included...two with Neurofibromatosis-Noonan (NF1)..."

Confirms clinically relevant NS vs NF1-overlap differential diagnosis in molecularly evaluated RASopathy cohorts.

Noonan syndrome with multiple lentigines MONDO:0007893

Overlapping Features Noonan syndrome with multiple lentigines shares core Noonan features but is separated by pigmentation pattern and genotype-phenotype context.

Distinguishing Features

Diffuse lentigines and characteristic pigmentary findings support NSML over classic Noonan syndrome.
PTPN11 variant context and clinical trajectory help separate NSML from other Noonan subtypes.

Show evidence (4 references)

PMID:41675685 SUPPORT Human clinical

"two with Noonan syndrome with multiple lentigines (both with variants in PTPN11)"

Supports NSML as a frequent practical differential diagnosis in Noonan-spectrum genomic evaluation.

PMID:20301557 SUPPORT REVIEW SYNTHESIS Human clinical

"Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis."

Supports the first distinguishing feature: lentigines are a cardinal NSML feature, alongside features NSML shares with Noonan syndrome.

PMID:20301557 SUPPORT REVIEW SYNTHESIS Human clinical

"In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines."

Supports the clinical-trajectory part of the second distinguishing feature: the separating pigmentary sign is age-dependent and can be absent, so young or lentigine-free patients are hard to separate from Noonan syndrome on examination.

+ 1 more reference

📊

Related Datasets

3

Aberrant cortical layer development of brain organoids developed from Noonan syndrome-iPSCs geo:GSE213798

Human induced pluripotent stem cell-derived cortical organoid transcriptomic resource profiling neurodevelopmental abnormalities in Noonan syndrome and matched isogenic corrected controls across developmental time points.

human SINGLE CELL RNA SEQ n=9 GPL24676

Conditions: Noonan syndrome iPSC-derived cortical organoids isogenic corrected control cortical organoids

GEO:GSE213798

Show evidence (1 reference)

GEO:GSE213798 SUPPORT In vitro / ex vivo

"single-cell transcriptomic analysis represented increment of EN population and overexpression of cortical layer markers in NS-COs."

Provides disease-relevant human neurodevelopmental transcriptomic evidence for cortical-layer and neuronal-connectivity abnormalities in Noonan syndrome.

Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome geo:GSE188238

Bulk transcriptomic dataset integrating left ventricular myocardial tissue and patient-derived PTPN11N308S/+ iPSC-cardiomyocyte modeling to define mechanisms of Noonan syndrome-associated childhood cardiomyopathy.

human BULK RNA SEQ n=11 GPL20301

Conditions: Noonan syndrome-associated cardiomyopathy sarcomeric hypertrophic cardiomyopathy comparator non-diseased cardiac control

PMID:34988410

Show evidence (2 references)

GEO:GSE188238 SUPPORT Human clinical

"gene expression in left ventricular myocardial tissue from NS-CM, HCM and normal hearts"

Supports human myocardial tissue evidence for transcriptomic distinctions between Noonan cardiomyopathy and sarcomeric HCM.

GEO:GSE188238 SUPPORT In vitro / ex vivo

"complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11N308S/+ induced pluripotent stem cells"

Supports complementary in vitro iPSC-cardiomyocyte modeling of Noonan cardiomyopathy mechanisms.

Differential gene expression in human RAF1 S257L/+ and isogenic corrected iPSC-derived cardiomyocytes geo:GSE131069

Bulk RNA-seq dataset from human RAF1 S257L/+ Noonan syndrome iPSC-derived cardiomyocytes and isogenic corrected controls, including pathway-perturbation conditions targeting MEK/ERK signaling.

human BULK RNA SEQ n=12 GPL23934

Conditions: RAF1 S257L/+ Noonan syndrome iPSC-derived cardiomyocytes isogenic corrected control cardiomyocytes MEK/ERK pathway inhibition perturbation

PMID:31163979

Show evidence (1 reference)

GEO:GSE131069 SUPPORT In vitro / ex vivo

"Hence, to gain insights into the transcriptional alterations induced by the NS-associated RAF1S257L/+ mutation in human iPSC-derived cardiomyocytes, we performed quantitative transcriptome profiling by RNA-sequencing."

Supports a mutation-specific human cardiomyocyte transcriptomic resource linking RAF1-driven signaling dysregulation to Noonan cardiac phenotypes.

🧫

Experimental Models

3

Noonan syndrome cortical organoid model ORGANOID namo:Organoid

Human Noonan syndrome induced pluripotent stem cell-derived cortical organoids with matched corrected controls used to study cortical layer specification and neuronal connectivity phenotypes.

Organism

human NCBITaxon:9606

Tissue

cerebral cortex UBERON:0000956

Cell source

Noonan syndrome induced pluripotent stem cells differentiated into cortical organoids

Culture

Three-dimensional cortical organoid time-course culture

Publication

PMID:36430334

Pathograph links

Cortical Layer Development Abnormalities recapitulates fidelity: moderate NS iPSC-derived cortical organoids reproduce the excitatory-neuron overrepresentation, aberrant SATB2/CTIP2 co-expressing layer identity, and reduced synaptic connectivity that define this node.

Limitations: Organoids "develop normally in their appearance" — the defect is transcriptomic and connectivity-level rather than gross morphological, and the model lacks vasculature and microglia, so non-cell-autonomous contributions to cortical development cannot be assessed.

Readouts

Excitatory neuron population size

Single-cell transcriptomic quantification of excitatory neurons in NS cortical organoids versus isogenic controls.

Direction: INCREASED

Interpretation: An expanded excitatory-neuron population is the cellular-composition correlate of the layer-identity disruption this node describes.

Show evidence (1 reference)

PMID:36430334 SUPPORT In vitro / ex vivo

"single-cell transcriptomic analysis revealed an increase in the EN population and overexpression of cortical layer markers in NS-COs."

Directly reports the excitatory-neuron population readout.

SATB2/CTIP2 co-expressing subpopulation

Frequency of the upper-layer/deep-layer marker co-expressing excitatory neuron subpopulation.

Direction: INCREASED

Interpretation: A layer-marker co-expressing subpopulation is a specific signature of disrupted cortical layer specification.

Show evidence (1 reference)

PMID:36430334 SUPPORT In vitro / ex vivo

"the EN subpopulation co-expressing the upper layer marker SATB2 and the deep layer maker CTIP2 was enriched in NS-COs during cortical development."

Directly reports the SATB2/CTIP2 co-expression readout.

Synaptic connectivity

Synaptic connectivity assessment in NS cortical organoids.

Direction: DECREASED

Interpretation: Reduced synaptic connectivity is the functional correlate accompanying the layer-identity disruption.

Show evidence (1 reference)

PMID:36430334 SUPPORT In vitro / ex vivo

"NS-COs also exhibited reduced synaptic connectivity."

Directly reports the synaptic connectivity readout.

Show evidence (1 reference)

PMID:36430334 SUPPORT In vitro / ex vivo

"Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs)."

Establishes the cortical organoid as informative for the Cortical Layer Development Abnormalities node.

Findings

Noonan cortical organoids show abnormal excitatory-neuron composition, cortical-layer identity, and reduced synaptic connectivity

Show evidence (2 references)

PMID:36430334 SUPPORT In vitro / ex vivo

"Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs)."

Establishes that NS-derived cortical organoids capture disease-relevant neurodevelopmental abnormalities.

PMID:36430334 SUPPORT In vitro / ex vivo

"Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity contribute to the neurological manifestations of NS."

Supports mechanistic alignment of the organoid model with neurological manifestations in Noonan syndrome.

Replaces the prior implicit reliance on GEO-only cross-reference with a direct disease-model anchor publication.

Show evidence (1 reference)

PMID:36430334 SUPPORT In vitro / ex vivo

"Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs)."

Supports a first-class cortical organoid model for Noonan syndrome.

Noonan syndrome iPSC-cardiomyocyte model IPSC_DERIVED_MODEL namo:TwoDCellCulture

Patient-derived Noonan syndrome induced pluripotent stem cell cardiomyocytes modeling childhood-onset cardiomyopathy and RAF1/PTPN11-driven transcriptional dysregulation with matched corrected or comparator controls.

Organism

human NCBITaxon:9606

Tissue

heart UBERON:0000948

Cell source

Patient-derived induced pluripotent stem cell-derived cardiomyocytes with isogenic or non-diseased controls

Culture

Two-dimensional iPSC-cardiomyocyte differentiation with transcriptomic and pathway-perturbation readouts

Publication

PMID:34988410

Pathograph links

Cardiomyocyte Hypertrophy partially recapitulates fidelity: low PTPN11 N308S/+ iPSC-cardiomyocytes reproduce the hypertrophic phenotype but argue it is driven by cell-cycle defects rather than by the ERK/AKT-mTOR hypertrophic-growth program this node describes.

Limitations: The paper's central argument is that NS-CM is mechanistically distinct from sarcomeric HCM and driven by cell-cycle defects in cardiomyocytes, a mechanism this node's description (sustained ERK plus AKT/mTOR driving hypertrophic growth and fetal gene reprogramming) does not represent. The entry has no dedicated cell-cycle pathophysiology node to link this model to instead.

Show evidence (1 reference)

PMID:34988410 SUPPORT In vitro / ex vivo

"Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11 N308S/+ induced..."

States the paper's own conclusion that cell-cycle defects, not the ERK/AKT-mTOR program, are the candidate driver of NS-CM.

ERK Cascade Hyperactivation perturbs fidelity: moderate Pharmacological and genetic perturbation of MEK1/2, ERK1/2, and ERK5 in RAF1 S257L/+ iPSC-cardiomyocytes dissects which arm of RAS-MAPK signaling drives which part of the hypertrophic phenotype.

Readouts

Cardiomyocyte hypertrophy after MEK1/2-ERK1/2 inhibition

Cell surface area of RAF1S257L/+ iPSC-cardiomyocytes treated with the MEK1/2 inhibitors PD98059 or Trametinib, which strongly reduce ERK1/2 phosphorylation.

Direction: UNCHANGED

Interpretation: MEK1/2-ERK1/2 inhibition abolishes ERK1/2 activation without reducing cell size, so this model refutes ERK1/2 signaling specifically as the driver of the hypertrophy this entry's ERK Cascade Hyperactivation to Cardiomyocyte Hypertrophy edge asserts. The paper instead attributes the enlarged-cell phenotype to ERK5, a MAPK pathway this entry does not otherwise model.

Show evidence (2 references)

PMID:31163979 REFUTE In vitro / ex vivo

"Importantly, although ERK1/2 activation was strongly reduced, there was no significant effect on hypertrophy in RAF1S257L/+ iCMs in response to treatment with either PD98059 or Trametinib (Fig.4C–D), suggesting that MEK1/2-ERK1/2 activation is not the principal driver of hypertrophy in..."

Directly reports the negative result for ERK1/2 as the hypertrophy driver.

+ 1 more reference

Show evidence (1 reference)

PMID:31163979 SUPPORT In vitro / ex vivo

"METHODS: We used patient-derived RAF1S257L/+ and CRISPR-Cas9-generated isogenic control inducible pluripotent stem cell (iPSC)-derived cardiomyocytes to model NS RAF1-associated HCM and to further delineate the molecular mechanisms underlying the disease."

Establishes the model as informative for dissecting which arm of the ERK cascade node drives which part of the phenotype.

Findings

Noonan iPSC-cardiomyocytes capture cardiomyopathy-linked cell-cycle and signaling defects in a genotype-resolved human cardiac model

Show evidence (2 references)

PMID:34988410 SUPPORT In vitro / ex vivo

"Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11 N308S/+ induced..."

Supports patient-derived iPSC-cardiomyocytes as a disease-relevant Noonan cardiomyopathy model.

PMID:31163979 SUPPORT In vitro / ex vivo

"METHODS: We used patient-derived RAF1S257L/+ and CRISPR-Cas9-generated isogenic control inducible pluripotent stem cell (iPSC)-derived cardiomyocytes to model NS RAF1-associated HCM and to further delineate the molecular mechanisms underlying the disease."

Supports mutation-specific mechanistic modeling in Noonan iPSC-cardiomyocytes.

Groups the two strongest existing dismech cardiac experimental-model resources under a single disease-level experimental-model concept.

Show evidence (1 reference)

PMID:34988410 SUPPORT In vitro / ex vivo

"Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11 N308S/+ induced..."

Supports this as a first-class Noonan iPSC-cardiomyocyte model entry.

Paediatric Noonan syndrome myocardial tissue slice model OTHER

Living right ventricular myocardial slices cut from myocardium resected at surgery from a child with RASopathy-associated hypertrophic cardiomyopathy, cultivated in biomimetic cultivation chambers and electrically stimulated. Slices were treated with trametinib, rapamycin, dasatinib or DMSO, and contractile force, force-frequency relationship and post-pause potentiation were compared before and after treatment. It is the only human, force-generating, multicellular system linked to the cardiac axis of this entry; the curated iPSC-cardiomyocyte model is human but unloaded, and the Raf1 L613V knock-in is loaded but murine.

Organism

human NCBITaxon:9606

Tissue

right ventricular myocardium UBERON:0002080

Cell source

Right ventricular myocardium resected at surgery from a paediatric Noonan syndrome hypertrophic cardiomyopathy patient carrying RAF1 c.775T>A (p.Ser259Thr)

Culture

Electrically stimulated living myocardial slices in biomimetic cultivation chambers

Publication

PMID:39573843

Pathograph links

Cardiomyocyte Hypertrophy recapitulates fidelity: moderate observes: tissue The slices are the patient's own hypertrophic myocardium rather than a system engineered to resemble it, so the human genotype, the multicellular composition and the contractile apparatus are all native.

Limitations: Tissue from a single patient, so nothing here speaks to variability across RASopathy genotypes. Slices are explanted, so they carry no haemodynamic load, no circulating neurohormonal input and no ongoing remodelling, and culture duration bounds the timescale observable.

Show evidence (1 reference)

PMID:39573843 SUPPORT In vitro / ex vivo

"Contracting right ventricular (RV) tissue slices were prepared from resected myocardium, cultivated in BMCCs and treated with distinct molecules directly and indirectly targeting the RAS-MAPK pathway"

Establishes that the system is contracting native myocardium from the affected patient, which is what grounds its use for the hypertrophy node.

ERK Cascade Hyperactivation perturbs fidelity: moderate observes: tissue Trametinib is applied directly to the slices, so the system reports what acute MEK inhibition does to contractile and calcium-handling behaviour in human RASopathy myocardium. The contractile and calcium readouts it produces sit on the MEASURES link below, since neither of them measures ERK activity.

Limitations: Acute drug exposure in explanted tissue, so it cannot show whether the force reduction persists, resolves or compounds over a treatment course, and single-patient tissue gives no estimate of variability. Mitochondrial respiration and STAT3 serine-727 phosphorylation, the readouts the cardiotoxicity module is built on, were not measured.

Show evidence (1 reference)

PMID:39573843 SUPPORT PRIMARY RESULT Human clinical

"off-label treatment with MAPK kinase (MEK) inhibitor trametinib of a child with severe RAS-CM resulted in a modest reduction of RV outflow tract (RVOT) obstruction"

The same report's in vivo arm, in the patient the slices came from, supports MEK inhibition acting on this pathway clinically as well as ex vivo.

Cardiomyocyte Hypertrophy measures fidelity: moderate observes: tissue What the slices actually measure under acute MEK inhibition: developed force and sarcoplasmic reticulum calcium handling in the patient's own hypertrophic myocardium. The two move in opposite directions, which is the only dataset in this entry touching both the therapeutic and the cardiotoxic reading of MEK inhibition at once.

Limitations: Neither readout measures hypertrophy itself; they report the contractile and calcium behaviour of hypertrophic tissue, which is why this link is MEASURES rather than a claim that the model reproduces the node. Acute exposure in one patient's explanted slices, so nothing here shows whether the force reduction persists, resolves or compounds over a treatment course.

Readouts

Contractile force after trametinib

Direction: DECREASED

Interpretation: Acute MEK inhibition lowers developed force in human RASopathy myocardium. This is the direction the mek_inhibition_cardiac_mitochondrial_injury module's terminal node describes, measured here in a Noonan-variant context.

Show evidence (1 reference)

PMID:39573843 SUPPORT In vitro / ex vivo

"In cultivated RV myocardial tissue slices, contraction force decreased after addition of trametinib and rapamycin but not after addition of DMSO and dasatinib."

Reports the force measurement, with vehicle and inactive-comparator arms, that grounds this readout.

Post-pause potentiation after trametinib

Direction: INCREASED

Interpretation: Sarcoplasmic reticulum calcium handling improves under the same exposure that lowers developed force, so the two readouts of MEK inhibition in this tissue do not agree in sign.

Show evidence (1 reference)

PMID:39573843 SUPPORT In vitro / ex vivo

"Improvement of Ca2+ handling, as depicted by a more positive force-frequency relationship and enhanced post-pause potentiation (31.2%), was noted in the trametinib-treated slice."

Reports the calcium-handling measurement that grounds this readout.

🐁

Animal Models

6

Chick neural tube electroporation of PTPN11 variants somatic gene transfer model

An accessible in vivo assay for the neural crest arm of Noonan syndrome. Constructs are electroporated unilaterally into the chick neural tube, so the contralateral side and a parallel empty-vector condition serve as internal controls, and GFP-positive descendants are then scored at 24 and 48 hours in neural-crest derivatives — dorsal root ganglia, melanocyte precursors and Schwann cell precursors. Its value here is that it reads out neural crest *behaviour* in an intact embryo rather than steady-state pathway activity in a cell line, and it is what produced the observation that a variant with no measurable increase in ERK phosphorylation can still perturb neural crest development.

Species

Chicken

Genotype

Wild-type and Noonan-spectrum PTPN11 variants (including c.172A>G/N58D, c.922A>G/N308D and c.1282G>A/V428M) cloned into pCIG and unilaterally electroporated into the neural tube at HH10-11

Genes

PTPN11 hgnc:9644

Publication

PPR:PPR1278294

Pathograph links

Neural Crest Cell Developmental Dysregulation perturbs fidelity: low Variant-specific perturbation of neural crest allocation and spatial organisation, assayed directly in the migrating lineage.

Limitations: Three caveats stack here and none should be dropped when citing this model. It is a *preprint* — not peer reviewed — so it must not be sole support for any mechanistic claim. It is an overexpression assay: mutant constructs produced higher-than-endogenous SHP2 levels, so dosage effects cannot be cleanly separated from allele-specific effects, and the reported lineage-sensitivity ordering rests on that. And avian trunk neural crest is not the cranial neural crest that generates the human Noonan facial skeleton, with some conditions run at n = 2 embryos.

Readouts

Melanocyte precursor distribution in skin

Spatial distribution of GFP-positive melanocyte precursors in whole-mount cleared embryos at 48 hours post-electroporation, compared against the wild-type PTPN11 condition.

Direction: ALTERED

Interpretation: Clustering rather than even distribution indicates altered allocation of a neural crest derivative; it is a spatial-organisation readout, not a cell-number one.

Show evidence (1 reference)

PPR:PPR1278294 Preprint · not peer-reviewed SUPPORT Model organism

"In contrast, all mutant PTPN11 variants induced a clustered distribution of melanocyte precursors."

Reports the measurement in the stated direction, and notably as a shared effect of every mutant tested rather than a single-variant finding.

Show evidence (1 reference)

PPR:PPR1278294 Preprint · not peer-reviewed SUPPORT Model organism

"These findings highlight the sensitivity of neural crest development to variant-specific perturbations of SHP2 function."

Supports treating the chick neural tube assay as informative for the neural crest node, while the preprint status keeps it corroborative rather than load-bearing — the node itself rests on the peer-reviewed mouse and zebrafish evidence.

RIT1 mutant Noonan syndrome mouse model Mouse mutant mouse model

Pathogenic RIT1 mouse modeling supports aberrant RAF/MAPK activation as a driver of Noonan-associated cardiac hypertrophy and as a tractable therapeutic axis.

Species

Mouse

Genotype

RIT1 mutant Noonan syndrome mouse model

Genes

RIT1 hgnc:10023

Show evidence (2 references)

DOI:10.1126/sciadv.adf4766 SUPPORT Model organism

"Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK) hyperactivation"

Supports MAPK hyperactivation as a disease-relevant signaling phenotype in pathogenic RIT1 Noonan syndrome models.

DOI:10.1126/sciadv.adf4766 SUPPORT Model organism

"RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary for MAPK activation."

Identifies RAF-dependent MAPK activation as a mechanistic feature of the RIT1 mutant model.

Lztr1G245R/+ and Lztr1R409C/+ knock-in Mouse knock-in model

Dominant LZTR1 knock-in mouse models reproduce Noonan-like growth, facial, and cardiac phenotypes with activated ventricular MAPK signaling.

Species

Mouse

Genotype

Lztr1G245R/+ and Lztr1R409C/+ knock-in

Genes

LZTR1 hgnc:6742

Show evidence (2 references)

PMID:39352760 SUPPORT Model organism

"LZTR1-mutant male mice exhibit low birth weight, distinctive facial features, and cardiac hypertrophy."

Directly supports LZTR1 knock-in mice as a Noonan-like animal model with growth, craniofacial, and cardiac phenotypes.

PMID:39352760 SUPPORT Model organism

"Multi-omics analysis revealed that the mitogen-activated protein kinase (MAPK) signaling pathway was activated in the LVs of mutant mice."

Supports MAPK pathway activation as a mechanistic readout in the LZTR1 knock-in model.

Noonan syndrome-causing SHP2 mutant mouse model Mouse mutant mouse model

SHP2/PTPN11 Noonan mouse modeling links local RAS/ERK hyperactivation in growth-plate chondrocytes to impaired endochondral bone growth.

Species

Mouse

Genotype

Noonan syndrome-causing SHP2 mutant mouse model

Genes

PTPN11 hgnc:9644

Show evidence (2 references)

PMID:29659837 SUPPORT Model organism

"We demonstrated that growth plate length was reduced in NS mice, mostly due to a shortening of the hypertrophic zone and to a lesser extent of the proliferating zone."

Supports growth-plate shortening as a phenotype reproduced in Noonan syndrome SHP2 mutant mice.

PMID:29659837 SUPPORT Model organism

"NS-causing SHP2 mutants enhance RAS/ERK activation in chondrocytes in vivo (NS mice) and in vitro (ATDC5 cells)"

Supports local chondrocyte RAS/ERK activation as a mechanistic feature of the PTPN11/SHP2 growth-plate model.

Raf1 L613V knock-in mouse knock-in mouse model

Heterozygous knock-in of the Noonan-associated Raf1 L613V allele at the endogenous locus. The mice reproduce short stature, craniofacial dysmorphia, hematologic abnormalities and eccentric cardiac hypertrophy with reactivation of the cardiac fetal gene programme, and MEK inhibition started after birth normalizes the growth, facial and cardiac phenotypes. Valvuloseptal development is normal, so the model separates the postnatal hypertrophic arm of RAF1-driven disease from the valve arm.

Species

Mouse

Genotype

Raf1 L613V/+ heterozygous knock-in

Genes

RAF1 hgnc:9829

Publication

PMID:21339642

Pathograph links

RAF1 Kinase Hyperactivation recapitulates fidelity: high observes: organism The disease allele is knocked in at the endogenous Raf1 locus, so the model carries the kinase-activating lesion itself rather than a downstream surrogate of it.

Limitations: L613V is a murine knock-in of a human NS allele; allele-specific differences between RAF1 variants are not captured by a single knock-in.

Show evidence (1 reference)

PMID:21339642 SUPPORT Model organism

"we generated knockin mice expressing the NS-associated Raf1(L613V) mutation"

Establishes that the model carries the Noonan-associated kinase-activating RAF1 allele at the endogenous locus.

ERK Cascade Hyperactivation recapitulates fidelity: high observes: organism Agonist-evoked MEK-ERK signalling is elevated across several cell types in the knock-in, and pharmacological MEK inhibition reverses the organ-level phenotypes it drives.

Show evidence (1 reference)

PMID:21339642 SUPPORT Model organism

"Agonist-evoked MEK-ERK activation was enhanced in multiple cell types"

Reports elevated MEK-ERK signalling in the knock-in, the node this link claims the model reproduces.

Cardiomyocyte Hypertrophy recapitulates fidelity: high observes: organism The knock-in develops eccentric cardiac hypertrophy with fetal gene reactivation and decompensates under pressure overload. MEK inhibition begun postnatally normalizes the cardiac phenotype, which is the result behind treating MEK as the actionable node for RAF1-driven hypertrophy.

Limitations: The hypertrophy is eccentric, whereas RAF1-associated human disease is typically concentric obstructive hypertrophic cardiomyopathy. Contractile and mitochondrial function were not assessed, so this model says nothing about the cardiotoxic arm of MEK inhibition.

Readouts

Cardiac mass and fetal gene programme

Direction: INCREASED

Interpretation: Structural and transcriptional correlate of the hypertrophy node in this model.

Show evidence (1 reference)

PMID:21339642 SUPPORT Model organism

"L613V/+ mice exhibited eccentric cardiac hypertrophy and aberrant cardiac fetal gene expression, and decompensated following pressure overload"

Reports the hypertrophy and fetal gene reactivation measured in this model.

Show evidence (1 reference)

PMID:21339642 SUPPORT Model organism

"postnatal MEK inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice"

Supports treating the model as informative for the hypertrophy node, since inhibiting the pathway after birth reverses the cardiac phenotype.

Cardiac Valve Morphogenesis Defects fails to recapitulate fidelity: low observes: organism Valvuloseptal development is explicitly normal in this model, so a RAF1 kinase-activating allele sufficient to drive postnatal hypertrophy does not on its own reproduce the valve lesion.

Limitations: The negative result is specific to the L613V allele on this background and does not exclude a valve phenotype from other Noonan genotypes; the Tie2-Cre Q79R-Shp2 endocardial-cushion model does reproduce that node.

Show evidence (1 reference)

PMID:21339642 REFUTE Model organism

"Valvuloseptal development was normal, but L613V/+ mice exhibited eccentric cardiac hypertrophy"

States directly that valve and septal development are unaffected in this model, refuting its use for the valve morphogenesis node.

Tie2-Cre Q79R-Shp2 endocardial cushion mouse conditional transgenic mouse model

Endocardial-lineage expression of the Noonan-associated Q79R-Shp2 allele, activated by Tie2-Cre in endothelial-derived cells. Mutant embryos die by E14.5 with enlarged atrioventricular canal and outflow tract cushions, which wild-type Shp2 at comparable levels does not cause. Deleting ERK1 fully rescues the cushion phenotype, placing ERK1 downstream of SHP2 in the valve arm of the disease.

Species

Mouse

Genotype

Tie2-Cre driven endothelial-lineage Q79R-Shp2 transgene

Genes

PTPN11 hgnc:9644

Publication

PMID:19017799

Pathograph links

Cardiac Valve Morphogenesis Defects recapitulates fidelity: moderate observes: organism An embryonic system at the developmental stage the valve node describes, observing the cushion overgrowth that precedes the pulmonary valve lesion. It is the only model linked to this node; the postnatal Raf1 L613V knock-in has normal valvuloseptal development.

Limitations: Embryonic lethality by E14.5 precludes any postnatal or adult valve readout, so mature valve morphology and its haemodynamic consequences are outside the model. The allele is transgenically overexpressed in the endothelial lineage rather than carried at the endogenous locus.

Readouts

Endocardial cushion size

Direction: INCREASED

Interpretation: Cushion overgrowth is the embryonic correlate of the valve morphogenesis node.

Show evidence (1 reference)

PMID:19017799 SUPPORT Model organism

"mutant embryos showed significantly enlarged endocardial cushions in the atrioventricular canal and in the outflow tract"

Reports the cushion measurement that grounds this readout.

Show evidence (1 reference)

PMID:19017799 SUPPORT Model organism

"Deletion of ERK1 completely rescued the endocardial cushion phenotype, whereas ERK2 protein reduction did not affect endocardial cushion size."

The genetic rescue establishes that the cushion phenotype in this model is driven by the pathway the node describes, supporting its use for the valve morphogenesis node.

ERK Cascade Hyperactivation perturbs fidelity: moderate observes: organism Mutant Shp2 expression raises ERK1/2 activation in cushion mesenchyme, and the ERK1 deletion cross shows that this activation is necessary for the resulting phenotype.

Show evidence (1 reference)

PMID:19017799 SUPPORT Model organism

"Expression of Q79R-Shp2 was accompanied by increased ERK1/2 activation in a subset of cells within the cushion mesenchyme"

Reports the ERK activation this link claims the model perturbs.

🧮

Computational Models

5

LZTR1-RIT1 Recruitment Docking and Molecular-Dynamics Model PDB MODELLER 9.23, HHpred, Maestro 2019-4, ClusPro, ZDOCK, PatchDock, FRODOCK, FoldX, GROMACS 5.1.5 with Amber03/TIP3P, and VMD MOLECULAR_DOCKING

Integrated structural model of the near-full-length human CUL3 substrate adaptor LZTR1 (modeled residues 35-833) binding substrate RIT1. A multi-template LZTR1 homology model was combined with consensus protein-protein docking, FoldX calculations and duplicate 200-ns atomistic simulations of wild-type LZTR1 and the disease-associated G248R, R283Q and R412C variants in free and RIT1-bound states. The deposited artifact preserves wild-type static structures, not the mutant trajectories used for the published comparisons.

Repository ↗ PMID:33792302 Base model: HHpred multi-template LZTR1 model using PDB 5A10 and 4J8Z

Variable	Model ID	Unit
LZTR1-RIT1 interface contacts Electrostatic and hydrogen-bond contacts in the consensus docked complex.
LZTR1 backbone displacement Molecular-dynamics deviation from the starting conformation.	`RMSD`	nm
LZTR1 residue fluctuation Per-residue conformational fluctuation across each simulation.	`RMSF`	nm

Pathograph links

LZTR1-Mediated RAS Proteostasis Defect partially recapitulates fidelity: low Models the LZTR1-RIT1 recognition step that precedes CUL3-mediated ubiquitination and degradation, and tests how three LZTR1 substitutions alter the predicted interface or propagate conformational effects.

Limitations: The study did not measure ubiquitination, RIT1 turnover, RAS abundance or MAPK signaling, and performed no new experimental validation. LZTR1 was assembled from low-identity domain templates, the clinical annotation of R283Q was conflicting, and the deposit lacks mutant coordinates, trajectories, topologies, run parameters, docking outputs and random seeds. The static wild-type structures therefore support visualization, not end-to-end replay of the disease simulations.

Readouts

Predicted LZTR1-RIT1 electrostatic interface network

Interpretation: A consensus interaction pose places an electrostatic contact network at the putative substrate-recognition surface; it is a computational hypothesis rather than an experimentally solved complex in this study.

Show evidence (1 reference)

PMID:33792302 SUPPORT Computational

"We observe that the interaction model LZTR1-RIT1 is stabilized by an electrostatic bond network established between the two protein surfaces"

Identifies the principal structural feature reported by the docking model.

Variant-specific LZTR1 recognition and allosteric dynamics

Direction: ALTERED

Interpretation: G248R and R283Q altered the predicted substrate-recognition surface, whereas R412C was interpreted as a possible allosteric perturbation linking the Kelch and C-terminal BTB regions.

Show evidence (1 reference)

PMID:33792302 SUPPORT Computational

"We identify G248R and R283Q as damaging mutations involved in the recognition process of the substrate RIT1 and R412C as a possible allosteric mutation"

Reports the variant-specific interpretations from the docking and molecular-dynamics analyses.

Show evidence (1 reference)

PMID:33792302 SUPPORT Computational

"Here, we address the interaction model between adaptor LZTR1 and substrate RIT1 by applying an integrated computational approach, including molecular modeling and docking techniques."

Establishes the model's LZTR1-RIT1 recruitment scope and computational methods.

Findings

The consensus complex predicts an electrostatic LZTR1-RIT1 recognition surface resembling substrate interfaces in homologous ubiquitin ligases.

Show evidence (1 reference)

PMID:33792302 SUPPORT Computational

"We observe that the interaction model LZTR1-RIT1 is stabilized by an electrostatic bond network established between the two protein surfaces, which is reminiscent of homologous ubiquitin ligases complexes."

States the model's central interface prediction and its structural comparator.

Notes

Zenodo record 4593670 (DOI 10.5281/zenodo.4593670) is immutable and CC BY 4.0. Curator smoke checks confirmed both PDB files parse as single-model coordinate sets and match the deposited checksums: LZTR1-RIT1.pdb SHA256 e8d6ccd42ed610ae23f490f4e0d5b274a5cb2eb09413b3243a72d058df704a29 and full-lengthLZTR1.pdb SHA256 05fabfd85279a69056e95244ea94ef561d66c5b604a5b4f4ff76f7226082a891. The latter begins at residue 35 and ends at 833 despite its filename. The bundled predict_pathogenicity.pl is actually a shell-style ANNOVAR command, fails Perl syntax checking, and depends on separately obtained databases; it is not part of a runnable molecular-dynamics workflow. A later experimental LZTR1 Kelch-RIT1 structure (PMID:40934300; PDB 9MEY) supersedes this model for current interface geometry; the 2021 model is retained as a historical, variant-dynamics hypothesis with LOW fidelity.

Show evidence (1 reference)

PMID:33792302 SUPPORT Computational

"Then, running MD simulations, we characterize differential conformational dynamics of the multi-domain LZTR1, offering interesting implications on the mechanistic role of specific point mutations."

Establishes that atomistic simulations were used to compare the variant-specific conformational behavior.

LZTR1 L580P AlphaFold-Multimer Polymerization Model ColabFold version 02c53 with AlphaFold-Multimer v2; six recycles, no templates, NVIDIA A5000 24 GB, two independent runs STRUCTURAL_PREDICTION

ColabFold/AlphaFold-Multimer comparison of wild-type and homozygous Noonan syndrome LZTR1 L580P trimers. The highest-ranked wild-type arrangement contained a BACK2-BACK2 dimer plus a monomer, whereas the L580P arrangement added a BACK1-BACK1 interface to form a linear trimer, providing a structural hypothesis for the higher-order polymers observed experimentally.

PMID:39003740

Variable	Model ID	Unit
Predicted local-distance difference test Per-residue AlphaFold confidence score.	`pLDDT`	score
Predicted aligned error Pairwise confidence in relative residue positions across chains.	`PAE`	angstrom
LZTR1 multimer interface topology BACK1 and BACK2 domain contacts joining the predicted chains.

Pathograph links

LZTR1-Mediated RAS Proteostasis Defect partially recapitulates fidelity: moderate Predicts an allele-specific change in LZTR1 self-association that offers a structural explanation for impaired LZTR1 complex function and consequent loss of RAS-family protein turnover.

Limitations: AlphaFold-Multimer was not trained to resolve single-residue variant effects, only three chains could be modeled, and none of the predicted coordinates, PAE matrices, inputs or seeds was deposited. Endogenous polymers could not be imaged without overexpression. The patient-derived cardiomyocytes and CRISPR rescue strongly validate the broader mechanism, but polymer geometry itself was not solved experimentally and the model does not simulate ubiquitination, degradation or downstream signaling.

Readouts

Predicted LZTR1 homotrimer chain topology

Direction: ALTERED

Interpretation: L580P changes the top-ranked assembly from a dimer-plus-monomer configuration to a linear trimer with an additional BACK1-BACK1 interface.

Show evidence (1 reference)

PMID:39003740 SUPPORT INDIRECT Computational

"The variant is predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymers."

Supports the linear-polymer prediction, but not the more detailed BACK1/BACK2 topology reported in the article body.

Show evidence (1 reference)

PMID:39003740 SUPPORT Computational

"The variant is predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymers."

Supports the model's partial representation of the LZTR1 proteostasis mechanism.

Findings

Uni- or biallelic correction of LZTR1 L580P rescued the molecular and cellular disease phenotype surrounding the structural prediction.

Show evidence (1 reference)

PMID:39003740 SUPPORT In vitro / ex vivo

"Uni- or biallelic genetic correction of the LZTR1L580P missense variant rescues the molecular and cellular disease phenotype"

Provides isogenic rescue of the disease mechanism surrounding the structural prediction, while not independently resolving the modeled interfaces.

Notes

The article is CC BY-NC 4.0 and explicitly reports no original code. It provides no reusable paper-specific coordinates or prediction metadata; PXD038425 and PXD038417 are proteomics deposits, not model archives. The generic mutable ColabFold notebook is therefore not recorded as this model's repository. Evidence comes from one homozygous patient and family; iPSC-cardiomyocytes are developmentally immature and engineered heart muscle does not reproduce whole-organ physiology.

Show evidence (1 reference)

PMID:39003740 SUPPORT Computational

"Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1L580P-specific disease mechanism provoking cardiac hypertrophy."

Establishes that in-silico structure prediction was integrated into the allele-specific mechanistic study.

RIT1 A57G-RAF1 Interface Structural Model STRUCTURAL_PREDICTION

Active-state structural models of wild-type and Noonan-associated RIT1 A57G bound to the RAF1 RAS-binding domain, compared with the solved KRAS-RAF1 complex and annotated with NMR chemical-shift perturbations. The model localizes a shared switch-I interface and proposes that A57G increases local backbone flexibility and RAF1 affinity.

PMID:37450595 Base model: KRAS-RAF1-RBD crystal structure PDB 6VJJ

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
RIT1-RAF1 interface residues Modeled switch-I and RAF1-RBD contacts annotated by NMR perturbations.
RIT1-RAF1 dissociation constant Experimental affinity used to assess the modeled interface.	`KD`	micromolar

Pathograph links

RIT1-Mediated RAF Recruitment partially recapitulates fidelity: moderate Represents the RIT1 switch-I contact surface with RAF1 and predicts an allele-specific interface change that was tested by binding assays and interface mutagenesis.

Limitations: The paper does not identify the model-building engine or release the modeled coordinates. The structure is a static template-based complex, while cellular assays use ectopic protein expression. A57G enhances direct RAF1 binding but that interaction is weak and insufficient for MAPK activation without membrane localization and classical RAS. The in-vivo trametinib rescue used a different RIT1 allele, M90I, and does not validate A57G-specific model geometry.

Readouts

RIT1 A57G binding affinity for RAF1-RBD

Direction: INCREASED

Interpretation: Isothermal titration calorimetry and cellular BRET provide experimental correspondence for the modeled A57G interface, but do not establish the complete activation mechanism.

Show evidence (1 reference)

PMID:37450595 SUPPORT In vitro / ex vivo

"bound approximately five times more tightly to RAF1-RBD compared with WT"

Reports the allele-specific binding difference used to test the structural interpretation.

Show evidence (1 reference)

PMID:37450595 SUPPORT Computational

"Perturbed residues were then mapped onto modeled structures of WT and A57G mutants of RIT1 in the active state"

Establishes the disease-variant structural comparison and its NMR-based interface mapping.

Findings

The A57G interface model and NMR mapping predict differential engagement of RAF1-RBD around RIT1 switch I, consistent with higher measured affinity.

Show evidence (1 reference)

PMID:37450595 SUPPORT Computational

"These data suggest that the switch I of RIT1A57G differentially engages RAF1-RBD, potentially providing the enhanced stability exhibited by the pathogenic variant."

States the structural inference supported by the modeled complex and NMR comparison.

Direct RAF binding does not let pathogenic RIT1 bypass classical RAS; classical RAS remains necessary for MAPK activation.

Show evidence (1 reference)

PMID:37450595 SUPPORT In vitro / ex vivo

"Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins."

Defines the experimentally tested sufficiency boundary for the structural recruitment model.

Notes

The article is CC BY 4.0. Neither model coordinates nor code were deposited; GEO GSE207187 and GSE207188 contain RNA-seq rather than model artifacts. PDB 6VJJ is an experimental KRAS-RAF1 template, not the modeled RIT1 complex. The paper does not report the model-building engine or output format; PyMOL was used only to map NMR perturbations. Consequently, the published geometry cannot be independently rebuilt from the reported methods alone. Inefficient RAF1 cysteine-rich-domain engagement is an author hypothesis, not an output of the modeled RIT1-RAF1-RBD complex.

Show evidence (1 reference)

PMID:37450595 SUPPORT Computational

"Perturbed residues were then mapped onto modeled structures of WT and A57G mutants of RIT1 in the active state"

Establishes the disease-variant structural comparison used for the interface model.

SHP2 N308S Molecular-Dynamics and Interaction-Network Model

Molecular-dynamics and protein-interaction-network analysis of the PTPN11 N308S variant that co-segregated with Noonan syndrome in seven affected relatives. The integrated model predicts loss of stabilizing hydrogen bonds, greater conformational heterogeneity and a shift toward an activated open SHP2 state, followed by stronger predicted interactions with signaling hubs including GRB2 and SRC.

PMID:41843963

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
SHP2 hydrogen-bond network Intramolecular contacts altered by N308S in the structural analysis.
SHP2 conformational-state shift Qualitative modeled shift from the closed toward an activated open conformation.
Predicted SHP2 interaction network Variant-associated protein interactions including GRB2 and SRC.

Pathograph links

SHP2 Gain-of-Function Activation partially recapitulates fidelity: low Represents an allele-specific conformational route from N308S to reduced autoinhibitory stability and a qualitative shift toward an activated open state.

Limitations: The result comes from one related pedigree and has no independent family replication. The article does not expose model coordinates, trajectories, simulation duration, force field, code or a reusable configuration, and validation used HEK293T cells rather than developmental tissues. The inferred GRB2/SRC and ERK-to-chromatin axis combines separate network, phosphoproteomic and cellular layers and is not a single prospectively validated simulation.

Readouts

SHP2 conformational heterogeneity

Direction: INCREASED

Interpretation: Broader modeled conformational sampling is interpreted as destabilization of the autoinhibited state rather than a quantitative clinical predictor.

Show evidence (1 reference)

PMID:41843963 SUPPORT Computational

"This change enhances conformational heterogeneity and shifts the protein into an activated "open" state."

Reports the direction of the principal molecular-dynamics readout.

Predicted shift toward an activated open state

Direction: ALTERED

Interpretation: The qualitative modeled shift toward open SHP2 provides structural support for gain of function; no open-state fraction or patient-specific threshold was reported.

Show evidence (1 reference)

PMID:41843963 SUPPORT Computational

"This change enhances conformational heterogeneity and shifts the protein into an activated "open" state."

Connects the modeled conformational shift directly to the SHP2 activation node.

Show evidence (1 reference)

PMID:41843963 SUPPORT Computational

"This revealed that the mutation disrupts critical hydrogen bonds and remodels the interaction network."

Supports the modeled structural perturbation underlying the activation link.

Findings

N308S was predicted to disrupt hydrogen bonds, increase conformational heterogeneity and favor an open SHP2 conformation.

Show evidence (1 reference)

PMID:41843963 SUPPORT Computational

"This revealed that the mutation disrupts critical hydrogen bonds and remodels the interaction network. This change enhances conformational heterogeneity and shifts the protein into an activated "open" state."

Summarizes the atomistic prediction without extending it to clinical outcome prediction.

Notes

This 2026 study is a pedigree-specific mechanistic model, not a longitudinal digital twin. The article is not openly licensed and no model repository was identified. PXD068242/IPX0011703000 contains the phosphoproteomics data, not the molecular-dynamics model, and has no stated reusable model license. The model-building engine, force field, duration, trajectory files and output format are not publicly reported. `model_type` is omitted because the current enum has no category for disease-variant molecular dynamics without docking.

Show evidence (1 reference)

PMID:41843963 SUPPORT Computational

"Using a multi-level approach that integrated experimental structural analysis, molecular dynamics simulations, protein-protein interaction network analysis, quantitative phosphoproteomics, and functional validation in cellular models"

Establishes the computational components and the distinct experimental validation layers.

SOS1 R1131K Transfer-Entropy Signaling Model Jupyter Notebook and CSV single-cell time series Python 3.9.7, Jupyter, NumPy, pandas, matplotlib, and seaborn

Information-theoretic model of bidirectional predictive dependence between SOS1 and RAF from simultaneous single-cell membrane-translocation trajectories. A Gaussian covariance approximation estimates time-resolved transfer entropy in wild-type and Noonan-associated SOS1 R1131K cells with or without MEK inhibition, revealing phase-specific effective regulation consistent with feedback changes or shared hidden inputs.

Repository ↗ PMID:40047537 Base model: Gaussian-approximation transfer-entropy method of Imaizumi et al. 2022

Variable	Model ID	Unit
SOS1 membrane-translocation trajectory One-minute single-cell Halo-SOS1 response sequence after EGF stimulation.	`X(t)`
RAF membrane-translocation trajectory Simultaneously measured single-cell GFP-RAF response sequence.	`Y(t)`
SOS-to-RAF transfer entropy Forward predictive information flow from SOS to RAF.	`fw-TE`	nat
RAF-to-SOS transfer entropy Backward predictive information flow reflecting feedback or shared hidden inputs.	`bw-TE`	nat

Pathograph links

SOS-Family-Mediated RAS-GTP Loading partially recapitulates fidelity: low Uses SOS1 and RAF membrane-translocation dynamics to measure how R1131K changes effective information flow through the SOS-RAF signaling system. This is an indirect functional readout of the SOS node; RAS-GTP loading is not measured.

Limitations: Transfer entropy quantifies predictive dependence and does not identify a unique biochemical path or prove molecular causality; hidden or common inputs can generate backward information flow. The acute EGF experiment uses SOS1-knockout HeLa cells with ectopic Halo-SOS1 and GFP-RAF, retains endogenous SOS2, pools cells across independent measurements, and does not model development or patient phenotypes. The Gaussian approximation is a first-order treatment of noisy, potentially non-Gaussian trajectories.

Readouts

Early RAF-to-SOS backward transfer entropy

Direction: INCREASED

Interpretation: R1131K increases the early backward information-flow peak, indicating an altered effective feedback regime rather than increased RAS-GTP itself.

Show evidence (1 reference)

PMID:40047537 SUPPORT Computational

"Similar to the MEK inhibitor, R1131K significantly increased the early bw-TE peak."

Reports the direction of the early transfer-entropy effect.

Late RAF-to-SOS backward transfer entropy

Direction: DECREASED

Interpretation: R1131K decreases the late backward information-flow peak without MEK inhibition, showing that the same allele has opposite phase-specific effects.

Show evidence (1 reference)

PMID:40047537 SUPPORT Computational

"In addition, R1131K specifically decreased the late bw-TE peak."

Reports the direction of the late transfer-entropy effect.

Late-phase transfer-entropy abnormality after MEK inhibition

Direction: RESTORED

Interpretation: Trametinib removed the late-phase abnormality but did not normalize the early phase, so the rescue is explicitly phase-specific.

Show evidence (1 reference)

PMID:40047537 SUPPORT Computational

"MEK inhibition rescued the abnormality in the late phase but not in the early phase."

Defines the limited temporal scope of the perturbation rescue.

Show evidence (1 reference)

PMID:40047537 SUPPORT Computational

"Furthermore, TE analysis identified the functional disorder of a SOS mutation associated with Noonan syndrome"

Establishes the allele-specific application of the transfer-entropy model.

Findings

R1131K raises early backward transfer entropy and lowers late backward transfer entropy, revealing a signaling defect not evident from RAF activation or translocation amplitude alone.

Show evidence (1 reference)

PMID:40047537 SUPPORT Computational

"The information flow was perturbed in Noonan cells carrying the R1131K mutation. The mutation had opposite impacts on the early and late phases in cells without the MEK inhibitor"

Summarizes the principal allele-specific dynamic result.

Trametinib restores the late-phase transfer-entropy abnormality but not the early-phase abnormality.

Show evidence (1 reference)

PMID:40047537 SUPPORT Computational

"MEK inhibition rescued the abnormality in the late phase but not in the early phase."

States the phase-specific perturbation result without treating it as clinical therapeutic efficacy.

Notes

`model_type` is deliberately omitted: information-theoretic network inference fits none of the current enum values and is not a kinetic, machine-learning or Boolean model. The paper-pinned Software Heritage revision is 7ff6a1cfdef5163ae98a663381e12cc4f065d3f6; the mutable repository home is https://github.com/YasushiSako/transfer_entropy_2. That revision has no software-license file; repository HEAD 3467850de2e45dfc2b7766ba4dce0d7af8839a00 only adds the MIT LICENSE. The README licenses the 16 CSV data files under CC BY-NC-SA 4.0. Curator static inspection confirmed that all wild-type and R1131K, vehicle and MEK-inhibitor CSVs are present. The seeded notebook has no environment lock and expects selected input pairs to be copied or renamed to SOStotal.csv and RAFtotal.csv. It also uses the removed pandas `set_axis(inplace=True)` API and fails under pandas 3.0.3 without a small compatibility edit, so it is not a one-command reproduction.

Show evidence (2 references)

PMID:40047537 SUPPORT Computational

"TE analysis allows for model-free assessment of the timing, direction, and strength of the information flow regulating the system response."

Defines the computational method and its explicitly model-free scope.

PMID:40047537 SUPPORT Computational

"The information flow was perturbed in Noonan cells carrying the R1131K mutation."

Ties the model to Noonan syndrome: the analysis was applied to cells carrying the Noonan-associated SOS1 R1131K variant.

{ }

Source YAML

click to show

name: Noonan Syndrome
creation_date: '2026-02-04T01:40:11Z'
description: >-
  Noonan syndrome is an autosomal dominant RASopathy caused by germline mutations
  in genes of the RAS-MAPK signaling pathway, most commonly PTPN11 but also SOS1,
  SOS2, RAF1, RIT1, KRAS, NRAS, MRAS, LZTR1, BRAF, MAP2K1, RASA2, and RRAS2.
  It is characterized by distinctive facial features, short stature, congenital
  heart defects (particularly pulmonary valve stenosis and hypertrophic cardiomyopathy),
  prenatal lymphatic anomalies, feeding and bleeding problems, hearing loss,
  and variable developmental delays.
  It is one of the most common genetic syndromes associated with congenital heart
  disease,
  with an estimated incidence of 1:1,000 to 1:2,500 live births.
category: Genetic
parents:
- RASopathy
- Congenital Heart Disease
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:Q87.1
      label: Congenital malformation syndromes predominantly associated with short stature
    mapping_predicate: skos:narrowMatch
    mapping_source: ORPHA:648
    mapping_justification: Orphanet lists ICD-10 Q87.1 as a narrower cross-reference for Noonan syndrome.
    consistency:
    - reference: ORPHA:648
      consistent: CONSISTENT
      notes: "ICD-10:Q87.1 | Narrower"
  mondo_mappings:
  - term:
      id: MONDO:0018997
      label: Noonan syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:648
    mapping_justification: Orphanet lists MONDO:0018997 as an exact cross-reference for Noonan syndrome.
    consistency:
    - reference: ORPHA:648
      consistent: CONSISTENT
      notes: "MONDO:0018997 | Exact"
disease_term:
  preferred_term: Noonan syndrome
  description: A RASopathy characterized by distinctive facial features, short stature, congenital heart defects, and variable developmental delays.
  term:
    id: MONDO:0018997
    label: Noonan syndrome
has_subtypes:
- name: NS1
  display_name: Noonan syndrome 1 (PTPN11-related)
  subtype_term:
    preferred_term: Noonan syndrome 1
    term:
      id: MONDO:0008104
      label: Noonan syndrome 1
  genes:
  - preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  description: Most common form caused by PTPN11 mutations, accounting for approximately 50% of cases.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included 15 individuals with Noonan syndrome (nine with
      variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS...)
    explanation: >-
      This cohort confirms PTPN11-positive Noonan syndrome as the predominant
      molecular subtype.
- name: NS2
  display_name: Noonan syndrome 2 (biallelic LZTR1)
  subtype_term:
    preferred_term: Noonan syndrome 2
    term:
      id: MONDO:0011531
      label: Noonan syndrome 2
  classification: molecular
  genes:
  - preferred_term: LZTR1
    term:
      id: hgnc:6742
      label: LZTR1
  description: >-
    The autosomal recessive LZTR1 form. MONDO carries "autosomal recessive
    Noonan syndrome" as a synonym of this class, and ClinGen curates a separate
    autosomal recessive LZTR1-Noonan syndrome assertion alongside the dominant
    one. Distinguished from NS10 by zygosity rather than by gene.
  evidence:
  - reference: CGGV:assertion_7aa1e103-4f77-4c50-99c5-621a6a837b95-2020-08-27T160000.000Z
    reference_title: "LZTR1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LZTR1 | HGNC:6742 | Noonan syndrome | MONDO:0018997 | AR | Definitive"
    explanation: ClinGen curates a definitive autosomal recessive LZTR1-Noonan syndrome relationship, which is the relationship this subtype names.
  - reference: PMID:20301303
    reference_title: Noonan Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents of an individual with autosomal recessive NS are typically
      heterozygotes (i.e., have one LZTR1 pathogenic variant), and may either be
      asymptomatic or have mild features of NS.
    explanation: >-
      The GeneReviews chapter states that the recessive form of Noonan syndrome
      is the biallelic LZTR1 form, which is what separates this subtype from NS10.
- name: NS3
  display_name: Noonan syndrome 3 (KRAS-related)
  subtype_term:
    preferred_term: Noonan syndrome 3
    term:
      id: MONDO:0012371
      label: Noonan syndrome 3
  classification: molecular
  genes:
  - preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  description: >-
    The KRAS form. MONDO defines this class as "Any Noonan syndrome in which the
    cause of the disease is a mutation in the KRAS gene."
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KRAS mutations account for <5% of cases of Noonan syndrome"
    explanation: Establishes KRAS as a rare molecular cause of Noonan syndrome, which is the relationship this subtype names.
  - reference: CGGV:assertion_6476a5fd-8f66-462b-b17a-43540dad3c1f-2018-07-24T160000.000Z
    reference_title: "KRAS / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KRAS | HGNC:6407 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the KRAS-Noonan syndrome relationship as definitive with autosomal dominant inheritance.
- name: NS4
  display_name: Noonan syndrome 4 (SOS1-related)
  subtype_term:
    preferred_term: Noonan syndrome 4
    term:
      id: MONDO:0012547
      label: Noonan syndrome 4
  classification: molecular
  genes:
  - preferred_term: SOS1
    term:
      id: hgnc:11187
      label: SOS1
  description: >-
    The SOS1 form, which the founding report identifies as a major cause of
    Noonan syndrome in patients without a PTPN11 mutation. MONDO defines this
    class as "Any Noonan syndrome in which the cause of the disease is a
    mutation in the SOS1 gene."
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation."
    explanation: The founding report establishes SOS1 as a major cause of PTPN11-negative Noonan syndrome, which is the relationship this subtype names.
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results identify SOS1 mutants as a major cause of Noonan syndrome
    explanation: The source for this subtype's description calling SOS1 a major cause.
  - reference: CGGV:assertion_9781b6bf-9b1e-4a10-a0a9-7e56562a6e3a-2018-07-24T160000.000Z
    reference_title: "SOS1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SOS1 | HGNC:11187 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the SOS1-Noonan syndrome relationship as definitive with autosomal dominant inheritance.
- name: NS5
  display_name: Noonan syndrome 5 (RAF1-related)
  subtype_term:
    preferred_term: Noonan syndrome 5
    term:
      id: MONDO:0012690
      label: Noonan syndrome 5
  classification: molecular
  genes:
  - preferred_term: RAF1
    term:
      id: hgnc:9829
      label: RAF1
  description: >-
    The RAF1 form, notable for its association with hypertrophic cardiomyopathy.
    MONDO defines this class as "Any Noonan syndrome in which the cause of the
    disease is a mutation in the RAF1 gene."
  evidence:
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals)...have missense mutations in RAF1"
    explanation: Quantifies the RAF1 share of Noonan syndrome, which is the relationship this subtype names.
  - reference: CGGV:assertion_85645d27-2056-4ad3-9593-8d7739aa4121-2024-10-23T160000.000Z
    reference_title: "RAF1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RAF1 | HGNC:9829 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the RAF1-Noonan syndrome relationship as definitive with autosomal dominant inheritance.
- name: NS6
  display_name: Noonan syndrome 6 (NRAS-related)
  subtype_term:
    preferred_term: Noonan syndrome 6
    term:
      id: MONDO:0013186
      label: Noonan syndrome 6
  classification: molecular
  genes:
  - preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  description: >-
    The NRAS form. Curated in full as the standalone entry
    kb/disorders/Noonan_Syndrome_6.yaml; the row is retained here so the
    numbered series reads as a complete catalog.
  evidence:
  - reference: PMID:19966803
    reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report that germline NRAS mutations conferring enhanced
      stimulus-dependent MAPK activation account for some cases of this disorder.
    explanation: The founding report establishes NRAS as a molecular cause of Noonan syndrome, which is the relationship this subtype names.
- name: NS7
  display_name: Noonan syndrome 7 (BRAF-related)
  subtype_term:
    preferred_term: Noonan syndrome 7
    term:
      id: MONDO:0013379
      label: Noonan syndrome 7
  classification: molecular
  genes:
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  description: >-
    The BRAF form, which overlaps clinically with cardiofaciocutaneous syndrome.
    MONDO defines this class as "Any Noonan syndrome in which the cause of the
    disease is a mutation in the BRAF gene." ClinGen grades the BRAF-Noonan
    syndrome relationship Moderate rather than Definitive.
  evidence:
  - reference: PMID:19953625
    reference_title: "Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a
      cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic
      SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients.
    explanation: Reports BRAF variants in a Noonan syndrome cohort, which is the relationship this subtype names.
  - reference: CGGV:assertion_47cf08d5-efc6-4d42-b031-a06619873161-2018-07-24T160000.000Z
    reference_title: "BRAF / Noonan syndrome (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BRAF | HGNC:1097 | Noonan syndrome | MONDO:0018997 | AD | Moderate"
    explanation: Records the Moderate ClinGen grade this subtype description states.
- name: NS8
  display_name: Noonan syndrome 8 (RIT1-related)
  subtype_term:
    preferred_term: Noonan syndrome 8
    term:
      id: MONDO:0014143
      label: Noonan syndrome 8
  classification: molecular
  genes:
  - preferred_term: RIT1
    term:
      id: hgnc:10023
      label: RIT1
  description: >-
    The RIT1 form. MONDO defines this class as "Any Noonan syndrome in which the
    cause of the disease is a mutation in the RIT1 gene."
  evidence:
  - reference: PMID:23791108
    reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a total of nine missense, nonsynonymous mutations in RIT1...in 17 of 180 individuals (9%) with Noonan syndrome"
    explanation: Quantifies the RIT1 share of Noonan syndrome, which is the relationship this subtype names.
  - reference: CGGV:assertion_240565fc-61b9-4ff8-9f5a-85938f17cdd9-2018-07-24T160000.000Z
    reference_title: "RIT1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RIT1 | HGNC:10023 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the RIT1-Noonan syndrome relationship as definitive with autosomal dominant inheritance.
- name: NS9
  display_name: Noonan syndrome 9 (SOS2-related)
  subtype_term:
    preferred_term: Noonan syndrome 9
    term:
      id: MONDO:0014691
      label: Noonan syndrome 9
  classification: molecular
  genes:
  - preferred_term: SOS2
    term:
      id: hgnc:11188
      label: SOS2
  description: >-
    The SOS2 form. MONDO defines this class as "Any Noonan syndrome in which the
    cause of the disease is a mutation in the SOS2 gene."
  evidence:
  - reference: PMID:25795793
    reference_title: "Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified rare, segregating or de novo missense variants in SOS2
      and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands.
    explanation: The discovery cohort establishes SOS2 as a cause of Noonan syndrome, which is the relationship this subtype names.
  - reference: CGGV:assertion_f20a1034-e29d-49bb-aed9-b4ba63dc5968-2020-08-27T160000.000Z
    reference_title: "SOS2 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SOS2 | HGNC:11188 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the SOS2-Noonan syndrome relationship as definitive with autosomal dominant inheritance.
- name: NS10
  display_name: Noonan syndrome 10 (heterozygous LZTR1)
  subtype_term:
    preferred_term: Noonan syndrome 10
    term:
      id: MONDO:0014693
      label: Noonan syndrome 10
  classification: molecular
  genes:
  - preferred_term: LZTR1
    term:
      id: hgnc:6742
      label: LZTR1
  description: >-
    The autosomal dominant LZTR1 form. MONDO defines this class as "Any Noonan
    syndrome in which the cause of the disease is a mutation in the LZTR1 gene";
    it is separated from NS2 by zygosity, not by gene.
  evidence:
  - reference: PMID:25795793
    reference_title: "Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified rare, segregating or de novo missense variants in SOS2
      and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands.
    explanation: The discovery cohort establishes LZTR1 as a cause of Noonan syndrome, which is the relationship this subtype names.
  - reference: CGGV:assertion_6f21db9c-87ea-4095-96ca-4277eaa21232-2020-04-23T170000.000Z
    reference_title: "LZTR1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LZTR1 | HGNC:6742 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the dominant LZTR1-Noonan syndrome relationship as definitive, which is the relationship that separates this subtype from NS2.
- name: NS11
  display_name: Noonan syndrome 11 (MRAS-related)
  subtype_term:
    preferred_term: Noonan syndrome 11
    term:
      id: MONDO:0032786
      label: Noonan syndrome 11
  classification: molecular
  genes:
  - preferred_term: MRAS
    term:
      id: hgnc:7227
      label: MRAS
  description: >-
    The MRAS form. Curated in full as the standalone entry
    kb/disorders/Noonan_Syndrome_11.yaml; the row is retained here so the
    numbered series reads as a complete catalog.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included 15 individuals with Noonan syndrome (nine with
      variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS...)
    explanation: Reports an MRAS-positive Noonan syndrome diagnosis in a contemporary molecular cohort, which is the relationship this subtype names.
- name: NS12
  display_name: Noonan syndrome 12 (RRAS2-related)
  subtype_term:
    preferred_term: noonan syndrome 12
    term:
      id: MONDO:0032839
      label: noonan syndrome 12
  classification: molecular
  genes:
  - preferred_term: RRAS2
    term:
      id: hgnc:17271
      label: RRAS2
  description: >-
    The RRAS2 form. MONDO carries no text definition for this class; the gene
    assignment rests on the founding report and the ClinGen assertion cited here.
  evidence:
  - reference: PMID:31130282
    reference_title: "Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using a mixed strategy of functional candidacy and exome sequencing,
      we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families.
    explanation: The founding report establishes RRAS2 as a cause of Noonan syndrome, which is the relationship this subtype names.
  - reference: CGGV:assertion_c5742615-3820-41dd-a523-e660a498f9e8-2022-12-14T170000.000Z
    reference_title: "RRAS2 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RRAS2 | HGNC:17271 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the RRAS2-Noonan syndrome relationship as definitive with autosomal dominant inheritance.
- name: NS13
  display_name: Noonan syndrome 13 (MAPK1-related)
  subtype_term:
    preferred_term: Noonan syndrome 13
    term:
      id: MONDO:0033669
      label: Noonan syndrome 13
  classification: molecular
  genes:
  - preferred_term: MAPK1
    term:
      id: hgnc:6871
      label: MAPK1
  description: >-
    The MAPK1 form, in which the mutated gene encodes ERK2, the terminal kinase
    of the cascade every other subtype in this series acts upstream of. The
    attribution is weaker than for the rest of the series and the row records
    that: the founding report describes the phenotype as a neurodevelopmental
    disorder within the RASopathy spectrum that is Noonan-like in only some
    subjects, the 2025 GeneReviews chapter does not list MAPK1 among the genes
    whose variants establish a Noonan syndrome diagnosis, and the committed
    ClinGen Gene-Disease Validity snapshot carries no MAPK1 assertion for any
    disease.
  evidence:
  - reference: PMID:32721402
    reference_title: "Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report that de novo missense variants in MAPK1, encoding the
      mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated
      protein kinase 2, ERK2), cause a neurodevelopmental disease within the
      RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some
      subjects.
    explanation: >-
      The founding report states both the gene-disease relationship and the
      hedge on its Noonan attribution that this subtype description records.
  - reference: PMID:32721402
    reference_title: "Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After nearly 20 years from the discovery of the first gene implicated in
      Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group
      of genes mutated in RASopathies.
    explanation: >-
      Source for this subtype's description placing MAPK1 at the terminal tier
      of the cascade the rest of the series acts upstream of.
  - 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: >-
      The GeneReviews diagnostic gene list, quoted here because MAPK1 is absent
      from it; this is the source for the caveat in this subtype's description.
- name: NS14
  display_name: Noonan syndrome 14 (biallelic SPRED2)
  subtype_term:
    preferred_term: Noonan syndrome 14
    term:
      id: MONDO:0030679
      label: Noonan syndrome 14
  classification: molecular
  genes:
  - preferred_term: SPRED2
    term:
      id: hgnc:17722
      label: SPRED2
  description: >-
    The SPRED2 form, which its founding report identifies as the second
    recessive form of Noonan syndrome. SPRED2 negatively modulates
    EGF-promoted RAF1, MEK and ERK phosphorylation, so the entry point is loss
    of a brake rather than gain of a signal. As with NS13, the attribution is
    weaker than for the rest
    of the series: the 2025 GeneReviews chapter does not list SPRED2 among the
    diagnostic genes, and the committed ClinGen Gene-Disease Validity snapshot
    carries no SPRED2 assertion.
  evidence:
  - reference: PMID:34626534
    reference_title: "SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report that SPRED2 loss of function is causally linked to a
      recessive phenotype evocative of Noonan syndrome.
    explanation: >-
      The founding report states the gene-disease relationship and the recessive
      mode this subtype names.
  - reference: PMID:34626534
    reference_title: "SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      When overexpressed in cells, all variants were unable to negatively
      modulate EGF-promoted RAF1, MEK, and ERK phosphorylation
    explanation: >-
      Source for the negative-regulator role this subtype's description gives
      SPRED2, and for calling the entry point loss of a brake.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPRED2 | sprouty related EVH1 domain containing 2 | hgnc:17722 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records SPRED2 as disease-causing for Noonan syndrome, the second attestation this subtype rests on.
- name: Noonan Syndrome with Multiple Lentigines
  subtype_term:
    preferred_term: Noonan syndrome with multiple lentigines
    term:
      id: MONDO:0007893
      label: Noonan syndrome with multiple lentigines
  genes:
  - preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  description: >-
    Formerly known as LEOPARD syndrome, characterized by lentigines and
    hypertrophic cardiomyopathy. Only PTPN11 is bound here: the cohort cited
    below found PTPN11 variants in both of its lentigines cases, and RAF1 and
    BRAF, which MONDO also records against MONDO:0007893, are not attested for
    this subtype by a source this entry cites.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two with Noonan syndrome with multiple lentigines (both with variants in PTPN11)

    explanation: >-
      Confirms Noonan syndrome with multiple lentigines as a related and
      clinically relevant subtype in modern RASopathy cohorts.
prevalence:
- population: Live births
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 40.0
  rate_high: 100.0
  percentage: 1 in 1,000 to 1 in 2,500
  notes: >-
    Noonan syndrome is among the more common rare Mendelian syndromes and a
    leading syndromic cause of congenital heart disease.
  evidence:
  - reference: PMID:18047172
    reference_title: "Supporting children with Noonan syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Noonan syndrome, a genetic condition occurring in around 1 in 2,000 live births, was first described in 1968 by Dr Jacqueline Noonan, an American cardiologist, who noticed that patients attending her clinic often had similar features."
    explanation: This review provides a commonly cited live-birth frequency estimate for Noonan syndrome.
  - reference: PMID:10912404
    reference_title: "Pregnancy in women with Noonan syndrome: report of two cases"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Background: Noonan syndrome is similar phenotypically to Turner syndrome, accounting for one in 1000-2500 live births."
    explanation: This paper supports the broader conventional birth-frequency range cited for Noonan syndrome.
- population: United States (Orphanet prevalence at birth)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 60.0
  rate_high: 90.0
  percentage: 0.06-0.09
  notes: Orphanet reports a prevalence-at-birth class of 6-9 per 10,000 in the United States.
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "6-9 / 10 000 | United States | Prevalence at birth | PMID:3895929"
    explanation: The Orphanet epidemiology table provides a US prevalence-at-birth class for Noonan syndrome.
- population: Worldwide (Orphanet point prevalence)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 10.0
  rate_high: 50.0
  percentage: 0.01-0.05
  notes: Orphanet reports a worldwide point-prevalence class of 1-5 per 10,000.
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Worldwide | Point prevalence | EXPERT"
    explanation: The Orphanet epidemiology table provides a worldwide point-prevalence class for Noonan syndrome.
pathophysiology:
- name: SHP2 Gain-of-Function Activation
  description: >-
    PTPN11 mutations destabilize the autoinhibitory interaction between the N-SH2
    and PTP domains, resulting in constitutively elevated phosphatase activity.
    SHP2 is a positive regulator of RAS-MAPK signaling and gain-of-function mutations
    lead to enhanced ERK activation.
  genes:
  - preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  molecular_functions:
  - preferred_term: protein tyrosine phosphatase activity
    term:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Enhanced SHP2 phosphatase activity promotes RAS activation and downstream ERK signaling.
    evidence:
    - reference: PMID:17143285
      reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and
        Noonan syndrome mutants enhance ERK activation ex vivo and in mice.
      explanation: >-
        Supports SHP2 gain-of-function as an upstream driver of ERK cascade
        hyperactivation in Noonan syndrome.
    - reference: PMID:11992261
      reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A gain of function was postulated as a mechanism for the disease.
      explanation: >-
        Provides direct Noonan/PTPN11 human-genetics evidence supporting
        gain-of-function SHP2 signaling upstream of ERK hyperactivation.
  - target: Hematologic Dysregulation
    description: >-
      PTPN11-driven Noonan syndrome can include mutation-associated hematologic
      abnormalities, including bleeding diathesis and JMML risk.
    evidence:
    - reference: PMID:15240615
      reference_title: "Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        hematological abnormalities, such as bleeding diathesis and juvenile
        myelomonocytic leukemia, were exclusively present in mutation-positive
        patients (5 of 18 vs. 0 of 27; P = 0.007).
      explanation: >-
        Supports a PTPN11-associated hematologic branch downstream of SHP2
        gain-of-function in Noonan syndrome.
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains"
    explanation: PTPN11 mutations cluster at the N-SH2/PTP interface, disrupting autoinhibition.

- name: SOS-Family-Mediated RAS-GTP Loading
  description: >-
    SOS-family gain-of-function mutations encode guanine nucleotide exchange
    factor variants with enhanced activity, increasing the rate of RAS-GDP to
    RAS-GTP conversion and amplifying downstream MAPK signaling.
  genes:
  - preferred_term: SOS1
    term:
      id: hgnc:11187
      label: SOS1
  - preferred_term: SOS2
    term:
      id: hgnc:11188
      label: SOS2
  molecular_functions:
  - preferred_term: guanyl-nucleotide exchange factor activity
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Enhanced RAS-GTP loading directly amplifies RAF-MEK-ERK cascade activation.
    evidence:
    - reference: PMID:17143285
      reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Noonan syndrome-associated SOS1 mutations are hypermorphs encoding
        products that enhance RAS and ERK activation.
      explanation: >-
        Cell-based functional assays show SOS1 Noonan variants are hypermorphs
        that amplify RAS/ERK activation.
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation."
    explanation: Cell-based functional assays show SOS1 mutations are gain-of-function, enhancing RAS-GTP loading.

- name: RAF1 Kinase Hyperactivation
  description: >-
    RAF1 mutations, particularly those altering Ser259 and flanking residues,
    disrupt 14-3-3 binding and autoinhibition, resulting in constitutively
    elevated serine-threonine kinase activity and enhanced MEK phosphorylation.
  genes:
  - preferred_term: RAF1
    term:
      id: hgnc:9829
      label: RAF1
  molecular_functions:
  - preferred_term: protein serine/threonine kinase activity
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Hyperactive RAF1 directly phosphorylates MEK, amplifying ERK signaling.
    evidence:
    - reference: PMID:17603483
      reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ...have missense mutations in RAF1, which encodes a serine-threonine
        kinase that activates MEK1 and MEK2.
      explanation: >-
        Supports mechanistic linkage from RAF1 activation to downstream MEK/ERK
        cascade signaling.
  - target: Cardiomyocyte Hypertrophy
    description: RAF1 kinase hyperactivation is strongly associated with hypertrophic cardiomyopathy development.
    evidence:
    - reference: PMID:17603483
      reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings further implicate increased RAS signaling in pathological
        cardiomyocyte hypertrophy.
      explanation: >-
        Supports RAF1-mediated signaling as a proximal driver of cardiomyocyte
        hypertrophic remodeling.
  evidence:
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding."
    explanation: RAF1 mutations disrupt autoinhibitory 14-3-3 binding.

- name: RIT1-Mediated RAF Recruitment
  description: >-
    Pathogenic RIT1 proteins evade LZTR1-mediated degradation and accumulate.
    When membrane-bound, they directly bind and recruit RAF, increasing its
    local availability for MAPK signaling. Full RAF-MAPK activation nevertheless
    remains dependent on classical RAS proteins rather than bypassing them.
  genes:
  - preferred_term: RIT1
    term:
      id: hgnc:10023
      label: RIT1
  biological_processes:
  - preferred_term: Ras protein signal transduction
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Aberrant RIT1-mediated RAF recruitment amplifies downstream ERK signaling.
    evidence:
    - reference: DOI:10.1126/sciadv.adf4766
      reference_title: "RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Pathogenic RIT1 proteins promote mitogen-activated protein kinase
        (MAPK) hyperactivation; however, this mechanism remains poorly understood.
      explanation: >-
        Supports RIT1 mutant signaling as a direct contributor to MAPK/ERK
        hyperactivation.
  - target: Cardiomyocyte Hypertrophy
    description: RIT1 mutations are strongly associated with hypertrophic cardiomyopathy.
    evidence:
    - reference: PMID:23791108
      reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Seventy percent of mutation-positive individuals presented with
        hypertrophic cardiomyopathy; this frequency is high relative to the
        overall 20% incidence in individuals with Noonan syndrome.
      explanation: >-
        Supports RIT1-associated signaling as strongly linked to hypertrophic
        myocardial phenotype.
  evidence:
  - reference: PMID:23791108
    reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes."
    explanation: RIT1 gain-of-function mutations drive aberrant MAPK signaling.
  - reference: PMID:37450595
    reference_title: "RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although mutant RIT1 binds to RAF kinases directly, it fails to activate
      MAPK signaling in the absence of classical RAS proteins.
    explanation: >-
      Corrects the former implication that pathogenic RIT1 bypasses classical
      RAS regulation: direct RAF recruitment is necessary but not sufficient for
      MAPK activation.

- name: LZTR1-Mediated RAS Proteostasis Defect
  conforms_to: "cul3_substrate_adaptor_dysfunction#Mis-Set CRL3 Ubiquitination of the Adaptor's Substrate"
  description: >-
    Loss of LZTR1-mediated RAS proteostasis through CRL3 E3 ligase
    increases RAS-family protein levels (including MRAS, RIT1, and KRAS)
    and MAPK signaling. Dominant LZTR1 mutations act in a dominant-negative
    manner to disrupt ubiquitination and degradation of RAS proteins.
  genes:
  - preferred_term: LZTR1
    term:
      id: hgnc:6742
      label: LZTR1
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
  - preferred_term: regulation of proteolysis
    term:
      id: GO:0030162
      label: regulation of proteolysis
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Accumulated RAS proteins lead to increased basal MAPK signaling.
    evidence:
    - reference: PMID:39352760
      reference_title: "Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Multi-omics analysis revealed that the mitogen-activated protein kinase
        (MAPK) signaling pathway was activated in the LVs of mutant mice.
      explanation: >-
        Demonstrates MAPK pathway activation downstream of dominant-negative
        LZTR1 dysfunction.
  evidence:
  - reference: PMID:39352760
    reference_title: "Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiomyocyte size and the expression of RAS subfamily members, including
      MRAS and RIT1, were significantly increased in the left ventricles (LVs)
      of mutant male mice.
    explanation: >-
      Supports LZTR1 loss-of-function effects on RAS-family proteostasis and
      downstream tissue-level cardiac phenotypes.

- name: Additional RAS-MAPK Signal-Amplifying Variants
  description: >-
    Additional established Noonan genes affecting small GTPases, RAF/MEK
    kinases, and RasGAP regulation converge on increased RAS-MAPK pathway
    throughput despite diverse molecular entry points. Two of the genes bound
    here reach that endpoint by losing a brake rather than by gaining a
    signal: CBL is an E3 ubiquitin ligase whose mutations impair receptor
    ubiquitylation, and SPRED2 is a negative modulator of EGF-promoted RAF1,
    MEK and ERK phosphorylation. SPRED2 is the exception to this entry's
    dominant pattern - it acts recessively - and is recorded in the autosomal
    recessive inheritance block alongside LZTR1.
  genes:
  - preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  - preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  - preferred_term: MRAS
    term:
      id: hgnc:7227
      label: MRAS
  - preferred_term: RRAS2
    term:
      id: hgnc:17271
      label: RRAS2
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  - preferred_term: MAP2K1
    term:
      id: hgnc:6840
      label: MAP2K1
  - preferred_term: RASA2
    term:
      id: hgnc:9872
      label: RASA2
  - preferred_term: CBL
    term:
      id: hgnc:1541
      label: CBL
  - preferred_term: SPRED2
    term:
      id: hgnc:17722
      label: SPRED2
  downstream:
  - target: ERK Cascade Hyperactivation
    description: >-
      Diverse rare Noonan genotypes affecting RAS-MAPK components still
      converge on excess ERK pathway output.
    evidence:
    - reference: DOI:10.1007/s00431-023-05263-y
      reference_title: "Novel therapeutic perspectives in Noonan syndrome and RASopathies"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Collectively, all these pathogenic variants lead to increased
        RAS/MAPK activation.
      explanation: >-
        Supports a convergent pathway-activation node for rarer established
        Noonan genotypes.
  evidence:
  - reference: PMID:20619386
    reference_title: "Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations were shown to affect CBL-mediated receptor ubiquitylation and
      dysregulate signal flow through RAS.
    explanation: >-
      Supports the CBL entry point this node's description names: loss of
      receptor ubiquitylation reaching the same RAS output as the activating
      genotypes.
  - reference: PMID:34626534
    reference_title: "SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      When overexpressed in cells, all variants were unable to negatively
      modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course
      experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs∗95)
      documented an increased and prolonged activation of the MAPK cascade in
      response to EGF stimulation.
    explanation: >-
      Supports the SPRED2 entry point: loss of a negative modulator raising
      MAPK output, measured in patient fibroblasts as well as by overexpression.
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DIAGNOSIS/TESTING: 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 enumerates these rare but established Noonan genes that
      converge mechanistically on the same signaling pathway.

- name: ERK Cascade Hyperactivation
  description: >-
    Convergent point where all upstream RAS-MAPK pathway defects lead to
    sustained ERK1/2 phosphorylation and hyperactivation. This affects
    cell proliferation, differentiation, and survival during embryonic
    development and postnatal life. MAPK1 is bound here rather than on an
    upstream node because it encodes ERK2 itself: the NS13 genotype alters the
    effector this node names instead of altering an input to it.
  genes:
  - preferred_term: MAPK1
    term:
      id: hgnc:6871
      label: MAPK1
  biological_processes:
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: regulation of ERK1 and ERK2 cascade
    term:
      id: GO:0070372
      label: regulation of ERK1 and ERK2 cascade
  molecular_functions:
  - preferred_term: MAP kinase activity
    term:
      id: GO:0004707
      label: MAP kinase activity
    modifier: INCREASED
  downstream:
  - target: Neural Crest Cell Developmental Dysregulation
    description: >-
      ERK1/2 hyperactivation within the neural crest lineage itself is
      sufficient to produce the craniofacial malformations of Noonan syndrome,
      and suppressing that hyperactivation prevents them.
    evidence:
    - reference: PMID:19706403
      reference_title: "Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hyperactivation of ERK1/2 led to craniofacial defects that included
        smaller skull lengths, greater inner canthal distances, and taller
        frontal bone heights.
      explanation: >-
        Expression of the Noonan SHP2 Q79R allele restricted to neural crest
        cells produced craniofacial defects, placing the neural crest
        downstream of ERK cascade hyperactivation rather than in parallel
        to it.
    - reference: PMID:19706403
      reference_title: "Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data show that normal ERK1/2 signaling in the neural crest is
        imperative for normal craniofacial development
      explanation: >-
        States the ERK-in-neural-crest requirement directly; MEK inhibition
        during pregnancy reversed the defects, establishing the edge as
        ERK-dependent rather than merely correlated.
  - target: Cardiac Valve Morphogenesis Defects
    description: Perturbed ERK signaling alters endocardial-mesenchymal transition during valve development.
    evidence:
    - reference: PMID:11992261
      reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ...pulmonic stenosis was more prevalent among the group of subjects with
        NS who had PTPN11 mutations than it was in the group without them
        (70.6% vs. 46.2%; P<.01)...
      explanation: >-
        Supports a mechanistic link from upstream RAS-MAPK dysregulation to
        abnormal cardiac valve development outcomes in Noonan syndrome.
  - target: Cardiomyocyte Hypertrophy
    description: Sustained ERK signaling promotes hypertrophic growth and fetal gene reprogramming.
    evidence:
    - reference: DOI:10.1126/sciadv.adf4766
      reference_title: "RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Consistent with aberrant RAF/MAPK activation as a driver of disease, we
        show that pathway inhibition alleviates cardiac hypertrophy in a mouse
        model of RIT1 mutant Noonan syndrome.
      explanation: >-
        Reversibility of hypertrophy with MAPK-pathway inhibition supports ERK
        cascade hyperactivation as a proximal hypertrophic driver.
  - target: Cortical Layer Development Abnormalities
    description: >-
      Sustained RAS-MAPK signaling perturbs cortical neuronal lineage patterning
      and synaptic maturation programs in Noonan syndrome models.
    evidence:
    - reference: GEO:GSE213798
      reference_title: "Aberrant cortical layer development of brain organoids developed from Noonan syndrome-iPSCs"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        single-cell transcriptomic analysis represented increment of EN
        population and overexpression of cortical layer markers in NS-COs.
      explanation: >-
        Supports a downstream neurodevelopmental consequence of pathway
        dysregulation in NS-derived cortical organoid models.
  - target: Lymphatic Structural Abnormalities
    description: >-
      RAS-MAPK pathway overactivation contributes to clinically severe lymphatic
      anomalies in Noonan syndrome.
    evidence:
    - reference: DOI:10.3389/fped.2025.1475143
      reference_title: "Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most are dominant gain-of-function variants that cause an overactivation
        of the RAS/MAPK signaling pathway leading to uncontrolled cell
        proliferation in many organs and systems.
      explanation: >-
        Supports pathway overactivation as an upstream driver for systemic,
        including lymphatic, NS manifestations.
  - target: Growth Plate Chondrocyte Differentiation Defect
    description: >-
      ERK hyperactivation in growth plate cartilage impairs chondrocyte
      differentiation and endochondral bone growth.
    evidence:
    - reference: PMID:29659837
      reference_title: "Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In conclusion, we demonstrated that hyperactive NS-causing SHP2 mutants
        impair chondrocyte differentiation during endochondral bone growth
        through a local hyperactivation of the RAS/ERK signalling pathway,
      explanation: >-
        Directly supports ERK-driven growth plate dysfunction as a mechanism
        for growth impairment in Noonan syndrome.
  - target: Congenital Cardiac Structural Defects
    description: >-
      Dysregulated embryonic cardiac development in Noonan syndrome produces
      septation defects and additional right-sided outflow lesions beyond
      pulmonary valve dysplasia.
    evidence:
    - reference: PMID:20301303
      reference_title: "Noonan Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other structural defects include atrial and ventricular septal defects,
        branch pulmonary artery stenosis, and tetralogy of Fallot.
      explanation: >-
        Supports an additional congenital structural-heart-disease branch within
        the Noonan pathograph.
  - target: RASopathy Neoplastic Predisposition
    description: >-
      Chronic dysregulation of the RAS-MAPK pathway in Noonan syndrome
      contributes to elevated risk of benign and malignant neoplasms.
    evidence:
    - reference: DOI:10.1158/1078-0432.ccr-24-1611
      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: HUMAN_CLINICAL
      snippet: >-
        Neurofibromatosis type 1 (NF1), Noonan syndrome, and related syndromes,
        grouped as RASopathies, result from dysregulation of the RAS-MAPK
        pathway and demonstrate varied multisystemic clinical phenotypes.
      explanation: >-
        This surveillance review anchors Noonan neoplastic predisposition to the
        same pathway dysregulation that drives other RASopathy complications.
  - target: Hypertelorism
  - target: High Palate
  - target: Triangular Face
  - target: Downslanted Palpebral Fissures
  - target: Ptosis
  - target: Strabismus
  - target: Low-set Ears
  - target: Posteriorly Rotated Ears
  - target: Cryptorchidism
  - target: Hypogonadotropic Hypogonadism
  - target: Hearing Loss
  - target: Peripheral Neuropathy
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and
      Noonan syndrome mutants enhance ERK activation ex vivo and in mice.
    explanation: >-
      Supports ERK cascade hyperactivation as a convergent signaling consequence
      of NS-associated upstream mutations.
  - reference: PMID:32721402
    reference_title: "Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pathogenic variants promote increased phosphorylation of the kinase, which
      enhances translocation to the nucleus and boosts MAPK signaling
    explanation: >-
      States that the MAPK1 genotype raises MAPK signaling output, which is the
      state this node asserts and the reason MAPK1 is bound here.

- name: Growth Plate Chondrocyte Differentiation Defect
  description: >-
    Local RAS-ERK hyperactivation in the growth plate impairs chondrocyte
    differentiation during endochondral bone growth, contributing to the
    characteristic postnatal growth impairment of Noonan syndrome.
  biological_processes:
  - preferred_term: chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:29659837
    reference_title: "Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Growth retardation is a constant feature of Noonan syndrome (NS) but its
      physiopathology remains poorly understood.
    explanation: >-
      Frames this growth plate defect as a disease-relevant explanatory branch
      for the short-stature phenotype in Noonan syndrome.
  downstream:
  - target: Short Stature
    description: >-
      Impaired endochondral bone growth reduces linear growth and contributes to
      short stature.
    evidence:
    - reference: PMID:29659837
      reference_title: "Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In conclusion, we demonstrated that hyperactive NS-causing SHP2 mutants
        impair chondrocyte differentiation during endochondral bone growth
        through a local hyperactivation of the RAS/ERK signalling pathway,
      explanation: >-
        Supports impaired chondrocyte differentiation as a proximal cause of
        reduced linear growth in Noonan syndrome.
  - target: Pectus Deformity
  - target: Pectus Carinatum
  - target: Joint Hypermobility
  - target: Scoliosis
  - target: Delayed Skeletal Maturation

- name: Cortical Layer Development Abnormalities
  description: >-
    NS-derived cortical organoid models show abnormal excitatory-neuron layer
    specification and reduced synaptic connectivity, consistent with
    neurodevelopmental pathway disruption.
  biological_processes:
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  downstream:
  - target: Global Developmental Delay
    description: >-
      Perturbed cortical development and connectivity likely contributes to
      delayed neurodevelopmental trajectories.
    evidence:
    - reference: GEO:GSE213798
      reference_title: "Aberrant cortical layer development of brain organoids developed from Noonan syndrome-iPSCs"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Collectively, our findings suggest that perturbed cortical layer
        identity and impeded neuronal connectivity account for the neurological
        manifestations of NS.
      explanation: >-
        Supports mechanistic linkage from cortical developmental defects to
        global developmental phenotypes in NS.
  - target: Mild Intellectual Disability
    description: >-
      Abnormal cortical-layer identity and synaptic organization can contribute
      to persistent cognitive impairment in a subset of patients.
    evidence:
    - reference: GEO:GSE213798
      reference_title: "Aberrant cortical layer development of brain organoids developed from Noonan syndrome-iPSCs"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Collectively, our findings suggest that perturbed cortical layer
        identity and impeded neuronal connectivity account for the neurological
        manifestations of NS.
      explanation: >-
        Supports a biologically plausible causal route to intellectual and
        learning phenotypes in Noonan syndrome.
  - target: Hypotonia
  - target: Feeding Difficulties in Infancy
  evidence:
  - reference: GEO:GSE213798
    reference_title: "Aberrant cortical layer development of brain organoids developed from Noonan syndrome-iPSCs"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly, EN subpopulation co-expressing upper layer marker SATB2 and
      deep layer maker CTIP2 was enriched in NS-COs during the cortical
      development.
    explanation: >-
      Provides direct transcriptomic evidence of abnormal cortical layering in
      NS-derived organoid models.

- name: Lymphatic Structural Abnormalities
  description: >-
    Noonan syndrome can include severe central and peripheral lymphatic
    abnormalities that produce clinically significant fluid and lymphatic-flow
    complications.
  biological_processes:
  - preferred_term: lymphangiogenesis
    term:
      id: GO:0001946
      label: lymphangiogenesis
  cell_types:
  - preferred_term: endothelial cell of lymphatic vessel
    term:
      id: CL:0002138
      label: endothelial cell of lymphatic vessel
  downstream:
  - target: Increased Nuchal Translucency
    description: >-
      Prenatal lymphatic dysfunction can manifest as increased nuchal fluid on
      fetal ultrasound.
    evidence:
    - reference: PMID:17222357
      reference_title: "Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        NS should be considered in all foetuses with polyhydramnion, pleural
        effusions, oedema and increased nuchal fluid with a normal karyotype.
      explanation: >-
        Supports increased nuchal translucency or fluid as a prenatal
        manifestation of the lymphatic disease branch in Noonan syndrome.
  - target: Lymphedema
    description: >-
      Structural and flow abnormalities in lymphatic channels manifest clinically
      as peripheral or generalized lymphedema.
    evidence:
    - reference: PMID:38618951
      reference_title: "Central conducting lymphatic anomaly: from bench to bedside."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CCLA...may present with nonimmune fetal hydrops, chylothorax, chylous
        ascites, or lymphedema.
      explanation: >-
        Supports lymphedema as a downstream clinical consequence of central
        lymphatic structural pathology.
  - target: Chylothorax
    description: >-
      Central conducting lymphatic dysfunction can produce chylous pleural
      effusions.
    evidence:
    - reference: PMID:38618951
      reference_title: "Central conducting lymphatic anomaly: from bench to bedside."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CCLA...may present with nonimmune fetal hydrops, chylothorax, chylous
        ascites, or lymphedema.
      explanation: >-
        Supports chylothorax as a direct downstream consequence of the Noonan
        lymphatic-anomaly branch.
  - target: Thickened Nuchal Skin Fold
  - target: Cystic Hygroma
  - target: Webbed Neck
  evidence:
  - reference: DOI:10.3389/fped.2025.1475143
    reference_title: "Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Albeit phenotypically heterogeneous, NS can be associated with severe
      cardiovascular and lymphatic anomalies, potentially lethal during infancy,
      neonatal and fetal periods.
    explanation: >-
      Supports the presence of clinically severe lymphatic disease as part of
      the Noonan syndrome pathophysiologic spectrum.

- name: Hematologic Dysregulation
  description: >-
    PTPN11-associated Noonan syndrome can include mutation-associated bleeding
    diathesis and predisposition to juvenile myelomonocytic leukemia, indicating
    a distinct hematologic disease branch.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  evidence:
  - reference: PMID:15240615
    reference_title: "Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hematological abnormalities, such as bleeding diathesis and juvenile
      myelomonocytic leukemia, were exclusively present in mutation-positive
      patients (5 of 18 vs. 0 of 27; P = 0.007).
    explanation: >-
      Supports a clinically distinct hematologic branch in PTPN11-positive
      Noonan syndrome.
  downstream:
  - target: Bruising Susceptibility
    description: >-
      Bleeding diathesis and coagulation abnormalities manifest clinically as
      easy bruising or excessive bleeding.
    evidence:
    - reference: PMID:15240615
      reference_title: "Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        hematological abnormalities, such as bleeding diathesis and juvenile
        myelomonocytic leukemia, were exclusively present in mutation-positive
        patients (5 of 18 vs. 0 of 27; P = 0.007).
      explanation: >-
        Supports bleeding diathesis as a proximal hematologic cause of bruising
        susceptibility in Noonan syndrome.
  - target: Juvenile Myelomonocytic Leukemia
    description: >-
      Myeloid dysregulation in susceptible genotypes can progress to JMML in a
      small subset of affected individuals.
    evidence:
    - reference: PMID:15723289
      reference_title: "Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In one patient with NS and mild juvenile myelomonocytic leukemia (JMML)
        the mutation 218C --> T (Thr73Ile) was found. This confirms previous
        findings indicating that individuals with NS with specific mutations in
        PTPN11 are at risk of developing JMML.
      explanation: >-
        Supports JMML as a downstream hematologic malignancy in a subset of
        PTPN11-associated Noonan syndrome.
  - target: Abnormal Bleeding
  - target: Abnormality of Coagulation

- name: Cardiac Valve Morphogenesis Defects
  description: >-
    In endocardial and valvular tissues, perturbed ERK signaling alters
    endocardial-mesenchymal transition and valve morphogenesis, underlying
    pulmonary valve stenosis, the most common cardiac defect in Noonan syndrome.
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition involved in endocardial cushion formation
    term:
      id: GO:0003198
      label: epithelial to mesenchymal transition involved in endocardial cushion formation
  - preferred_term: heart valve morphogenesis
    term:
      id: GO:0003179
      label: heart valve morphogenesis
  cell_types:
  - preferred_term: endocardial cell
    term:
      id: CL:0002350
      label: endocardial cell
  locations:
  - preferred_term: pulmonary valve
    term:
      id: UBERON:0002146
      label: pulmonary valve
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01)"
    explanation: Demonstrates that pulmonary valve stenosis is highly associated with PTPN11 mutations in Noonan syndrome.
  downstream:
  - target: Pulmonary Valve Stenosis
    description: >-
      Valve morphogenesis defects in the pulmonary outflow tract manifest as
      dysplastic pulmonary valve stenosis.
    evidence:
    - reference: PMID:11992261
      reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ...pulmonic stenosis was more prevalent among the group of subjects with
        NS who had PTPN11 mutations than it was in the group without them
        (70.6% vs. 46.2%; P<.01)...
      explanation: >-
        Supports direct phenotypic consequence of valvulogenesis defects as
        pulmonary valve stenosis.
- name: Congenital Cardiac Structural Defects
  description: >-
    Beyond pulmonary valve dysplasia, disturbed embryonic cardiac morphogenesis
    in Noonan syndrome can produce septation defects and branch pulmonary artery
    abnormalities.
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other structural defects include atrial and ventricular septal defects,
      branch pulmonary artery stenosis, and tetralogy of Fallot.
    explanation: >-
      GeneReviews supports a broader congenital structural-heart-disease branch
      in Noonan syndrome beyond pulmonary valve stenosis alone.
  downstream:
  - target: Atrial Septal Defect
    description: >-
      Abnormal cardiac septation can manifest as secundum or other atrial
      septal defects.
    evidence:
    - reference: PMID:20301303
      reference_title: "Noonan Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other structural defects include atrial and ventricular septal defects,
        branch pulmonary artery stenosis, and tetralogy of Fallot.
      explanation: >-
        Supports atrial septal defect as a downstream expression of the
        congenital cardiac structural-defect branch.
  - target: Ventricular Septal Defect
    description: >-
      Abnormal ventricular septation can produce clinically significant
      ventricular septal defects.
    evidence:
    - reference: PMID:20301303
      reference_title: "Noonan Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other structural defects include atrial and ventricular septal defects,
        branch pulmonary artery stenosis, and tetralogy of Fallot.
      explanation: >-
        Supports ventricular septal defect as a downstream expression of
        abnormal cardiac morphogenesis in Noonan syndrome.
  - target: Branch Pulmonary Artery Stenosis
    description: >-
      Aberrant development of the pulmonary outflow tract can narrow the branch
      pulmonary arteries.
    evidence:
    - reference: PMID:20301303
      reference_title: "Noonan Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other structural defects include atrial and ventricular septal defects,
        branch pulmonary artery stenosis, and tetralogy of Fallot.
      explanation: >-
        Supports branch pulmonary artery stenosis as part of the structural
        congenital heart disease branch in Noonan syndrome.

- name: RASopathy Neoplastic Predisposition
  description: >-
    Noonan syndrome shares the broader RASopathy tendency toward benign and
    malignant neoplasia, reflecting chronic developmental dysregulation of the
    RAS-MAPK pathway.
  evidence:
  - reference: DOI:10.1158/1078-0432.ccr-24-1611
    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: HUMAN_CLINICAL
    snippet: >-
      When compared with the general population, children with RASopathies are
      at significantly increased risk of benign and malignant neoplasms.
    explanation: >-
      Supports a pathway-linked neoplastic predisposition branch for Noonan
      syndrome within the broader RASopathy family.
  downstream:
  - target: Tumor Predisposition
    description: >-
      This shared RASopathy cancer-predisposition branch manifests clinically as
      increased risk of diverse solid and hematologic neoplasms.
    evidence:
    - reference: PMID:19953625
      reference_title: "Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Three patients with SOS1 mutations presented with tumors (embryonal
        rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of
        the skin). One patient with a RAF1 mutation had a lesion suggestive for a
        giant cell tumor.
      explanation: >-
        Provides phenotype-level evidence for the tumor-predisposition outcome of
        this oncologic branch in Noonan syndrome.
  - target: Neuroblastoma
    description: >-
      Neuroblastoma has been reported in people with germline mutations in
      RAS-pathway (RASopathy) genes, including people with Noonan syndrome,
      which places it within the reported tumor spectrum of this shared
      predisposition. The cited consensus reports cases rather than a measured
      risk, and it gives no neuroblastoma risk figure for Noonan syndrome.
    evidence:
    - reference: PMID:28674118
      reference_title: "Retinoblastoma and Neuroblastoma Predisposition and Surveillance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: "In addition to ALK and PHOX2B, NB has been reported in individuals with germline mutations in genes involved in the RAS pathway (RASopathies). This includes Costello syndrome (HRAS gene), Noonan syndrome (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, MEK1, and RIT1 genes), neurofibromatosis type 1 (NF1), and others (90-96)."
      explanation: >-
        Kamihara et al. (2017), the consensus paper from the AACR Childhood
        Cancer Predisposition Workshop on hereditary retinoblastoma and
        neuroblastoma, states in its review of neuroblastoma predisposition
        genes that neuroblastoma (NB) has been reported in people with germline
        mutations in RAS pathway genes (the RASopathies). It names Noonan
        syndrome, with the genes the paper lists for it, among them. That
        places NB within the reported tumor spectrum of the shared RASopathy
        predisposition. The passage reports cases, not a mechanism or a
        measured risk, and the same paragraph hedges further: it says the
        reported NF1 cases may be attributed to fortuitous coincidence, and
        that NB may be frequent enough to warrant surveillance in Costello
        syndrome and perhaps some forms of Noonan syndrome, without naming the
        forms or giving a frequency. So this is INDIRECT support for the causal
        edge.

- name: Cardiomyocyte Hypertrophy
  description: >-
    In cardiomyocytes, sustained ERK signaling (and intersecting AKT/mTOR activity)
    promotes hypertrophic growth and fetal gene reprogramming, leading to
    hypertrophic cardiomyopathy, particularly in patients with RAF1 and RIT1 mutations.
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Demonstrates strong association between RAF1 mutations and HCM, implicating the kinase pathway in cardiac hypertrophy.
  - reference: PMID:23791108
    reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome."
    explanation: RIT1 mutations are strongly associated with hypertrophic cardiomyopathy.
  downstream:
  - target: Hypertrophic Cardiomyopathy
    description: >-
      Persistent cardiomyocyte hypertrophic remodeling yields clinical
      hypertrophic cardiomyopathy.
    evidence:
    - reference: PMID:17603483
      reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%)
        showed hypertrophic cardiomyopathy (HCM)...
      explanation: >-
        Supports direct connection from hypertrophic cardiomyocyte remodeling to
        overt HCM phenotype in NS.
  - target: Abnormal EKG
  - target: Arrhythmia

- name: Neural Crest Cell Developmental Dysregulation
  biological_scale: CELLULAR
  description: >-
    The neural crest is the lineage in which the RAS-MAPK lesion reaches the
    conotruncal and craniofacial features of Noonan syndrome. Neural crest cells
    populate the cardiac outflow tract and supply a large share of the facial and
    cranial skeleton, and SHP2 is separately required within them: ablating
    PTPN11 in premigratory neural crest blocks outflow-tract colonisation and
    produces persistent truncus arteriosus with pronounced craniofacial deficits,
    while driving the Noonan SHP2 Q79R allele in neural crest is by itself enough
    to cause craniofacial malformation. Modelling this as an explicit node makes
    the neural crest step visible instead of leaving the craniofacial and
    conotruncal outcomes hanging directly off the ERK node.

    The `modifier` on neural crest cell migration is deliberately DYSREGULATED
    rather than INCREASED or DECREASED: the direction is not fixed across
    lesions. Loss of SHP2 in neural crest impairs migration into the outflow
    tract, whereas at least one Noonan-spectrum missense variant has been
    reported to drive excessive migration. Which lesions move it which way, and
    whether that is ERK-dependent, is captured as an open question in
    `discussions` (`noonan_erk_magnitude_vs_neural_crest_phenotype`).
  genes:
  - preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  cell_types:
  - preferred_term: migratory neural crest cell
    term:
      id: CL:0000333
      label: migratory neural crest cell
  biological_processes:
  - preferred_term: neural crest cell migration
    term:
      id: GO:0001755
      label: neural crest cell migration
    modifier: DYSREGULATED
  - preferred_term: neural crest cell development
    term:
      id: GO:0014032
      label: neural crest cell development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19541608
    reference_title: "Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The data show that SHP2 activity in the NCC is essential for normal
      migration and differentiation into the diverse lineages found in the heart
      and skull
    explanation: >-
      Establishes the neural crest as a lineage with its own SHP2 requirement
      for both of the organ systems Noonan syndrome affects most
      characteristically.
  - reference: PMID:20493809
    reference_title: "Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we identify a phosphatase- and Erk-dependent role for Shp2 in neural crest
      specification and migration
    explanation: >-
      Independent (zebrafish) confirmation that Shp2 acts in neural crest
      specification and migration, and that this arm of its function is
      ERK-dependent.
  downstream:
  - target: Congenital Cardiac Structural Defects
    description: >-
      Neural crest cells that fail to colonise the developing outflow tract
      leave conotruncal and great-vessel malformations.
    evidence:
    - reference: PMID:19541608
      reference_title: "Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        SHP2-deficient NCCs initially exhibited normal migratory and
        proliferative patterns, but in the developing heart failed to migrate
        into the developing outflow tract.
      explanation: >-
        Directly links the neural crest migration defect to outflow-tract
        malformation; the same embryos showed persistent truncus arteriosus and
        great-vessel abnormalities.
  - target: Hypertelorism
    description: >-
      Neural-crest-derived frontonasal skeleton is affected, widening the
      interorbital distance.
    evidence:
    - reference: PMID:19706403
      reference_title: "Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hyperactivation of ERK1/2 led to craniofacial defects that included
        smaller skull lengths, greater inner canthal distances, and taller
        frontal bone heights.
      explanation: >-
        Increased inner canthal distance in neural-crest-targeted Q79R mice is
        the model correlate of the hypertelorism/telecanthus seen clinically.
  - target: Triangular Face
    description: >-
      Reduced skull length with altered mandibular proportion in
      neural-crest-targeted models parallels the Noonan facial gestalt.
    evidence:
    - reference: PMID:19706403
      reference_title: "Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In proportion to the smaller skull length, mandibular bone length was
        also reduced.
      explanation: >-
        Supports altered craniofacial proportion, rather than isolated bone
        loss, as the neural-crest-mediated output.

phenotypes:
- category: Prenatal
  name: Increased Nuchal Translucency
  phenotype_term:
    preferred_term: Increased nuchal translucency
    term:
      id: HP:0010880
      label: Increased nuchal translucency
  description: >-
    Increased nuchal fluid or translucency on prenatal ultrasound can be an early
    clue to Noonan syndrome, especially when the fetal karyotype is normal.
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NS should be considered in all foetuses with polyhydramnion, pleural
      effusions, oedema and increased nuchal fluid with a normal karyotype.
    explanation: >-
      Supports increased nuchal translucency or fluid as a recognizable prenatal
      Noonan syndrome manifestation.
- category: Prenatal and Birth
  name: Thickened Nuchal Skin Fold
  phenotype_term:
    preferred_term: Thickened nuchal skin fold
    term:
      id: HP:0000474
      label: Thickened nuchal skin fold
  description: >-
    Thickened nuchal tissue or excess posterior neck skin is a frequent prenatal
    and early-life manifestation of Noonan syndrome lymphatic dysplasia.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000474 | Thickened nuchal skin fold | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports thickened nuchal skin fold as very frequent in Noonan syndrome.
- category: Prenatal and Birth
  name: Cystic Hygroma
  phenotype_term:
    preferred_term: Cystic hygroma
    term:
      id: HP:0000476
      label: Cystic hygroma
  description: >-
    Prenatal cystic hygroma can occur as part of the Noonan syndrome lymphatic
    dysplasia spectrum.
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000476 | Cystic hygroma | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports cystic hygroma as a Noonan syndrome-associated prenatal lymphatic phenotype; frequency is not asserted here because prenatal ascertainment may inflate the structured frequency band.
- category: Craniofacial
  name: Hypertelorism
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  description: >-
    Widely spaced eyes are a characteristic facial feature of Noonan syndrome.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 22-year-old woman presented with typical dysmorphic features of NS,
      including short stature, broad forehead, hypertelorism, low-set
      posteriorly rotated ears, and a broad neck.
    explanation: >-
      Supports hypertelorism as part of the characteristic craniofacial
      phenotype in clinically diagnosed Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000316 | Hypertelorism | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports hypertelorism as very frequent in Noonan syndrome.
- category: Head and Neck
  name: High Palate
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  description: >-
    A high-arched palate is part of the craniofacial phenotype spectrum of
    Noonan syndrome.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000218 | High palate | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports high palate as very frequent in Noonan syndrome.
- category: Head and Neck
  name: Triangular Face
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  description: >-
    A triangular facial shape is a common component of the evolving Noonan
    syndrome facial gestalt.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000325 | Triangular face | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports triangular face as very frequent in Noonan syndrome.
- category: Craniofacial
  name: Downslanted Palpebral Fissures
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  description: >-
    Downward slanting of the eye openings is a common facial feature.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main facial features of NS are hypertelorism with down-slanting
      palpebral fissures, ptosis and low-set posteriorly rotated ears with a
      thickened helix.
    explanation: >-
      Review evidence explicitly identifies down-slanting palpebral fissures
      as a main facial feature in Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000494 | Downslanted palpebral fissures | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports downslanted palpebral fissures as very frequent in Noonan syndrome.
- category: Craniofacial
  name: Ptosis
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  description: >-
    Drooping of the upper eyelids is frequently observed.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main facial features of NS are hypertelorism with down-slanting
      palpebral fissures, ptosis and low-set posteriorly rotated ears with a
      thickened helix.
    explanation: >-
      Review evidence explicitly identifies ptosis as a core facial feature in
      Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000508 | Ptosis | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports ptosis as very frequent in Noonan syndrome.
- category: Eye
  name: Strabismus
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  description: >-
    Ocular misalignment is a frequent ophthalmologic manifestation requiring
    vision surveillance in Noonan syndrome.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000486 | Strabismus | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation supports strabismus as frequent in Noonan syndrome.
- category: Craniofacial
  name: Low-set Ears
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  description: >-
    Posteriorly rotated, low-set ears are characteristic.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 22-year-old woman presented with typical dysmorphic features of NS,
      including short stature, broad forehead, hypertelorism, low-set
      posteriorly rotated ears, and a broad neck.
    explanation: >-
      Case-based clinical evidence supports low-set/posteriorly rotated ears
      as a characteristic facial finding in Noonan syndrome.
- category: Head and Neck
  name: Posteriorly Rotated Ears
  phenotype_term:
    preferred_term: Posteriorly rotated ears
    term:
      id: HP:0000358
      label: Posteriorly rotated ears
  description: >-
    Posterior rotation of the ears is a characteristic ear-position finding in
    Noonan syndrome and is often described together with low-set ears.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 22-year-old woman presented with typical dysmorphic features of NS,
      including short stature, broad forehead, hypertelorism, low-set
      posteriorly rotated ears, and a broad neck.
    explanation: >-
      Case-based clinical evidence supports posteriorly rotated ears as part of
      the characteristic Noonan syndrome facial phenotype.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000358 | Posteriorly rotated ears | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports posteriorly rotated ears as very frequent in Noonan syndrome.
- category: Craniofacial
  name: Webbed Neck
  phenotype_term:
    preferred_term: Webbed neck
    term:
      id: HP:0000465
      label: Webbed neck
  description: >-
    Excess skin on the lateral neck creating a webbed appearance.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other associated features are webbed neck, chest deformity, mild
      intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding
      tendency and lymphatic dysplasias.
    explanation: >-
      Review evidence explicitly identifies webbed neck as a recognized
      associated feature in Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000465 | Webbed neck | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports webbed neck as very frequent in Noonan syndrome.
- category: Cardiovascular
  name: Pulmonary Valve Stenosis
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  description: >-
    Dysplastic pulmonary valve stenosis is the most common cardiac defect, occurring
    in approximately 50-60% of patients. Associated with PTPN11 and SOS1 genotypes.
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01)"
    explanation: Confirms high prevalence of pulmonary stenosis in Noonan syndrome, especially with PTPN11 mutations.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001641 | Abnormal pulmonary valve morphology | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation for abnormal pulmonary valve morphology directly supports the pulmonary valve stenosis phenotype in this entry at a frequent classification.
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  description: >-
    Left ventricular hypertrophy occurring in approximately 20% of patients overall,
    but up to 70-95% in those with RAF1 or RIT1 mutations. Can be present
    at birth or develop during infancy.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: RAF1 mutations are strongly associated with HCM.
  - reference: PMID:23791108
    reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome."
    explanation: RIT1 mutations confer high risk of hypertrophic cardiomyopathy.
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005)"
    explanation: PTPN11 mutations are associated with lower HCM risk compared to other NS genes.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001639 | Hypertrophic cardiomyopathy | Occasional (29-5%)"
    explanation: Orphanet classifies hypertrophic cardiomyopathy as occasional in Noonan syndrome overall, consistent with the approximately 20% general prevalence cited here.
- category: Cardiovascular
  name: Abnormal EKG
  phenotype_term:
    preferred_term: Abnormal EKG
    term:
      id: HP:0003115
      label: Abnormal EKG
  description: >-
    Electrocardiographic abnormalities are common in Noonan syndrome and may
    accompany structural heart disease or cardiomyopathy surveillance.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003115 | Abnormal EKG | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports abnormal EKG as very frequent in Noonan syndrome.
- category: Cardiovascular
  name: Arrhythmia
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  description: >-
    Cardiac rhythm abnormalities are part of the broader cardiovascular
    phenotype spectrum in Noonan syndrome.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011675 | Arrhythmia | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation supports arrhythmia as frequent in Noonan syndrome.
- category: Cardiovascular
  name: Atrial Septal Defect
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  description: >-
    Atrial septal defects occur in 6-10% of individuals with Noonan syndrome.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41718520
    reference_title: "Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An infant presented with a large secundum atrial septal defect
      complicating NS-HCM.
    explanation: >-
      Supports atrial septal defect as a documented structural cardiac
      manifestation in Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001631 | Atrial septal defect | Occasional (29-5%)"
    explanation: Orphanet phenotype annotation supports atrial septal defect as occasional in Noonan syndrome.
- category: Cardiovascular
  name: Ventricular Septal Defect
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  description: >-
    Ventricular septal defects are part of the broader congenital heart disease
    spectrum in Noonan syndrome.
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other structural defects include atrial and ventricular septal defects,
      branch pulmonary artery stenosis, and tetralogy of Fallot.
    explanation: >-
      GeneReviews identifies ventricular septal defect as part of the structural
      cardiac phenotype spectrum in Noonan syndrome.
- category: Cardiovascular
  name: Branch Pulmonary Artery Stenosis
  phenotype_term:
    preferred_term: Branch pulmonary artery stenosis
    term:
      id: HP:0004969
      label: Peripheral pulmonary artery stenosis
  description: >-
    Peripheral or branch pulmonary artery stenosis is a recognized additional
    right-sided outflow lesion in Noonan syndrome.
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other structural defects include atrial and ventricular septal defects,
      branch pulmonary artery stenosis, and tetralogy of Fallot.
    explanation: >-
      GeneReviews identifies branch pulmonary artery stenosis as part of the
      Noonan congenital heart disease spectrum.
- category: Growth
  name: Short Stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  description: >-
    Postnatal growth retardation resulting in adult height typically at or below the
    third percentile for the general population. Linked to RAS/MAPK effects on GH
    signaling and chondrocyte differentiation.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:41577878
    reference_title: "Noonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Short stature is a key NSSD feature.
    explanation: >-
      Large multicenter Noonan-spectrum cohort data support short stature as a
      prevalent and clinically significant growth phenotype.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004322 | Short stature | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports short stature as very frequent in Noonan syndrome.
- category: Musculoskeletal
  name: Pectus Deformity
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  description: >-
    Chest wall deformities including pectus excavatum and pectus carinatum are common.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups."
    explanation: Pectus deformity is recognized as a common feature across genotypes.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000767 | Pectus excavatum | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation classifies pectus excavatum as very frequent in Noonan syndrome.
- category: Musculoskeletal
  name: Pectus Carinatum
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  description: >-
    Superior pectus carinatum can occur with inferior pectus excavatum as part
    of the characteristic Noonan syndrome chest-wall configuration.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings can include broad or webbed neck, unusual chest shape with
      superior pectus carinatum and inferior pectus excavatum,
    explanation: >-
      GeneReviews identifies pectus carinatum as part of the characteristic
      chest-wall phenotype in Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000768 | Pectus carinatum | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports pectus carinatum as very frequent in Noonan syndrome.
- category: Musculoskeletal
  name: Joint Hypermobility
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  description: >-
    Increased joint mobility is a common musculoskeletal feature of Noonan
    syndrome.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001382 | Joint hypermobility | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports joint hypermobility as very frequent in Noonan syndrome.
- category: Musculoskeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  description: >-
    Spinal curvature is a recurrent musculoskeletal manifestation in Noonan
    syndrome.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002650 | Scoliosis | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation supports scoliosis as frequent in Noonan syndrome.
- category: Musculoskeletal
  name: Delayed Skeletal Maturation
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  description: >-
    Delayed skeletal maturation can accompany postnatal growth impairment in
    Noonan syndrome.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002750 | Delayed skeletal maturation | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation supports delayed skeletal maturation as frequent in Noonan syndrome.
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  description: >-
    Undescended testes in males is a common finding.
  frequency: FREQUENT
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups."
    explanation: Cryptorchidism is recognized as a common feature across Noonan syndrome genotypes.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000028 | Cryptorchidism | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation supports cryptorchidism as frequent in Noonan syndrome.
- category: Endocrine
  name: Hypogonadotropic Hypogonadism
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  description: >-
    Pubertal and gonadal-axis abnormalities can occur in Noonan syndrome,
    including hypogonadotropic hypogonadism.
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000044 | Hypogonadotropic hypogonadism | Very frequent (99-80%)"
    explanation: Orphanet phenotype annotation supports hypogonadotropic hypogonadism as an associated Noonan syndrome phenotype; frequency is not asserted here because the broader literature more consistently supports pubertal delay than 80-99% prevalence of frank hypogonadotropic hypogonadism.
- category: Hematologic
  name: Bruising Susceptibility
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  description: >-
    Coagulation defects including factor XI deficiency and platelet dysfunction,
    leading to easy bruising and prolonged bleeding after surgery or trauma.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24444506
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected individuals have 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.
    explanation: >-
      This clinical review supports bleeding tendency/easy bruising as a recognized
      hematologic phenotype in Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000978 | Bruising susceptibility | Occasional (29-5%)"
    explanation: Orphanet phenotype annotation supports bruising susceptibility as occasional in Noonan syndrome.
- category: Blood
  name: Abnormal Bleeding
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  description: >-
    Excessive or abnormal bleeding can occur in Noonan syndrome, especially in
    individuals with coagulation-factor defects or platelet dysfunction.
  frequency: FREQUENT
  evidence:
  - reference: PMID:24444506
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected individuals have 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.
    explanation: >-
      Clinical review evidence identifies increased bleeding tendency as part of
      the Noonan syndrome phenotype spectrum.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001892 | Abnormal bleeding | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation supports abnormal bleeding as frequent in Noonan syndrome.
- category: Blood
  name: Abnormality of Coagulation
  phenotype_term:
    preferred_term: Abnormality of coagulation
    term:
      id: HP:0001928
      label: Abnormality of coagulation
  description: >-
    Coagulation abnormalities are part of the Noonan syndrome bleeding
    diathesis and can affect perioperative management.
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    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 identifies varied coagulation defects as a recognized Noonan
      syndrome finding.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001928 | Abnormality of coagulation | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation supports abnormality of coagulation as frequent in Noonan syndrome.
- category: Oncologic
  name: Tumor Predisposition
  phenotype_term:
    preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
    coarse_binding_basis: PATHOGRAPH_HUB
  notes: >-
    Bound at HP:0002664 deliberately. RASopathy Neoplastic Predisposition is the
    only node that targets this one. Its one other edge reaches Neuroblastoma,
    one specific tumour from the reported spectrum, curated as its own phenotype
    beside this node, so the mechanism converges here rather than this being
    one arm of a wide fan-out, and the coarseness is a property of the biology:
    germline RAS/MAPK hyperactivation raises risk across haematopoietic and
    solid lineages instead of producing one characteristic tumour. The reported tumours differ by
    genotype, so no narrower HP term is the right binding for the node the
    mechanism reaches.
  description: >-
    Noonan syndrome confers increased susceptibility to both hematologic and
    solid neoplasms, with reported tumors including rhabdomyosarcoma, Sertoli
    cell tumor, granular cell tumors, and giant cell tumor-like lesions in
    specific genotypic subsets.
  evidence:
  - reference: PMID:19953625
    reference_title: "Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients with SOS1 mutations presented with tumors (embryonal
      rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of
      the skin). One patient with a RAF1 mutation had a lesion suggestive for a
      giant cell tumor.
    explanation: >-
      Supports a clinically relevant tumor predisposition phenotype in Noonan
      syndrome, particularly in SOS1- and RAF1-associated disease.
- category: Oncologic
  name: Juvenile Myelomonocytic Leukemia
  phenotype_term:
    preferred_term: Juvenile myelomonocytic leukemia
    term:
      id: HP:0012209
      label: Juvenile myelomonocytic leukemia
  description: >-
    A subset of individuals with Noonan syndrome, especially with specific
    PTPN11 variants, can develop juvenile myelomonocytic leukemia as part of
    the syndrome's hematologic cancer predisposition spectrum.
  evidence:
  - reference: PMID:15240615
    reference_title: "Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hematological abnormalities, such as bleeding diathesis and juvenile
      myelomonocytic leukemia, were exclusively present in mutation-positive
      patients (5 of 18 vs. 0 of 27; P = 0.007).
    explanation: >-
      OMIM/HPOA-linked cohort data support juvenile myelomonocytic leukemia as
      a recognized hematologic malignancy in PTPN11-associated Noonan syndrome.
  - reference: PMID:15723289
    reference_title: "Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In one patient with NS and mild juvenile myelomonocytic leukemia (JMML)
      the mutation 218C --> T (Thr73Ile) was found. This confirms previous
      findings indicating that individuals with NS with specific mutations in
      PTPN11 are at risk of developing JMML.
    explanation: >-
      Independent cohort-review evidence further supports JMML risk as a rare
      but important oncologic manifestation of Noonan syndrome.
- category: Oncologic
  name: Neuroblastoma
  phenotype_term:
    preferred_term: Neuroblastoma
    term:
      id: HP:0003006
      label: Neuroblastoma
  description: >-
    Neuroblastoma is among the cancer types reported in Noonan syndrome. The
    2024 AACR update on pediatric cancer surveillance in the RASopathies lists
    it in the Noonan syndrome cancer spectrum, and in a German registry-matching
    study (Kratz et al. 2015) one of the 632 people in its combined Noonan
    syndrome group (classic Noonan syndrome together with its NSML and
    loose-anagen-hair forms), a girl with a PTPN11 variant, had neuroblastoma
    at age 3 years. Neither AACR
    consensus recommends radiologic or laboratory screening for neuroblastoma
    in Noonan syndrome: the 2017 workshop paper (Kamihara et al.) allowed that
    neuroblastoma might be frequent enough to warrant surveillance in perhaps
    some forms of Noonan syndrome but named Costello syndrome as the only
    RASopathy that warranted screening, and the 2024 update judges the absolute
    risk of non-hematologic cancers, neuroblastoma among them, not high enough
    to warrant it.
  frequency: VERY_RARE
  notes: >-
    Frequency is set to VERY_RARE on the count in Kratz et al. (2015): one
    neuroblastoma among the 632 people in the study's combined Noonan syndrome
    group (571 with classic Noonan syndrome, 44 with NSML and 17 with the
    NS-like disorder with loose anagen hair, per its Table 1) matched against
    the German Childhood Cancer Registry. The same table row gives 0.093 cases
    expected and an SIR of 10.8 (95% CI 0.3-59.9). One case, with an interval
    that includes 1, does not show that neuroblastoma risk is raised in Noonan
    syndrome. The 2024 update's surveillance table covering Noonan syndrome
    (its Table 2) has no neuroblastoma row, and its neuroblastoma risk figures
    belong to Costello syndrome (its Table 3 and its Costello syndrome
    section), so none is carried over here.
  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: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "The relative childhood cancer risk in NS is estimated to be increased approximately 8-fold over the general population(5). Due to the low baseline cancer risk in children, the high relative risk leads to a moderate absolute cancer risk(5). The spectrum of cancer types is broad and includes myeloid and lymphoblastic leukemia, RMS, NB, and glioma, among others(2,4,5,78-81)."
    explanation: >-
      In the Noonan syndrome (NS) section of this 2024 consensus update on
      pediatric cancer surveillance in the RASopathies, which originated from
      the 2023 AACR Childhood Cancer Predisposition Workshop, the authors
      estimate the relative childhood cancer risk in NS at about 8-fold that of
      the general population, which they describe as a moderate absolute risk,
      and list neuroblastoma (NB) in the broad NS cancer spectrum alongside
      myeloid and lymphoblastic leukemia, rhabdomyosarcoma (RMS) and glioma.
      The 8-fold figure is for all childhood cancers combined, not for NB, and
      the update gives no risk figure for NB in NS. The passage summarizes,
      with citations, the cancers reported in people with NS, so it is graded
      HUMAN_CLINICAL with quote_role REVIEW_SYNTHESIS. The same section notes
      that the majority of data on cancer incidence in NS is based on PTPN11
      cases.
  - reference: PMID:25742478
    reference_title: "Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "8 (NS) | F | 3 | I282M (1) | NBL (3) | Cosmic database"
    explanation: >-
      Kratz et al. (2015) matched people with a molecularly confirmed
      RASopathy, identified through German genetic laboratories, against the
      German Childhood Cancer Registry. Their Table 2 describes each person in
      the cohort who developed cancer. This row, in the table's PTPN11 section,
      is patient 8: a girl with Noonan syndrome (NS) carrying the PTPN11
      variant I282M, who had neuroblastoma (NBL) at age 3 years. Its last
      column cites the COSMIC database as having previously associated the
      variant with cancer. It is the study's own observation that NB occurs in
      NS, so it is graded HUMAN_CLINICAL with quote_role PRIMARY_RESULT. The
      row is in the paper's full text, not its abstract.
  - reference: PMID:25742478
    reference_title: "Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "NBL | 632 | 1 | 0.093 | 6535.6 | 10.8 (0.3-59.9)"
    explanation: >-
      Table 3 of Kratz et al. (2015) gives standardised incidence ratios (SIRs)
      for selected cancers. In its Noonan syndrome (NS) block, whose 'NS
      combined' label sits on the block's first row, this row reports
      neuroblastoma (NBL) among the 632 people with NS, the paper's 'NS, all
      subtypes combined' group (571 classic NS, 44 NS with multiple lentigines
      and 17 NS-like disorder with loose anagen hair, per its Table 1): 1 case
      observed against
      0.093 expected over 6535.6 person-years, an SIR of 10.8 with a 95%
      confidence interval of 0.3 to 59.9. The interval includes 1, so the study
      does not show a raised NB risk in NS; the authors attribute the cohort's
      raised overall cancer risk primarily to significant excesses of JMML,
      embryonal rhabdomyosarcoma and brain tumours. The one case among 632 is
      the basis for the VERY_RARE frequency. It is the study's own registry-matching
      result, so it is graded HUMAN_CLINICAL with quote_role PRIMARY_RESULT.
      The row is in the paper's full text, not its abstract.
  - 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
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    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: >-
      In its surveillance recommendations for Noonan syndrome (NS) and CBL
      syndrome, the same update says the absolute risk of non-hematologic
      cancers is not high enough to warrant radiologic or laboratory
      surveillance. It adds that education of patients and families about the
      signs and symptoms of rhabdomyosarcoma (RMS), gliomas and neuroblastoma
      (NB) can be considered. NB is a non-hematologic cancer and is named in
      that list, so the no-surveillance position covers it. This supports the
      description's statement that the 2024 update does not recommend
      radiologic or laboratory screening for NB in children with NS. It is a
      threshold judgment for non-hematologic cancers as a group, not a risk
      estimate: the update gives no risk figure for NB in NS and does not call
      that risk low, and earlier in the same section it describes the overall
      absolute childhood cancer risk in NS as moderate. The physical
      examination for hepatosplenomegaly
      that the update recommends for all patients is aimed at
      myeloproliferative disorder and leukemia, not at NB. The passage is a
      consensus surveillance recommendation, so it is graded OTHER with
      quote_role REVIEW_SYNTHESIS, and it is DIRECT for the no-screening
      statement it supports.
  - reference: PMID:28674118
    reference_title: "Retinoblastoma and Neuroblastoma Predisposition and Surveillance."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "However, the frequency of NB may be sufficiently high in individuals with Costello syndrome and perhaps some forms of Noonan syndrome to warrant surveillance."
    explanation: >-
      Kamihara et al. (2017) present the literature review and consensus
      recommendations of the AACR Childhood Cancer Predisposition Workshop on
      hereditary retinoblastoma and neuroblastoma (NB). In its review of NB
      predisposition genes, after naming Noonan syndrome among the RASopathies
      in which NB has been reported, the paper remarks that NB may be frequent
      enough to warrant surveillance in Costello syndrome and perhaps some
      forms of Noonan syndrome. The remark is hedged ('may', 'perhaps some
      forms'), does not say which forms, and gives no frequency. It did not
      become one of the paper's recommendations: its list of disorders for
      which it recommends NB surveillance names Costello syndrome with HRAS
      mutations but not Noonan syndrome. The quote directly supports the
      description's report of this 2017 remark. It is the paper's own judgment
      and presents no patient data, so it is graded OTHER with quote_role
      REVIEW_SYNTHESIS. The sentence is in the paper's full text, not its
      abstract.
  - reference: PMID:28674118
    reference_title: "Retinoblastoma and Neuroblastoma Predisposition and Surveillance."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "Costello syndrome is the only RASopathy that warrants NB screening at the present time."
    explanation: >-
      Kamihara et al. (2017) report the consensus of the AACR Childhood Cancer
      Predisposition Workshop on retinoblastoma and neuroblastoma (NB)
      surveillance. Footnote b to their table of genes that predispose to NB
      first names the genes that cause Costello syndrome and Noonan syndrome,
      then states that Costello syndrome is the only RASopathy that warrants
      NB screening "at the present time". Costello syndrome with HRAS
      mutations is also the only RASopathy in the main-text list of disorders
      for which the panel recommends NB surveillance. Read with this footnote,
      the paper's recommendation of biochemical and radiographic surveillance
      for people with a mutation in a known NB predisposition gene does not
      extend to the other RASopathies, although the same table lists them. The
      main text allows that individuals with other RASopathies may also be at
      significantly increased risk for NB, but that possibility did not become
      a recommendation. This supports the description's statement that in 2017
      the panel named Costello syndrome as the only RASopathy that warranted NB
      screening, so it did not recommend NB screening in Noonan syndrome. It is
      INDIRECT because the quoted sentence does not name Noonan syndrome: the
      exclusion follows from Noonan syndrome being a RASopathy other than
      Costello syndrome. The sentence is the panel's own recommendation, not
      patient data, so it is graded OTHER with quote_role REVIEW_SYNTHESIS. It
      is in the paper's full text, not its abstract.
- category: Neurologic
  name: Peripheral Neuropathy
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  description: >-
    Adult Noonan syndrome and Noonan syndrome with multiple lentigines can
    include neuropathic pain and objective peripheral nerve involvement, with
    enlarged nerves and impaired quality of life in symptomatic individuals.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41560462
    reference_title: "Neuropathic Pain and Enlarged Nerves in Adult Noonan Syndrome and Noonan Syndrome With Multiple Lentigines: Health-Related Quality of Life and Neurologic Symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients reported somatosensory symptoms consistent with peripheral
      neuropathy...electrodiagnostic testing was consistent with peroneal
      neuropathy in one patient.
    explanation: >-
      Supports peripheral neuropathy as a clinically meaningful neurologic
      manifestation in adults with Noonan-spectrum disorders.
- category: Auditory
  name: Hearing Loss
  phenotype_term:
    preferred_term: Hearing loss
    term:
      id: HP:0000365
      label: Hearing impairment
  description: >-
    Conductive or sensorineural hearing problems occur in a subset of individuals
    and justify formal audiology surveillance.
  evidence:
  - reference: PMID:24444506
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected individuals have 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.
    explanation: >-
      Supports hearing loss as part of the multisystem clinical phenotype in
      Noonan syndrome.
- category: Lymphatic
  name: Lymphedema
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  description: >-
    Peripheral lymphedema and central conducting lymphatic anomalies occur in a
    substantial minority. ERK/SOX18 signaling axis is implicated in lymphatic dysplasia.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24444506
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected individuals have 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.
    explanation: >-
      Supports lymphedema as a recognized clinical manifestation in Noonan
      syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001004 | Lymphedema | Occasional (29-5%)"
    explanation: Orphanet phenotype annotation supports lymphedema as occasional in Noonan syndrome.
- category: Lymphatic
  name: Chylothorax
  phenotype_term:
    preferred_term: Chylothorax
    term:
      id: HP:0010310
      label: Chylothorax
  description: >-
    Central conducting lymphatic dysfunction can manifest as fetal or postnatal
    chylous pleural effusions.
  evidence:
  - reference: DOI:10.3390/children11111342
    reference_title: "Refractory Chylothorax and Ventricular Hypertrophy Treated with Trametinib in a Patient with Noonan Syndrome: 18-Month Follow-Up"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype of Noonan syndrome includes characteristic facial and physical features, congenital cardiac defects, lymphatic and cerebrovascular anomalies, renal malformations, hematological abnormalities, developmental issues, and an increased risk of cancer.
    explanation: >-
      Noonan syndrome case report directly documents chylothorax as part of the lymphatic phenotype and confirms trametinib efficacy for this manifestation.
- category: Developmental
  name: Global Developmental Delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Mild cognitive impairment and motor delays are common, with learning disabilities
    in approximately 25% of individuals.
  frequency: FREQUENT
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups."
    explanation: Developmental delay is a recognized feature across Noonan syndrome genotypes.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012758 | Neurodevelopmental delay | Frequent (79-30%)"
    explanation: Orphanet lists neurodevelopmental delay as frequent, supporting the global developmental delay phenotype in this entry.
- category: Nervous System
  name: Hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: >-
    Decreased muscle tone is a frequent neurologic or neuromotor manifestation
    in Noonan syndrome.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001252 | Hypotonia | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation supports hypotonia as frequent in Noonan syndrome.
- category: Developmental
  name: Mild Intellectual Disability
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  description: >-
    Approximately 15-35% of individuals have mild intellectual disability.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Up to one fourth of affected individuals have mild intellectual
      disability, and language impairments in general are more common in NS
      than in the general population.
    explanation: >-
      GeneReviews reports mild intellectual disability in a substantial minority
      of individuals with Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Occasional (29-5%)"
    explanation: Orphanet classifies intellectual disability as occasional in Noonan syndrome, consistent with the mild intellectual disability reported in this entry.
- category: Feeding
  name: Feeding Difficulties in Infancy
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  description: >-
    Many infants experience feeding difficulties and failure to thrive in early life.
  frequency: FREQUENT
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other associated features are webbed neck, chest deformity, mild
      intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding
      tendency and lymphatic dysplasias.
    explanation: >-
      Supports poor feeding in infancy as a common early-life manifestation in
      Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008872 | Feeding difficulties in infancy | Frequent (79-30%)"
    explanation: Orphanet phenotype annotation supports feeding difficulties in infancy as frequent in Noonan syndrome.
genetic:
- name: PTPN11
  subtype: NS1
  case_fractions:
  - population: Individuals with Noonan syndrome
    case_fraction_percent: 50.0
    notes: Reported as "approximately 50% of Noonan syndrome cases".
    evidence:
    - reference: PMID:17143285
      reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase
        SHP2, cause approximately 50% of Noonan syndrome cases.
      explanation: States the PTPN11 share of Noonan syndrome cases recorded here.
  gene_term:
    preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  association: Pathogenic Variants
  frequency: VERY_FREQUENT
  notes: >-
    Most commonly mutated gene, accounting for approximately 50-60% of cases.
    Encodes SHP2 phosphatase. Gain-of-function mutations destabilize the
    autoinhibited conformation leading to increased phosphatase activity.
    Associated with pulmonary stenosis but lower HCM risk.
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS."
    explanation: Confirms PTPN11 mutations account for approximately half of Noonan syndrome cases.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PTPN11 | protein tyrosine phosphatase non-receptor type 11 | hgnc:9644 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports PTPN11 as causative for Noonan syndrome.
  - reference: CGGV:assertion_2bb08565-4669-4633-b6ed-c04e2a431cf9-2018-07-24T160000.000Z
    reference_title: "PTPN11 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PTPN11 | HGNC:9644 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the PTPN11-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: SOS1
  subtype: NS4
  case_fractions:
  - population: Individuals with Noonan syndrome without a PTPN11 mutation
    case_fraction_percent: 20.0
    notes: Reported as "approximately 20% of cases of Noonan syndrome without PTPN11 mutation".
    evidence:
    - reference: PMID:17143285
      reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation."
      explanation: States the SOS1 share of the PTPN11-negative cohort recorded here.
  gene_term:
    preferred_term: SOS1
    term:
      id: hgnc:11187
      label: SOS1
  association: Pathogenic Variants
  frequency: OCCASIONAL
  notes: >-
    Accounts for 10-20% of PTPN11-negative cases (approximately 10% overall).
    Encodes a RAS guanine nucleotide exchange factor. Gain-of-function mutations
    enhance RAS-GTP loading.
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation."
    explanation: SOS1 mutations are a significant cause of PTPN11-negative Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SOS1 | SOS Ras/Rac guanine nucleotide exchange factor 1 | hgnc:11187 | Disease-causing germline mutation(s) (gain of function) in"
    explanation: Orphanet gene-disease association supports SOS1 as causative for Noonan syndrome.
  - reference: CGGV:assertion_9781b6bf-9b1e-4a10-a0a9-7e56562a6e3a-2018-07-24T160000.000Z
    reference_title: "SOS1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SOS1 | HGNC:11187 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the SOS1-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: SOS2
  subtype: NS9
  case_fractions:
  - population: >-
      Brazilian probands negative for pathogenic variants in the known Noonan
      syndrome genes
    case_fraction_percent: 4.0
    cohort_size: 50
    evidence:
    - reference: PMID:25795793
      reference_title: "Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified rare, segregating or de novo missense variants in SOS2
        and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands.
      explanation: States the SOS2 share of the 50-proband discovery cohort recorded here.
    - reference: PMID:25795793
      reference_title: "Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A cohort of 50 Brazilian probands negative for pathogenic variants in
        the known genes associated with Noonan syndrome was tested through
        whole-exome sequencing along with the relatives in the familial cases.
      explanation: Defines the cohort this case fraction is computed in.
  gene_term:
    preferred_term: SOS2
    term:
      id: hgnc:11188
      label: SOS2
  association: Pathogenic Variants
  frequency: RARE
  notes: >-
    Rare Noonan syndrome gene encoding a homologous RAS guanine nucleotide
    exchange factor. Reported cases often show ectodermal findings resembling
    SOS1-associated disease.
  evidence:
  - reference: PMID:25795793
    reference_title: "Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified rare, segregating or de novo missense variants in SOS2
      and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands.
    explanation: >-
      Discovery-cohort evidence supports SOS2 as an established rare cause of
      Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SOS2 | SOS Ras/Rho guanine nucleotide exchange factor 2 | hgnc:11188 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports SOS2 as causative for Noonan syndrome.
  - reference: CGGV:assertion_f20a1034-e29d-49bb-aed9-b4ba63dc5968-2020-08-27T160000.000Z
    reference_title: "SOS2 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SOS2 | HGNC:11188 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the SOS2-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: RAF1
  subtype: NS5
  case_fractions:
  - population: Individuals with Noonan syndrome
    case_fraction_percent: 3.0
    notes: >-
      The source reports 18 RAF1-positive individuals among 231 with Noonan
      syndrome and no previously known mutation, and states that this
      corresponds to 3% of all affected individuals. The 3% figure recorded here
      is the whole-disease share the source states, not the share of its
      mutation-negative subcohort.
    evidence:
    - reference: PMID:17603483
      reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals)...have missense mutations in RAF1"
      explanation: States both the subcohort count and the whole-disease share recorded here.
  gene_term:
    preferred_term: RAF1
    term:
      id: hgnc:9829
      label: RAF1
  association: Pathogenic Variants
  frequency: OCCASIONAL
  notes: >-
    Accounts for 3-17% of cases. Strongly associated with hypertrophic cardiomyopathy
    (up to 95% of patients with RAF1 mutations have HCM).
  evidence:
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals)...have missense mutations in RAF1"
    explanation: RAF1 mutations account for approximately 3% of Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RAF1 | Raf-1 proto-oncogene, serine/threonine kinase | hgnc:9829 | Disease-causing germline mutation(s) (gain of function) in"
    explanation: Orphanet gene-disease association supports RAF1 as causative for Noonan syndrome.
  - reference: CGGV:assertion_85645d27-2056-4ad3-9593-8d7739aa4121-2024-10-23T160000.000Z
    reference_title: "RAF1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RAF1 | HGNC:9829 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the RAF1-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: BRAF
  subtype: NS7
  gene_term:
    preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  association: Pathogenic Variants
  frequency: VERY_RARE
  notes: >-
    Rare Noonan-spectrum genotype with substantial phenotypic overlap with
    cardiofaciocutaneous syndrome and ectodermal manifestations.
  evidence:
  - reference: PMID:19953625
    reference_title: "Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a
      cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic
      SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients.
    explanation: >-
      Supports BRAF as a rare molecular cause within the Noonan syndrome
      spectrum.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BRAF | B-Raf proto-oncogene, serine/threonine kinase | hgnc:1097 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports BRAF as causative for Noonan syndrome.
  - reference: CGGV:assertion_47cf08d5-efc6-4d42-b031-a06619873161-2018-07-24T160000.000Z
    reference_title: "BRAF / Noonan syndrome (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BRAF | HGNC:1097 | Noonan syndrome | MONDO:0018997 | AD | Moderate"
    explanation: ClinGen classifies the BRAF-Noonan syndrome gene-disease relationship as moderate with autosomal dominant inheritance.
- name: MAP2K1
  gene_term:
    preferred_term: MAP2K1
    term:
      id: hgnc:6840
      label: MAP2K1
  association: Pathogenic Variants
  frequency: VERY_RARE
  notes: >-
    Rare Noonan syndrome gene encoding MEK1; reported variants are activating
    and increase downstream RAS-ERK signaling.
  evidence:
  - reference: PMID:25049390
    reference_title: "Next-generation sequencing identifies rare variants associated with Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1)
      and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously
      unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2)
      that are likely to cause NS in these patients.
    explanation: >-
      Next-generation sequencing in mutation-negative cases supports MAP2K1 as
      an established rare cause of Noonan syndrome.
  - reference: CGGV:assertion_1eafd4b1-29b1-4a17-a7ac-2c555f2e2648-2018-07-24T160000.000Z
    reference_title: "MAP2K1 / Noonan syndrome (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAP2K1 | HGNC:6840 | Noonan syndrome | MONDO:0018997 | AD | Limited"
    explanation: ClinGen classifies the MAP2K1-Noonan syndrome gene-disease relationship as limited with autosomal dominant inheritance.
- name: RIT1
  subtype: NS8
  case_fractions:
  - population: >-
      Individuals with Noonan syndrome or a related condition and no detectable
      mutation in known Noonan-related genes
    case_fraction_percent: 9.0
    cohort_size: 180
    evidence:
    - reference: PMID:23791108
      reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        in 17 of 180 individuals (9%) with Noonan syndrome or a related
        condition but with no detectable mutations in known Noonan-related genes
      explanation: States the RIT1 share and the cohort it was measured in.
  gene_term:
    preferred_term: RIT1
    term:
      id: hgnc:10023
      label: RIT1
  association: Pathogenic Variants
  frequency: OCCASIONAL
  notes: >-
    Accounts for approximately 5-10% of cases. Associated with high incidence of
    hypertrophic cardiomyopathy (70% of mutation-positive individuals).
  evidence:
  - reference: PMID:23791108
    reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a total of nine missense, nonsynonymous mutations in RIT1...in 17 of 180 individuals (9%) with Noonan syndrome"
    explanation: RIT1 mutations account for approximately 9% of cases without mutations in other known genes.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RIT1 | Ras like without CAAX 1 | hgnc:10023 | Disease-causing germline mutation(s) (gain of function) in"
    explanation: Orphanet gene-disease association supports RIT1 as causative for Noonan syndrome.
  - reference: CGGV:assertion_240565fc-61b9-4ff8-9f5a-85938f17cdd9-2018-07-24T160000.000Z
    reference_title: "RIT1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RIT1 | HGNC:10023 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the RIT1-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: RRAS2
  subtype: NS12
  gene_term:
    preferred_term: RRAS2
    term:
      id: hgnc:17271
      label: RRAS2
  association: Pathogenic Variants
  frequency: VERY_RARE
  notes: >-
    Rare Noonan syndrome gene encoding a small GTPase whose activating variants
    increase MAPK cascade signaling.
  evidence:
  - reference: PMID:31130282
    reference_title: "Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using a mixed strategy of functional candidacy and exome sequencing,
      we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families.
    explanation: >-
      Supports RRAS2 as an established but very rare cause of Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RRAS2 | RAS related 2 | hgnc:17271 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports RRAS2 as causative for Noonan syndrome.
  - reference: CGGV:assertion_c5742615-3820-41dd-a523-e660a498f9e8-2022-12-14T170000.000Z
    reference_title: "RRAS2 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RRAS2 | HGNC:17271 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the RRAS2-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: KRAS
  subtype: NS3
  case_fractions:
  - population: Individuals with Noonan syndrome
    case_fraction_high: 5.0
    notes: >-
      The source gives an upper bound ("<5%") rather than a point estimate, so
      only case_fraction_high is populated.
    evidence:
    - reference: PMID:17143285
      reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "KRAS mutations account for <5% of cases of Noonan syndrome"
      explanation: States the upper bound on the KRAS share recorded here.
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  association: Pathogenic Variants
  frequency: VERY_RARE
  notes: >-
    Rare cause, less than 5% of cases. Germline activating variants often cause
    more severe phenotype with significant neurodevelopmental involvement.
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KRAS mutations account for <5% of cases of Noonan syndrome"
    explanation: KRAS mutations are a rare cause of Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KRAS | KRAS proto-oncogene, GTPase | hgnc:6407 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports KRAS as causative for Noonan syndrome.
  - reference: CGGV:assertion_6476a5fd-8f66-462b-b17a-43540dad3c1f-2018-07-24T160000.000Z
    reference_title: "KRAS / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KRAS | HGNC:6407 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the KRAS-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: NRAS
  subtype: NS6
  gene_term:
    preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  association: Pathogenic Variants
  frequency: VERY_RARE
  notes: >-
    Rare Noonan syndrome gene encoding a canonical RAS GTPase; reported
    germline variants enhance stimulus-dependent MAPK activation.
  evidence:
  - reference: PMID:19966803
    reference_title: "A restricted spectrum of NRAS mutations causes Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report that germline NRAS mutations conferring enhanced
      stimulus-dependent MAPK activation account for some cases of this disorder.
    explanation: >-
      Supports NRAS as a rare gain-of-function molecular cause of Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NRAS | NRAS proto-oncogene, GTPase | hgnc:7989 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports NRAS as causative for Noonan syndrome.
  - reference: CGGV:assertion_34419b69-59c3-458b-a2a5-38a401679deb-2018-05-30T160000.000Z
    reference_title: "NRAS / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NRAS | HGNC:7989 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the NRAS-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: RASA2
  gene_term:
    preferred_term: RASA2
    term:
      id: hgnc:9872
      label: RASA2
  association: Pathogenic Variants
  frequency: VERY_RARE
  notes: >-
    Rare Noonan syndrome gene encoding a RAS GTPase-activating negative
    regulator; pathogenic variants identified to date are loss of function.
  evidence:
  - reference: PMID:25049390
    reference_title: "Next-generation sequencing identifies rare variants associated with Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1)
      and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously
      unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2)
      that are likely to cause NS in these patients.
    explanation: >-
      Supports RASA2 loss of function as a rare molecular mechanism in
      Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RASA2 | RAS p21 protein activator 2 | hgnc:9872 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet gene-disease association supports RASA2 as causative for Noonan syndrome.
  - reference: CGGV:assertion_9635e391-79b6-4054-824e-1c607a02cd07-2018-07-24T160000.000Z
    reference_title: "RASA2 / Noonan syndrome (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RASA2 | HGNC:9872 | Noonan syndrome | MONDO:0018997 | AD | Limited"
    explanation: ClinGen classifies the RASA2-Noonan syndrome gene-disease relationship as limited with autosomal dominant inheritance.
- name: LZTR1
  subtype: NS10
  case_fractions:
  - population: >-
      Brazilian probands negative for pathogenic variants in the known Noonan
      syndrome genes
    case_fraction_percent: 8.0
    cohort_size: 50
    evidence:
    - reference: PMID:25795793
      reference_title: "Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified rare, segregating or de novo missense variants in SOS2
        and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands.
      explanation: States the LZTR1 share of the 50-proband discovery cohort recorded here.
  gene_term:
    preferred_term: LZTR1
    term:
      id: hgnc:6742
      label: LZTR1
  association: Pathogenic Variants
  frequency: OCCASIONAL
  notes: >-
    The dominant LZTR1 record. LZTR1 acts as a CUL3 adaptor controlling RAS
    proteostasis through ubiquitination, and dominant mutations act in a
    dominant-negative manner. The recessive form is a separate MONDO class and
    is recorded below as the LZTR1 (biallelic) entry, keyed to NS2.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included 15 individuals with Noonan syndrome...one each
      in LZTR1, A2ML1, and MRAS...
    explanation: >-
      Supports LZTR1 as a clinically observed Noonan syndrome genotype in
      contemporary molecular cohorts.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LZTR1 | leucine zipper like post translational regulator 1 | hgnc:6742 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports LZTR1 as causative for Noonan syndrome.
  - reference: CGGV:assertion_6f21db9c-87ea-4095-96ca-4277eaa21232-2020-04-23T170000.000Z
    reference_title: "LZTR1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LZTR1 | HGNC:6742 | Noonan syndrome | MONDO:0018997 | AD | Definitive"
    explanation: ClinGen classifies the LZTR1-Noonan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: MRAS
  subtype: NS11
  gene_term:
    preferred_term: MRAS
    term:
      id: hgnc:7227
      label: MRAS
  association: Pathogenic Variants
  frequency: RARE
  notes: >-
    Emerging Noonan syndrome gene associated with variable expressivity, including
    adult-onset hypertrophic cardiomyopathy in recent reports.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included 15 individuals with Noonan syndrome...one each
      in LZTR1, A2ML1, and MRAS...
    explanation: >-
      Supports MRAS as a rare but clinically confirmed contributor to Noonan syndrome.
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified a heterozygous MRAS c.203C>T
      (p.Thr68Ile) mutation affecting a highly conserved residue among
      RASopathy-associated GTPases, supporting the diagnosis of MRAS-associated
      Noonan syndrome complicated by infective endocarditis.
    explanation: >-
      Case-level molecular confirmation supports pathogenic MRAS-associated
      Noonan syndrome with cardiac involvement.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MRAS | muscle RAS oncogene homolog | hgnc:7227 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports MRAS as causative for Noonan syndrome.
  - reference: CGGV:assertion_04ca29c1-6b44-474c-b54b-1c8be52de172-2022-12-14T170000.000Z
    reference_title: "MRAS / Noonan syndrome (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MRAS | HGNC:7227 | Noonan syndrome | MONDO:0018997 | AD | Moderate"
    explanation: ClinGen classifies the MRAS-Noonan syndrome gene-disease relationship as moderate with autosomal dominant inheritance.
- name: CBL
  gene_term:
    preferred_term: CBL
    term:
      id: hgnc:1541
      label: CBL
  association: Pathogenic Variants
  frequency: VERY_RARE
  relationship_type: CAUSATIVE
  notes: >-
    Rare Noonan-spectrum gene encoding an E3 ubiquitin ligase and negative
    regulator of receptor tyrosine kinase signaling. Germline mutations cause
    a Noonan-like syndrome with predisposition to JMML (CBL syndrome). The
    founding report describes the resulting phenotype as fitting or partially
    overlapping Noonan syndrome rather than as classical Noonan syndrome, and
    found CBL mutations in two sporadic cases and two families among 365
    subjects who were negative for the previously known genes. The committed ClinGen Gene-Disease Validity
    snapshot carries no CBL-Noonan syndrome assertion.
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CBL | Cbl proto-oncogene | hgnc:1541 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports CBL as causative for Noonan syndrome.
  - reference: PMID:20619386
    reference_title: "Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Independent CBL mutations were identified in two sporadic cases and two
      families from among 365 unrelated subjects who had NS or suggestive
      features and were negative for mutations in previously identified disease
      genes.
    explanation: >-
      The human genetic evidence behind this record, and the source of the
      yield stated in the note.
- name: SPRED2
  subtype: NS14
  gene_term:
    preferred_term: SPRED2
    term:
      id: hgnc:17722
      label: SPRED2
  association: Pathogenic Variants
  frequency: VERY_RARE
  relationship_type: CAUSATIVE
  notes: >-
    Rare Noonan-spectrum gene encoding a negative regulator of the RAS-MAPK
    pathway. Biallelic loss-of-function variants lead to increased MAPK
    signaling. Unlike the rest of this entry's gene list, SPRED2 acts
    recessively: the reported subjects were homozygous, and the founding report
    calls it the second recessive form of Noonan syndrome. The committed
    ClinGen Gene-Disease Validity snapshot carries no SPRED2-Noonan syndrome
    assertion, so the attestation here is Orphanet plus this primary report.
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPRED2 | sprouty related EVH1 domain containing 2 | hgnc:17722 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease association supports SPRED2 as causative for Noonan syndrome.
  - reference: PMID:34626534
    reference_title: "SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report that SPRED2 loss of function is causally linked to a
      recessive phenotype evocative of Noonan syndrome.
    explanation: >-
      Primary-literature support for the gene-disease relationship and for the
      recessive mode this record now states.
- name: MAPK1
  subtype: NS13
  gene_term:
    preferred_term: MAPK1
    term:
      id: hgnc:6871
      label: MAPK1
  association: Pathogenic Variants
  frequency: VERY_RARE
  relationship_type: CAUSATIVE
  notes: >-
    MAPK1 encodes ERK2, the terminal kinase of the cascade the rest of this
    entry's genes act upstream of, and de novo missense variants in it were
    reported as a RASopathy-spectrum neurodevelopmental disorder that resembles
    Noonan syndrome in some subjects. CAUSATIVE is recorded against the NS13
    subtype, which OMIM and MONDO define by these variants, rather than against
    Noonan syndrome at large: the 2025 GeneReviews chapter does not include
    MAPK1 in the gene list whose variants establish the diagnosis, a grep of the
    committed ClinGen Gene-Disease Validity snapshot (data/clingen/gene_validity.csv)
    for "MAPK1" returns no row for any disease, and a grep of the cached Orphanet
    Noonan syndrome record (references_cache/ORPHA_648.md) returns no MAPK1 row
    in its gene table.
  evidence:
  - reference: PMID:32721402
    reference_title: "Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report that de novo missense variants in MAPK1, encoding the
      mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated
      protein kinase 2, ERK2), cause a neurodevelopmental disease within the
      RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some
      subjects.
    explanation: >-
      The founding report for the gene-disease relationship, and the source for
      the hedge this record states on its Noonan attribution.
  - reference: PMID:32721402
    reference_title: "Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pathogenic variants promote increased phosphorylation of the kinase
      [MAPK1/ERK2], which enhances translocation to the nucleus and boosts MAPK
      signaling
    explanation: >-
      Establishes the gain-of-function mechanism that places MAPK1 on the same
      convergent ERK output as the rest of this entry's genes. The kinase is
      ERK2, the MAPK1 product named in the preceding sentence of the abstract.
- name: LZTR1 (biallelic)
  subtype: NS2
  gene_term:
    preferred_term: LZTR1
    term:
      id: hgnc:6742
      label: LZTR1
  association: Pathogenic Variants
  frequency: VERY_RARE
  relationship_type: CAUSATIVE
  notes: >-
    The recessive LZTR1 record, separated from the dominant one above because
    the two are different MONDO classes (NS2 versus NS10) and ClinGen curates
    them as separate gene-disease assertions. Carriers of a single LZTR1
    pathogenic variant may be asymptomatic or mildly affected.
  evidence:
  - reference: CGGV:assertion_7aa1e103-4f77-4c50-99c5-621a6a837b95-2020-08-27T160000.000Z
    reference_title: "LZTR1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LZTR1 | HGNC:6742 | Noonan syndrome | MONDO:0018997 | AR | Definitive"
    explanation: ClinGen classifies the recessive LZTR1-Noonan syndrome relationship as definitive.
  - reference: PMID:20301303
    reference_title: Noonan Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents of an individual with autosomal recessive NS are typically
      heterozygotes (i.e., have one LZTR1 pathogenic variant), and may either be
      asymptomatic or have mild features of NS.
    explanation: >-
      The GeneReviews chapter states that recessive Noonan syndrome is the
      biallelic LZTR1 form and describes the carrier state recorded here.
- name: MAP2K2
  gene_term:
    preferred_term: MAP2K2
    term:
      id: hgnc:6842
      label: MAP2K2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_6a0eeefd-9105-435d-9daf-c748e52b0941-2018-06-01T160000.000Z
    reference_title: "MAP2K2 / Noonan syndrome (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAP2K2 | HGNC:6842 | Noonan syndrome | MONDO:0018997 | AD | Limited"
    explanation: ClinGen classifies the MAP2K2-Noonan syndrome gene-disease relationship as limited with autosomal dominant inheritance.
  notes: >-
    Deliberately not bound to a pathophysiology node. ClinGen classifies the
    MAP2K2-Noonan syndrome relationship as Limited, so wiring it beside the
    Definitive genes on the convergent RAS-MAPK node would give it equal weight
    in the pathograph with PTPN11 or SOS1. Reconsider if ClinGen upgrades the
    assertion.
- name: RRAS
  gene_term:
    preferred_term: RRAS
    term:
      id: hgnc:10447
      label: RRAS
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_96280a14-d8cd-4c9b-b3e0-d5fcd8bf9ef6-2018-07-24T160000.000Z
    reference_title: "RRAS / Noonan syndrome (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RRAS | HGNC:10447 | Noonan syndrome | MONDO:0018997 | AD | Limited"
    explanation: ClinGen classifies the RRAS-Noonan syndrome gene-disease relationship as limited with autosomal dominant inheritance.
  notes: >-
    Deliberately not bound to a pathophysiology node, for the same reason as
    MAP2K2: ClinGen classifies the RRAS-Noonan syndrome relationship as
    Limited. Reconsider if ClinGen upgrades the assertion.
inheritance:
- name: Autosomal Dominant
  description: Most cases follow autosomal dominant inheritance with variable expressivity. Approximately 30-75% of cases are de novo mutations.
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations were found in 54 of 119 (45%) unrelated individuals with
      sporadic or familial NS.
    explanation: >-
      Supports autosomal dominant inheritance with both familial transmission
      and de novo/sporadic occurrence.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for Noonan syndrome.
- name: Autosomal Recessive
  description: >-
    A subset of Noonan syndrome is inherited in an autosomal recessive manner,
    particularly in LZTR1-associated disease. SPRED2 is the other recessive
    locus: homozygosity for three different loss-of-function variants was
    reported in four subjects from three families, and the authors describe it
    as the second recessive form of Noonan syndrome.
  evidence:
  - reference: PMID:34626534
    reference_title: "SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygosity for three different variants-c.187C>T (p.Arg63∗), c.299T>C
      (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95)-were identified in
      four subjects from three families.
    explanation: >-
      The recessive segregation evidence behind adding SPRED2 to this block.
  - reference: PMID:34626534
    reference_title: "SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings identify the second recessive form of Noonan syndrome
    explanation: >-
      The authors' own framing, which is what this description asserts.
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NS caused by pathogenic variants in LZTR1 can be inherited in either an
      autosomal dominant or an autosomal recessive manner.
    explanation: >-
      Supports autosomal recessive inheritance in LZTR1-associated Noonan
      syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for Noonan syndrome.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Multigene RASopathy molecular testing is central to confirming Noonan
    syndrome and separating it from phenotypically overlapping RASopathies.
    Current diagnostic gene sets include BRAF, KRAS, MAP2K1, MRAS, NRAS,
    PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, SOS2, and heterozygous or
    biallelic LZTR1 variants.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This retrospective study analyzed...individuals diagnosed with Noonan
      syndrome and related disorders previously submitted to diagnostic molecular
      analysis through next-generation sequencing techniques.
    explanation: >-
      Supports molecular testing as a practical diagnostic discriminator in
      suspected Noonan-spectrum disorders.
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DIAGNOSIS/TESTING: 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 provides the current established molecular diagnostic gene set
      for classic Noonan syndrome.
- name: Clinical whole-exome sequencing
  description: >-
    Whole-exome sequencing can establish diagnosis in atypical or less common
    genotypes, including MRAS-associated Noonan syndrome.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified a heterozygous MRAS c.203C>T
      (p.Thr68Ile) mutation affecting a highly conserved residue among
      RASopathy-associated GTPases, supporting the diagnosis of MRAS-associated
      Noonan syndrome complicated by infective endocarditis.
    explanation: >-
      Demonstrates diagnostic utility of exome sequencing in genetically
      heterogeneous Noonan syndrome.
- name: Echocardiography
  description: >-
    Echocardiography is a key diagnostic assessment for structural defects and
    hypertrophic cardiomyopathy in Noonan syndrome.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Echocardiography demonstrated obstructive hypertrophic cardiomyopathy
      with vegetation located in the left ventricular outflow tract.
    explanation: >-
      Supports echocardiography as an essential modality for defining Noonan
      syndrome cardiac phenotype and complications.
differential_diagnoses:
- name: Cardiofaciocutaneous syndrome
  disease_term:
    preferred_term: cardiofaciocutaneous syndrome
    term:
      id: MONDO:0015280
      label: cardiofaciocutaneous syndrome
  description: >-
    Cardiofaciocutaneous syndrome is a RASopathy with substantial overlap in
    growth, dysmorphology, neurodevelopmental, and cardiac findings.
  distinguishing_features:
  - More often associated with BRAF-pathway variants than classic PTPN11-predominant Noonan syndrome.
  - Ectodermal/skin and hair abnormalities are often more prominent in CFC.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RASopathies are a heterogeneous group...presenting with overlapping
      features... Final diagnoses included...two with
      cardiofaciocutaneous syndrome (BRAF)...
    explanation: >-
      Demonstrates overlap requiring differential diagnosis, with BRAF genotype
      pattern helping separate CFC from classic Noonan syndrome.
- name: Costello syndrome
  disease_term:
    preferred_term: Costello syndrome
    term:
      id: MONDO:0009026
      label: Costello syndrome
  description: >-
    Costello syndrome is an overlapping RASopathy that can resemble Noonan
    syndrome in early referral contexts.
  distinguishing_features:
  - HRAS pathogenic variants support Costello syndrome rather than classic Noonan syndrome.
  - Relative burden of coarse facies, deep palmar/plantar creases, and tumor predisposition favors Costello syndrome.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included...one each with...Costello syndrome (HRAS)...
    explanation: >-
      Supports Costello syndrome as a practical molecular differential in
      suspected Noonan-spectrum patients.
- name: Neurofibromatosis type 1
  disease_term:
    preferred_term: neurofibromatosis type 1
    term:
      id: MONDO:0018975
      label: neurofibromatosis type 1
  description: >-
    NF1-related phenotypes can overlap with Noonan syndrome (including
    Neurofibromatosis-Noonan presentations) and require molecular distinction.
  distinguishing_features:
  - NF1 pathogenic variants and neurofibromatosis features (e.g., neurofibromas, cafe-au-lait patterning) support NF1-spectrum diagnosis.
  - Shared RAS-MAPK dysregulation can create overlapping craniofacial and growth findings.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included...two with Neurofibromatosis-Noonan (NF1)...
    explanation: >-
      Confirms clinically relevant NS vs NF1-overlap differential diagnosis in
      molecularly evaluated RASopathy cohorts.
- name: Noonan syndrome with multiple lentigines
  disease_term:
    preferred_term: Noonan syndrome with multiple lentigines
    term:
      id: MONDO:0007893
      label: Noonan syndrome with multiple lentigines
  description: >-
    Noonan syndrome with multiple lentigines shares core Noonan features but is
    separated by pigmentation pattern and genotype-phenotype context.
  distinguishing_features:
  - Diffuse lentigines and characteristic pigmentary findings support NSML over classic Noonan syndrome.
  - PTPN11 variant context and clinical trajectory help separate NSML from other Noonan subtypes.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two with Noonan syndrome with multiple lentigines (both with variants in PTPN11)
    explanation: >-
      Supports NSML as a frequent practical differential diagnosis in
      Noonan-spectrum genomic evaluation.
  - reference: PMID:20301557
    reference_title: "Noonan Syndrome with Multiple Lentigines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Noonan syndrome with multiple lentigines (NSML) is a condition in which the
      cardinal features consist of lentigines, hypertrophic cardiomyopathy, short
      stature, pectus deformity, and dysmorphic facial features including widely
      spaced eyes and ptosis.
    explanation: >-
      Supports the first distinguishing feature: lentigines are a cardinal NSML
      feature, alongside features NSML shares with Noonan syndrome.
  - reference: PMID:20301557
    reference_title: "Noonan Syndrome with Multiple Lentigines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In general, lentigines do not appear until age four to five years but then
      increase to the thousands by puberty. Some individuals with NSML do not
      exhibit lentigines.
    explanation: >-
      Supports the clinical-trajectory part of the second distinguishing
      feature: the separating pigmentary sign is age-dependent and can be
      absent, so young or lentigine-free patients are hard to separate from
      Noonan syndrome on examination.
  - reference: PMID:20301557
    reference_title: "Noonan Syndrome with Multiple Lentigines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The molecular diagnosis can be established in a proband with suggestive
      findings and a heterozygous pathogenic variant in one of four genes (BRAF,
      MAP2K1, PTPN11, and RAF1).
    explanation: >-
      Supports the variant-context part of the second distinguishing feature:
      the NSML gene set overlaps the Noonan gene set, so genotype alone does
      not separate the two and is read together with the clinical picture.
progression:
- phase: Onset
  age_range: Antenatal to Childhood
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Antenatal"
    explanation: Orphanet records antenatal onset as a recognized age-of-onset category for Noonan syndrome.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset for Noonan syndrome.
treatments:
- name: Growth Hormone Therapy
  description: >-
    Recombinant human growth hormone (rhGH) is FDA-approved for treatment of short
    stature
    in Noonan syndrome. Can improve final adult height by approximately 1 standard
    deviation.
  treatment_term:
    preferred_term: human growth hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:41577878
    reference_title: "Noonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GH therapy was associated with an increase in height SDS from -2.92 to
      -1.97 (median) following 5 years, and to -1.68 in those with final height.
    explanation: >-
      Large multicenter cohort evidence supports growth hormone therapy for
      short stature in Noonan syndrome spectrum disorders.
- name: Cardiac Surgical Intervention
  description: >-
    Percutaneous balloon pulmonary valvuloplasty for valvar pulmonary stenosis,
    with high reintervention rates in Noonan syndrome and surgery for a subset;
    septal myectomy for obstructive hypertrophic cardiomyopathy; and surgical
    closure of associated atrial septal defects.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:41718520
    reference_title: "Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was treated with trametinib to improve cardiac hypertrophy and
      then underwent successful surgical closure of the atrial septal defect.
    explanation: >-
      Supports the atrial septal defect closure part of the description, and
      shows surgery staged after medical treatment of severe Noonan-associated
      hypertrophic cardiomyopathy. It does not bear on pulmonary stenosis or
      myectomy, which the items below support.
  - reference: PMID:24534818
    reference_title: "Cardiovascular disease in Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiovascular outcomes that differed specifically in a NS cohort included
      high re-intervention rates (65%) after percutaneous balloon pulmonary
      valvuloplasty for valvar pulmonary stenosis.
    explanation: >-
      A 293-patient Noonan registry reports balloon pulmonary valvuloplasty as
      the intervention for valvar pulmonary stenosis, and its high
      reintervention rate in Noonan syndrome.
  - reference: PMID:23312968
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      About a third of patients with pulmonary stenosis needed surgery or a
      repeat procedure.
    explanation: >-
      Supports surgery or repeat intervention for pulmonary stenosis in a
      subset of Noonan patients on long-term follow-up.
  - reference: PMID:41288545
    reference_title: "Biventricular Surgical Approach in Noonan Syndrome With Hypertrophic Obstructive Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient developed symptomatic hypertrophic obstructive cardiomyopathy,
      characterized by biventricular outflow tract obstruction. Surgical
      intervention was performed, including atrial septal defect closure and
      myectomy through left and right ventriculotomy approaches.
    explanation: >-
      Case report of septal myectomy, with atrial septal defect closure, for
      obstructive hypertrophic cardiomyopathy in a patient with Noonan syndrome.
- name: MEK Inhibitor Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Trametinib (MEK1/2 inhibitor) has shown promising results in case reports
    for treatment-refractory hypertrophic cardiomyopathy and lymphatic complications
    such as chylothorax. Pathway inhibition alleviates cardiac hypertrophy in a
    RIT1 mutant mouse model.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: trametinib
      term:
        id: CHEBI:75998
        label: trametinib
  target_mechanisms:
  - target: ERK Cascade Hyperactivation
    treatment_effect: INHIBITS
    description: >-
      Trametinib directly reduces MEK-ERK pathway signaling, the convergent
      pathway node downstream of multiple Noonan genotypes.
    evidence:
    - reference: PMID:41718520
      reference_title: "Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Trametinib, an MEK inhibitor that attenuates abnormal signaling in the
        RAS/MAPK pathway, has been shown to improve NS-HCM outcomes.
      explanation: >-
        Directly supports trametinib as a MEK inhibitor that attenuates abnormal
        RAS/MAPK signaling in Noonan-associated hypertrophic cardiomyopathy.
  - target: Cardiomyocyte Hypertrophy
    treatment_effect: INHIBITS
    description: >-
      Off-label MEK inhibition ameliorates the hypertrophy itself, not only the
      signalling upstream of it, in an infant case report and in the Raf1 L613V
      knock-in. The adult RAF1 case report responded in outflow-tract
      obstruction, not in wall thickness or left ventricular mass, so
      regression of the hypertrophy itself has so far been reported only in the
      infant case and the mouse model.
    evidence:
    - reference: PMID:35052347
      reference_title: "MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Trametinib was introduced (0.022 mg/kg/day) with prompt clinical
        improvement and subsequent amelioration of HCM at ultrasound.
      explanation: >-
        Reports a hypertrophy outcome directly: the RAF1 p.Ser257Leu infant's
        hypertrophic cardiomyopathy improved at ultrasound on trametinib.
    - reference: PMID:21339642
      reference_title: "MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        postnatal MEK inhibition normalized the growth, facial, and cardiac
        defects in L613V/+ mice
      explanation: >-
        In the Raf1 L613V knock-in, whose cardiac defect is eccentric
        hypertrophy, postnatal MEK inhibition normalized it.
    - reference: PMID:38827265
      reference_title: "Treatment of RAF1-Related Obstructive Hypertrophic Cardiomyopathy by MEK Inhibition Using Trametinib."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiac magnetic resonance imaging following treatment with trametinib
        showed no objective differences with respect to maximal wall thickness,
        global left ventricular mass, left ventricular aneurysm, or myocardial
        fibrosis
      explanation: >-
        In the adult RAF1 patient, trametinib did not change wall thickness or
        left ventricular mass on cardiac MRI; the benefit was a reduction in
        outflow obstruction. The hypertrophy itself did not regress in this
        case.
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  - preferred_term: Chylothorax
    term:
      id: HP:0010310
      label: Chylothorax
  notes: >-
    Emerging therapy based on case reports; controlled trials are needed.
    Typical pediatric dosing 0.01-0.025 mg/kg/day.
  evidence:
  - reference: PMID:41718520
    reference_title: "Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trametinib, an MEK inhibitor that attenuates abnormal signaling in the
      RAS/MAPK pathway, has been shown to improve NS-HCM outcomes.
    explanation: >-
      Supports MEK inhibition as a targeted strategy for severe
      Noonan-associated hypertrophic cardiomyopathy in early clinical use.
  - reference: DOI:10.3389/fped.2025.1475143
    reference_title: "Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our patient, a five-week trametinib course, maximum dose 0.025
      mg/kg/day, led to chylothorax resolution and gradual pulmonary function
      improvement
    explanation: >-
      Case report supporting the lymphatic part of the description and the
      chylothorax target phenotype, in an infant with a PTPN11 Noonan variant.
  - reference: DOI:10.1126/sciadv.adf4766
    reference_title: "RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with aberrant RAF/MAPK activation as a driver of disease, we
      show that pathway inhibition alleviates cardiac hypertrophy in a mouse
      model of RIT1 mutant Noonan syndrome.
    explanation: >-
      Supports the animal-model sentence of the description.
  - reference: PMID:35052347
    reference_title: "MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trametinib was introduced (0.022 mg/kg/day) with prompt clinical
      improvement and subsequent amelioration of HCM at ultrasound.
    explanation: >-
      Preterm infant with the RAF1 p.Ser257Leu variant whose hypertrophic
      cardiomyopathy improved on trametinib, supporting MEK inhibition in
      RAF1-driven neonatal disease.
  - reference: PMID:35052347
    reference_title: "MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While MEK-inhibition appears a promising therapeutic option for HCM in
      RASopathies, it appears insufficient to revert pulmonary hypertension.
    explanation: >-
      The same patient's pulmonary vascular disease did not respond, so the
      benefit is bounded to the hypertrophic arm and does not extend to the
      pulmonary vascular arm of RAF1-associated disease.
  - reference: PMID:38827265
    reference_title: "Treatment of RAF1-Related Obstructive Hypertrophic Cardiomyopathy by MEK Inhibition Using Trametinib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide the first report of the successful treatment of an adult with
      RAF1-associated hypertrophic cardiomyopathy using trametinib, a MEK
      inhibitor.
    explanation: >-
      Extends a reported benefit beyond infancy to an 18-year-old with severe
      obstructive disease. The benefit in this adult was in left ventricular
      outflow tract obstruction, not in wall thickness or ventricular mass,
      which were unchanged on cardiac MRI.
- name: Early Intervention Services
  description: >-
    Developmental support including speech therapy, physical therapy, occupational
    therapy, and special education services for developmental delays and learning
    disabilities.
  treatment_term:
    preferred_term: early intervention services
    term:
      id: NCIT:C159524
      label: Early Intervention
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental disabilities are addressed by early intervention programs
      and individualized education strategies.
    explanation: >-
      GeneReviews supports early intervention services as standard management
      for developmental disability in Noonan syndrome.
- name: Speech Therapy
  description: >-
    Speech and language therapy for articulation difficulties and language delays.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physiotherapy and/or speech therapy should be offered if indicated.
    explanation: >-
      Supports speech therapy as recommended supportive care in Noonan syndrome
      management.
- name: Physical Therapy
  description: >-
    Physical therapy to address motor delays and hypotonia common in Noonan syndrome.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physiotherapy and/or speech therapy should be offered if indicated.
    explanation: >-
      Supports physiotherapy (physical therapy) for motor/developmental support
      in Noonan syndrome.
definitions:
- name: Noonan syndrome molecular-clinical case definition
  definition_type: CASE_DEFINITION
  description: >-
    Noonan syndrome is defined as a RASopathy with compatible craniofacial,
    growth, developmental, and cardiovascular phenotype supported by molecular
    evidence in a causative RAS-MAPK pathway gene.
  scope: Clinical genetics and pediatric cardiology evaluation for suspected RASopathy
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RASopathies are a heterogeneous group of conditions of the
      RAS/mitogen-activated protein kinase pathway presenting with overlapping
      features such as growth deficiency, neurodevelopmental disorders, cardiac
      defects, craniofacial dysmorphisms, cutaneous and ocular abnormalities,
      and increased cancer risk.
    explanation: >-
      Cohort evidence supports a combined phenotype-plus-genotype approach for
      Noonan syndrome case definition in modern practice.
- name: Orphanet disease definition
  definition_type: CASE_DEFINITION
  description: >
    Orphanet defines Noonan syndrome as a rare, highly variable, multisystemic
    disorder mainly characterized by short stature, distinctive facial features,
    congenital heart defects, cardiomyopathy and an increased risk to develop
    tumors in childhood.
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare, highly variable, multisystemic disorder mainly characterized by short stature, distinctive facial features, congenital heart defects, cardiomyopathy and an increased risk to develop tumors in childhood."
    explanation: Orphanet's definition supports the multisystem characterization of this entry.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:41675685
      reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        RASopathies are a heterogeneous group of conditions of the
        RAS/mitogen-activated protein kinase pathway presenting with
        overlapping features such as growth deficiency, neurodevelopmental
        disorders, cardiac defects, craniofacial dysmorphisms, cutaneous and
        ocular abnormalities, and increased cancer risk.
      explanation: >-
        Supports Noonan syndrome as an inherited RAS-MAPK pathway disorder
        within hereditary disease classification.
  - classification_value: CARDIOVASCULAR
    evidence:
    - reference: PMID:41675685
      reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main reason for referral was diagnostic assessment due to a
        combination of dysmorphic features (24/24; 100%), growth deficiency
        (18/24; 75%), neurodevelopmental disorders (15/24; 62.5%), and/or heart
        disease (13/24; 54.1%).
      explanation: >-
        Supports cardiovascular disorder classification based on substantial
        burden of congenital and structural heart disease in Noonan-spectrum
        patients.
external_assertions:
- name: Orphanet Noonan syndrome record
  source: Orphanet
  assertion_type: Structured disease record
  external_id: ORPHA:648
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=648
  description: >
    Orphanet structured record for Noonan syndrome, including curated
    cross-references to MONDO, ICD-10, ICD-11, OMIM, MeSH, MedDRA, and UMLS
    identifiers.
  evidence:
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0018997 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:648 to MONDO:0018997.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:Q87.1 | Narrower"
    explanation: The Orphanet cross-reference table maps ORPHA:648 to ICD-10 Q87.1 (narrower).
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-11:LD2F.15 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:648 to ICD-11 LD2F.15.
  - reference: ORPHA:648
    reference_title: "Noonan syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UMLS:C0028326 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:648 to UMLS C0028326.
animal_models:
- name: Chick neural tube electroporation of PTPN11 variants
  species: Chicken
  genotype: >-
    Wild-type and Noonan-spectrum PTPN11 variants (including c.172A>G/N58D,
    c.922A>G/N308D and c.1282G>A/V428M) cloned into pCIG and unilaterally
    electroporated into the neural tube at HH10-11
  category: somatic gene transfer model
  publication: PPR:PPR1278294
  description: >-
    An accessible in vivo assay for the neural crest arm of Noonan syndrome.
    Constructs are electroporated unilaterally into the chick neural tube, so the
    contralateral side and a parallel empty-vector condition serve as internal
    controls, and GFP-positive descendants are then scored at 24 and 48 hours in
    neural-crest derivatives — dorsal root ganglia, melanocyte precursors and
    Schwann cell precursors. Its value here is that it reads out neural crest
    *behaviour* in an intact embryo rather than steady-state pathway activity in
    a cell line, and it is what produced the observation that a variant with no
    measurable increase in ERK phosphorylation can still perturb neural crest
    development.
  genes:
  - preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  modeled_mechanisms:
  - target: Neural Crest Cell Developmental Dysregulation
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Variant-specific perturbation of neural crest allocation and spatial
      organisation, assayed directly in the migrating lineage.
    limitations: >-
      Three caveats stack here and none should be dropped when citing this
      model. It is a *preprint* — not peer reviewed — so it must not be sole
      support for any mechanistic claim. It is an overexpression assay: mutant
      constructs produced higher-than-endogenous SHP2 levels, so dosage effects
      cannot be cleanly separated from allele-specific effects, and the reported
      lineage-sensitivity ordering rests on that. And avian trunk neural crest is
      not the cranial neural crest that generates the human Noonan facial
      skeleton, with some conditions run at n = 2 embryos.
    readouts:
    - name: Melanocyte precursor distribution in skin
      target: Neural Crest Cell Developmental Dysregulation
      description: >-
        Spatial distribution of GFP-positive melanocyte precursors in
        whole-mount cleared embryos at 48 hours post-electroporation, compared
        against the wild-type PTPN11 condition.
      direction: ALTERED
      interpretation: >-
        Clustering rather than even distribution indicates altered allocation of
        a neural crest derivative; it is a spatial-organisation readout, not a
        cell-number one.
      evidence:
      - reference: PPR:PPR1278294
        reference_title: "An integrated computational, clinical, and functional framework for assessing  <i>PTPN11</i>  (SHP2) variant effects on ERK signaling and neural crest cell behavior in Noonan spectrum disorders"
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In contrast, all mutant PTPN11 variants induced a clustered
          distribution of melanocyte precursors.
        explanation: >-
          Reports the measurement in the stated direction, and notably as a
          shared effect of every mutant tested rather than a single-variant
          finding.
    evidence:
    - reference: PPR:PPR1278294
      reference_title: "An integrated computational, clinical, and functional framework for assessing  <i>PTPN11</i>  (SHP2) variant effects on ERK signaling and neural crest cell behavior in Noonan spectrum disorders"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These findings highlight the sensitivity of neural crest development to
        variant-specific perturbations of SHP2 function.
      explanation: >-
        Supports treating the chick neural tube assay as informative for the
        neural crest node, while the preprint status keeps it corroborative
        rather than load-bearing — the node itself rests on the peer-reviewed
        mouse and zebrafish evidence.
- species: Mouse
  genotype: RIT1 mutant Noonan syndrome mouse model
  category: mutant mouse model
  description: >-
    Pathogenic RIT1 mouse modeling supports aberrant RAF/MAPK activation as a
    driver of Noonan-associated cardiac hypertrophy and as a tractable
    therapeutic axis.
  genes:
  - preferred_term: RIT1
    term:
      id: hgnc:10023
      label: RIT1
  associated_phenotypes:
  - Cardiac hypertrophy
  - RAF/MAPK hyperactivation
  evidence:
  - reference: DOI:10.1126/sciadv.adf4766
    reference_title: "RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK)
      hyperactivation
    explanation: >-
      Supports MAPK hyperactivation as a disease-relevant signaling phenotype
      in pathogenic RIT1 Noonan syndrome models.
  - reference: DOI:10.1126/sciadv.adf4766
    reference_title: "RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary
      for MAPK activation.
    explanation: >-
      Identifies RAF-dependent MAPK activation as a mechanistic feature of the
      RIT1 mutant model.
- species: Mouse
  genotype: Lztr1G245R/+ and Lztr1R409C/+ knock-in
  category: knock-in model
  description: >-
    Dominant LZTR1 knock-in mouse models reproduce Noonan-like growth, facial,
    and cardiac phenotypes with activated ventricular MAPK signaling.
  genes:
  - preferred_term: LZTR1
    term:
      id: hgnc:6742
      label: LZTR1
  associated_phenotypes:
  - Low birth weight
  - Distinctive facial features
  - Cardiac hypertrophy
  - MAPK pathway activation
  evidence:
  - reference: PMID:39352760
    reference_title: "Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      LZTR1-mutant male mice exhibit low birth weight, distinctive facial
      features, and cardiac hypertrophy.
    explanation: >-
      Directly supports LZTR1 knock-in mice as a Noonan-like animal model with
      growth, craniofacial, and cardiac phenotypes.
  - reference: PMID:39352760
    reference_title: "Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Multi-omics analysis revealed that the mitogen-activated protein kinase
      (MAPK) signaling pathway was activated in the LVs of mutant mice.
    explanation: >-
      Supports MAPK pathway activation as a mechanistic readout in the LZTR1
      knock-in model.
- species: Mouse
  genotype: Noonan syndrome-causing SHP2 mutant mouse model
  category: mutant mouse model
  description: >-
    SHP2/PTPN11 Noonan mouse modeling links local RAS/ERK hyperactivation in
    growth-plate chondrocytes to impaired endochondral bone growth.
  genes:
  - preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  associated_phenotypes:
  - Growth plate shortening
  - Impaired chondrocyte differentiation
  - Growth retardation
  evidence:
  - reference: PMID:29659837
    reference_title: "Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We demonstrated that growth plate length was reduced in NS mice, mostly
      due to a shortening of the hypertrophic zone and to a lesser extent of the
      proliferating zone.
    explanation: >-
      Supports growth-plate shortening as a phenotype reproduced in Noonan
      syndrome SHP2 mutant mice.
  - reference: PMID:29659837
    reference_title: "Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      NS-causing SHP2 mutants enhance RAS/ERK activation in chondrocytes in
      vivo (NS mice) and in vitro (ATDC5 cells)
    explanation: >-
      Supports local chondrocyte RAS/ERK activation as a mechanistic feature of
      the PTPN11/SHP2 growth-plate model.
- name: Raf1 L613V knock-in mouse
  species: Mouse
  genotype: Raf1 L613V/+ heterozygous knock-in
  category: knock-in mouse model
  publication: PMID:21339642
  description: >-
    Heterozygous knock-in of the Noonan-associated Raf1 L613V allele at the
    endogenous locus. The mice reproduce short stature, craniofacial
    dysmorphia, hematologic abnormalities and eccentric cardiac hypertrophy
    with reactivation of the cardiac fetal gene programme, and MEK inhibition
    started after birth normalizes the growth, facial and cardiac phenotypes.
    Valvuloseptal development is normal, so the model separates the postnatal
    hypertrophic arm of RAF1-driven disease from the valve arm.
  genes:
  - preferred_term: RAF1
    term:
      id: hgnc:9829
      label: RAF1
  associated_phenotypes:
  - Eccentric cardiac hypertrophy
  - Short stature
  - Craniofacial dysmorphia
  modeled_mechanisms:
  - target: RAF1 Kinase Hyperactivation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      The disease allele is knocked in at the endogenous Raf1 locus, so the
      model carries the kinase-activating lesion itself rather than a
      downstream surrogate of it.
    limitations: >-
      L613V is a murine knock-in of a human NS allele; allele-specific
      differences between RAF1 variants are not captured by a single knock-in.
    evidence:
    - reference: PMID:21339642
      reference_title: "MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we generated knockin mice expressing the NS-associated Raf1(L613V)
        mutation
      explanation: >-
        Establishes that the model carries the Noonan-associated
        kinase-activating RAF1 allele at the endogenous locus.
  - target: ERK Cascade Hyperactivation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Agonist-evoked MEK-ERK signalling is elevated across several cell types
      in the knock-in, and pharmacological MEK inhibition reverses the
      organ-level phenotypes it drives.
    evidence:
    - reference: PMID:21339642
      reference_title: "MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Agonist-evoked MEK-ERK activation was enhanced in multiple cell types
      explanation: >-
        Reports elevated MEK-ERK signalling in the knock-in, the node this link
        claims the model reproduces.
  - target: Cardiomyocyte Hypertrophy
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      The knock-in develops eccentric cardiac hypertrophy with fetal gene
      reactivation and decompensates under pressure overload. MEK inhibition
      begun postnatally normalizes the cardiac phenotype, which is the result
      behind treating MEK as the actionable node for RAF1-driven hypertrophy.
    limitations: >-
      The hypertrophy is eccentric, whereas RAF1-associated human disease is
      typically concentric obstructive hypertrophic cardiomyopathy. Contractile
      and mitochondrial function were not assessed, so this model says nothing
      about the cardiotoxic arm of MEK inhibition.
    readouts:
    - name: Cardiac mass and fetal gene programme
      target: Cardiomyocyte Hypertrophy
      direction: INCREASED
      interpretation: >-
        Structural and transcriptional correlate of the hypertrophy node in
        this model.
      evidence:
      - reference: PMID:21339642
        reference_title: "MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          L613V/+ mice exhibited eccentric cardiac hypertrophy and aberrant
          cardiac fetal gene expression, and decompensated following pressure
          overload
        explanation: >-
          Reports the hypertrophy and fetal gene reactivation measured in this
          model.
    evidence:
    - reference: PMID:21339642
      reference_title: "MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        postnatal MEK inhibition normalized the growth, facial, and cardiac
        defects in L613V/+ mice
      explanation: >-
        Supports treating the model as informative for the hypertrophy node,
        since inhibiting the pathway after birth reverses the cardiac
        phenotype.
  - target: Cardiac Valve Morphogenesis Defects
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Valvuloseptal development is explicitly normal in this model, so a RAF1
      kinase-activating allele sufficient to drive postnatal hypertrophy does
      not on its own reproduce the valve lesion.
    limitations: >-
      The negative result is specific to the L613V allele on this background
      and does not exclude a valve phenotype from other Noonan genotypes; the
      Tie2-Cre Q79R-Shp2 endocardial-cushion model does reproduce that node.
    evidence:
    - reference: PMID:21339642
      reference_title: "MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Valvuloseptal development was normal, but L613V/+ mice exhibited
        eccentric cardiac hypertrophy
      explanation: >-
        States directly that valve and septal development are unaffected in
        this model, refuting its use for the valve morphogenesis node.
- name: Tie2-Cre Q79R-Shp2 endocardial cushion mouse
  species: Mouse
  genotype: Tie2-Cre driven endothelial-lineage Q79R-Shp2 transgene
  category: conditional transgenic mouse model
  publication: PMID:19017799
  description: >-
    Endocardial-lineage expression of the Noonan-associated Q79R-Shp2 allele,
    activated by Tie2-Cre in endothelial-derived cells. Mutant embryos die by
    E14.5 with enlarged atrioventricular canal and outflow tract cushions,
    which wild-type Shp2 at comparable levels does not cause. Deleting ERK1
    fully rescues the cushion phenotype, placing ERK1 downstream of SHP2 in
    the valve arm of the disease.
  genes:
  - preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  associated_phenotypes:
  - Enlarged endocardial cushions
  - Embryonic lethality
  modeled_mechanisms:
  - target: Cardiac Valve Morphogenesis Defects
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      An embryonic system at the developmental stage the valve node describes,
      observing the cushion overgrowth that precedes the pulmonary valve
      lesion. It is the only model linked to this node; the postnatal Raf1
      L613V knock-in has normal valvuloseptal development.
    limitations: >-
      Embryonic lethality by E14.5 precludes any postnatal or adult valve
      readout, so mature valve morphology and its haemodynamic consequences
      are outside the model. The allele is transgenically overexpressed in the
      endothelial lineage rather than carried at the endogenous locus.
    readouts:
    - name: Endocardial cushion size
      target: Cardiac Valve Morphogenesis Defects
      direction: INCREASED
      interpretation: >-
        Cushion overgrowth is the embryonic correlate of the valve
        morphogenesis node.
      evidence:
      - reference: PMID:19017799
        reference_title: "Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          mutant embryos showed significantly enlarged endocardial cushions in
          the atrioventricular canal and in the outflow tract
        explanation: >-
          Reports the cushion measurement that grounds this readout.
    evidence:
    - reference: PMID:19017799
      reference_title: "Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Deletion of ERK1 completely rescued the endocardial cushion phenotype,
        whereas ERK2 protein reduction did not affect endocardial cushion size.
      explanation: >-
        The genetic rescue establishes that the cushion phenotype in this model
        is driven by the pathway the node describes, supporting its use for the
        valve morphogenesis node.
  - target: ERK Cascade Hyperactivation
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Mutant Shp2 expression raises ERK1/2 activation in cushion mesenchyme,
      and the ERK1 deletion cross shows that this activation is necessary for
      the resulting phenotype.
    evidence:
    - reference: PMID:19017799
      reference_title: "Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Expression of Q79R-Shp2 was accompanied by increased ERK1/2 activation
        in a subset of cells within the cushion mesenchyme
      explanation: >-
        Reports the ERK activation this link claims the model perturbs.
experimental_models:
- name: Noonan syndrome cortical organoid model
  description: >-
    Human Noonan syndrome induced pluripotent stem cell-derived cortical organoids
    with matched corrected controls used to study cortical layer specification and
    neuronal connectivity phenotypes.
  experimental_model_type: ORGANOID
  namo_type: namo:Organoid
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  conditions:
  - Noonan syndrome
  - isogenic corrected control
  cell_source: Noonan syndrome induced pluripotent stem cells differentiated into cortical organoids
  culture_system: Three-dimensional cortical organoid time-course culture
  publication: PMID:36430334
  findings:
  - statement: Noonan cortical organoids show abnormal excitatory-neuron composition, cortical-layer identity, and reduced synaptic connectivity
    evidence:
    - reference: PMID:36430334
      reference_title: "Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs)."
      explanation: Establishes that NS-derived cortical organoids capture disease-relevant neurodevelopmental abnormalities.
    - reference: PMID:36430334
      reference_title: "Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity contribute to the neurological manifestations of NS."
      explanation: Supports mechanistic alignment of the organoid model with neurological manifestations in Noonan syndrome.
  modeled_mechanisms:
  - target: Cortical Layer Development Abnormalities
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      NS iPSC-derived cortical organoids reproduce the excitatory-neuron
      overrepresentation, aberrant SATB2/CTIP2 co-expressing layer identity,
      and reduced synaptic connectivity that define this node.
    limitations: >-
      Organoids "develop normally in their appearance" — the defect is
      transcriptomic and connectivity-level rather than gross morphological,
      and the model lacks vasculature and microglia, so non-cell-autonomous
      contributions to cortical development cannot be assessed.
    readouts:
    - name: Excitatory neuron population size
      target: Cortical Layer Development Abnormalities
      description: Single-cell transcriptomic quantification of excitatory neurons in NS cortical organoids versus isogenic controls.
      direction: INCREASED
      interpretation: An expanded excitatory-neuron population is the cellular-composition correlate of the layer-identity disruption this node describes.
      evidence:
      - reference: PMID:36430334
        reference_title: "Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "single-cell transcriptomic analysis revealed an increase in the EN population and overexpression of cortical layer markers in NS-COs."
        explanation: Directly reports the excitatory-neuron population readout.
    - name: SATB2/CTIP2 co-expressing subpopulation
      target: Cortical Layer Development Abnormalities
      description: Frequency of the upper-layer/deep-layer marker co-expressing excitatory neuron subpopulation.
      direction: INCREASED
      interpretation: A layer-marker co-expressing subpopulation is a specific signature of disrupted cortical layer specification.
      evidence:
      - reference: PMID:36430334
        reference_title: "Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "the EN subpopulation co-expressing the upper layer marker SATB2 and the deep layer maker CTIP2 was enriched in NS-COs during cortical development."
        explanation: Directly reports the SATB2/CTIP2 co-expression readout.
    - name: Synaptic connectivity
      target: Cortical Layer Development Abnormalities
      description: Synaptic connectivity assessment in NS cortical organoids.
      direction: DECREASED
      interpretation: Reduced synaptic connectivity is the functional correlate accompanying the layer-identity disruption.
      evidence:
      - reference: PMID:36430334
        reference_title: "Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "NS-COs also exhibited reduced synaptic connectivity."
        explanation: Directly reports the synaptic connectivity readout.
    evidence:
    - reference: PMID:36430334
      reference_title: "Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs)."
      explanation: Establishes the cortical organoid as informative for the Cortical Layer Development Abnormalities node.
  evidence:
  - reference: PMID:36430334
    reference_title: "Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs)."
    explanation: Supports a first-class cortical organoid model for Noonan syndrome.
  notes: >-
    Replaces the prior implicit reliance on GEO-only cross-reference with a
    direct disease-model anchor publication.
- name: Noonan syndrome iPSC-cardiomyocyte model
  description: >-
    Patient-derived Noonan syndrome induced pluripotent stem cell cardiomyocytes
    modeling childhood-onset cardiomyopathy and RAF1/PTPN11-driven transcriptional
    dysregulation with matched corrected or comparator controls.
  experimental_model_type: IPSC_DERIVED_MODEL
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  conditions:
  - Noonan syndrome-associated cardiomyopathy
  - RAF1 S257L/+ Noonan syndrome
  - PTPN11N308S/+ Noonan syndrome
  cell_source: Patient-derived induced pluripotent stem cell-derived cardiomyocytes with isogenic or non-diseased controls
  culture_system: Two-dimensional iPSC-cardiomyocyte differentiation with transcriptomic and pathway-perturbation readouts
  publication: PMID:34988410
  findings:
  - statement: Noonan iPSC-cardiomyocytes capture cardiomyopathy-linked cell-cycle and signaling defects in a genotype-resolved human cardiac model
    evidence:
    - reference: PMID:34988410
      reference_title: "Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, through analysis of sarcomeric myosin conformational states,
        histopathology, and gene expression in left ventricular myocardial tissue
        from NS-CM, HCM, and normal hearts complemented with disease modeling in
        cardiomyocytes differentiated from patient-derived PTPN11 N308S/+
        induced pluripotent stem cells, we demonstrate distinct disease
        phenotypes between NS-CM and HCM and uncover cell cycle defects as a
        potential driver of NS-CM.
      explanation: Supports patient-derived iPSC-cardiomyocytes as a disease-relevant Noonan cardiomyopathy model.
    - reference: PMID:31163979
      reference_title: "Inducible Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1-Associated Noonan Syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        METHODS: We used patient-derived RAF1S257L/+ and CRISPR-Cas9-generated
        isogenic control inducible pluripotent stem cell (iPSC)-derived
        cardiomyocytes to model NS RAF1-associated HCM and to further delineate
        the molecular mechanisms underlying the disease.
      explanation: Supports mutation-specific mechanistic modeling in Noonan iPSC-cardiomyocytes.
  modeled_mechanisms:
  - target: Cardiomyocyte Hypertrophy
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      PTPN11 N308S/+ iPSC-cardiomyocytes reproduce the hypertrophic phenotype
      but argue it is driven by cell-cycle defects rather than by the
      ERK/AKT-mTOR hypertrophic-growth program this node describes.
    limitations: >-
      The paper's central argument is that NS-CM is mechanistically distinct
      from sarcomeric HCM and driven by cell-cycle defects in cardiomyocytes,
      a mechanism this node's description (sustained ERK plus AKT/mTOR driving
      hypertrophic growth and fetal gene reprogramming) does not represent.
      The entry has no dedicated cell-cycle pathophysiology node to link this
      model to instead.
    evidence:
    - reference: PMID:34988410
      reference_title: "Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, through analysis of sarcomeric myosin conformational states,
        histopathology, and gene expression in left ventricular myocardial tissue
        from NS-CM, HCM, and normal hearts complemented with disease modeling in
        cardiomyocytes differentiated from patient-derived PTPN11 N308S/+
        induced pluripotent stem cells, we demonstrate distinct disease
        phenotypes between NS-CM and HCM and uncover cell cycle defects as a
        potential driver of NS-CM.
      explanation: States the paper's own conclusion that cell-cycle defects, not the ERK/AKT-mTOR program, are the candidate driver of NS-CM.
  - target: ERK Cascade Hyperactivation
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Pharmacological and genetic perturbation of MEK1/2, ERK1/2, and ERK5 in
      RAF1 S257L/+ iPSC-cardiomyocytes dissects which arm of RAS-MAPK
      signaling drives which part of the hypertrophic phenotype.
    readouts:
    - name: Cardiomyocyte hypertrophy after MEK1/2-ERK1/2 inhibition
      target: ERK Cascade Hyperactivation
      description: >-
        Cell surface area of RAF1S257L/+ iPSC-cardiomyocytes treated with the
        MEK1/2 inhibitors PD98059 or Trametinib, which strongly reduce ERK1/2
        phosphorylation.
      direction: UNCHANGED
      interpretation: >-
        MEK1/2-ERK1/2 inhibition abolishes ERK1/2 activation without reducing
        cell size, so this model refutes ERK1/2 signaling specifically as the
        driver of the hypertrophy this entry's ERK Cascade Hyperactivation to
        Cardiomyocyte Hypertrophy edge asserts. The paper instead attributes
        the enlarged-cell phenotype to ERK5, a MAPK pathway this entry does
        not otherwise model.
      evidence:
      - reference: PMID:31163979
        reference_title: "Inducible Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1-Associated Noonan Syndrome."
        supports: REFUTE
        evidence_source: IN_VITRO
        snippet: >-
          Importantly, although ERK1/2 activation was strongly reduced, there
          was no significant effect on hypertrophy in RAF1S257L/+ iCMs in
          response to treatment with either PD98059 or Trametinib (Fig.4C–D),
          suggesting that MEK1/2-ERK1/2 activation is not the principal driver
          of hypertrophy in NS-associated RAF1 mutations.
        explanation: Directly reports the negative result for ERK1/2 as the hypertrophy driver.
      - reference: PMID:31163979
        reference_title: "Inducible Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1-Associated Noonan Syndrome."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          the enlarged cardiomyocyte phenotype is a direct consequence of
          increased extracellular regulated kinase 5 (ERK5) signaling, a
          pathway not previously known to be involved in NS.
        explanation: Reports the alternative driver the paper identifies for the hypertrophic phenotype.
    evidence:
    - reference: PMID:31163979
      reference_title: "Inducible Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1-Associated Noonan Syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        METHODS: We used patient-derived RAF1S257L/+ and CRISPR-Cas9-generated
        isogenic control inducible pluripotent stem cell (iPSC)-derived
        cardiomyocytes to model NS RAF1-associated HCM and to further delineate
        the molecular mechanisms underlying the disease.
      explanation: Establishes the model as informative for dissecting which arm of the ERK cascade node drives which part of the phenotype.
  evidence:
  - reference: PMID:34988410
    reference_title: "Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, through analysis of sarcomeric myosin conformational states,
      histopathology, and gene expression in left ventricular myocardial tissue
      from NS-CM, HCM, and normal hearts complemented with disease modeling in
      cardiomyocytes differentiated from patient-derived PTPN11 N308S/+
      induced pluripotent stem cells, we demonstrate distinct disease
      phenotypes between NS-CM and HCM and uncover cell cycle defects as a
      potential driver of NS-CM.
    explanation: Supports this as a first-class Noonan iPSC-cardiomyocyte model entry.
  notes: >-
    Groups the two strongest existing dismech cardiac experimental-model resources under a single
    disease-level experimental-model concept.
- name: Paediatric Noonan syndrome myocardial tissue slice model
  description: >-
    Living right ventricular myocardial slices cut from myocardium resected at
    surgery from a child with RASopathy-associated hypertrophic cardiomyopathy,
    cultivated in biomimetic cultivation chambers and electrically stimulated.
    Slices were treated with trametinib, rapamycin, dasatinib or DMSO, and
    contractile force, force-frequency relationship and post-pause potentiation
    were compared before and after treatment. It is the only human,
    force-generating, multicellular system linked to the cardiac axis of this
    entry; the curated iPSC-cardiomyocyte model is human but unloaded, and the
    Raf1 L613V knock-in is loaded but murine.
  experimental_model_type: OTHER
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: right ventricular myocardium
    term:
      id: UBERON:0002080
      label: heart right ventricle
  conditions:
  - trametinib
  - rapamycin
  - dasatinib
  - DMSO vehicle control
  cell_source: Right ventricular myocardium resected at surgery from a paediatric Noonan syndrome hypertrophic cardiomyopathy patient carrying RAF1 c.775T>A (p.Ser259Thr)
  culture_system: Electrically stimulated living myocardial slices in biomimetic cultivation chambers
  publication: PMID:39573843
  modeled_mechanisms:
  - target: Cardiomyocyte Hypertrophy
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The slices are the patient's own hypertrophic myocardium rather than a
      system engineered to resemble it, so the human genotype, the
      multicellular composition and the contractile apparatus are all native.
    limitations: >-
      Tissue from a single patient, so nothing here speaks to variability
      across RASopathy genotypes. Slices are explanted, so they carry no
      haemodynamic load, no circulating neurohormonal input and no ongoing
      remodelling, and culture duration bounds the timescale observable.
    evidence:
    - reference: PMID:39573843
      reference_title: "Trametinib alters contractility of paediatric Noonan syndrome-associated hypertrophic myocardial tissue slices."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Contracting right ventricular (RV) tissue slices were prepared from
        resected myocardium, cultivated in BMCCs and treated with distinct
        molecules directly and indirectly targeting the RAS-MAPK pathway
      explanation: >-
        Establishes that the system is contracting native myocardium from the
        affected patient, which is what grounds its use for the hypertrophy
        node.
  - target: ERK Cascade Hyperactivation
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Trametinib is applied directly to the slices, so the system reports what
      acute MEK inhibition does to contractile and calcium-handling behaviour
      in human RASopathy myocardium. The contractile and calcium readouts it
      produces sit on the MEASURES link below, since neither of them measures
      ERK activity.
    limitations: >-
      Acute drug exposure in explanted tissue, so it cannot show whether the
      force reduction persists, resolves or compounds over a treatment course,
      and single-patient tissue gives no estimate of variability. Mitochondrial
      respiration and STAT3 serine-727 phosphorylation, the readouts the
      cardiotoxicity module is built on, were not measured.
    evidence:
    - reference: PMID:39573843
      reference_title: "Trametinib alters contractility of paediatric Noonan syndrome-associated hypertrophic myocardial tissue slices."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        off-label treatment with MAPK kinase (MEK) inhibitor trametinib of a
        child with severe RAS-CM resulted in a modest reduction of RV outflow
        tract (RVOT) obstruction
      explanation: >-
        The same report's in vivo arm, in the patient the slices came from,
        supports MEK inhibition acting on this pathway clinically as well as ex
        vivo.
  - target: Cardiomyocyte Hypertrophy
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      What the slices actually measure under acute MEK inhibition: developed
      force and sarcoplasmic reticulum calcium handling in the patient's own
      hypertrophic myocardium. The two move in opposite directions, which is
      the only dataset in this entry touching both the therapeutic and the
      cardiotoxic reading of MEK inhibition at once.
    limitations: >-
      Neither readout measures hypertrophy itself; they report the contractile
      and calcium behaviour of hypertrophic tissue, which is why this link is
      MEASURES rather than a claim that the model reproduces the node. Acute
      exposure in one patient's explanted slices, so nothing here shows
      whether the force reduction persists, resolves or compounds over a
      treatment course.
    readouts:
    - name: Contractile force after trametinib
      target: Cardiomyocyte Hypertrophy
      direction: DECREASED
      interpretation: >-
        Acute MEK inhibition lowers developed force in human RASopathy
        myocardium. This is the direction the mek_inhibition_cardiac_mitochondrial_injury
        module's terminal node describes, measured here in a Noonan-variant
        context.
      evidence:
      - reference: PMID:39573843
        reference_title: "Trametinib alters contractility of paediatric Noonan syndrome-associated hypertrophic myocardial tissue slices."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In cultivated RV myocardial tissue slices, contraction force
          decreased after addition of trametinib and rapamycin but not after
          addition of DMSO and dasatinib.
        explanation: >-
          Reports the force measurement, with vehicle and inactive-comparator
          arms, that grounds this readout.
    - name: Post-pause potentiation after trametinib
      target: Cardiomyocyte Hypertrophy
      direction: INCREASED
      interpretation: >-
        Sarcoplasmic reticulum calcium handling improves under the same
        exposure that lowers developed force, so the two readouts of MEK
        inhibition in this tissue do not agree in sign.
      evidence:
      - reference: PMID:39573843
        reference_title: "Trametinib alters contractility of paediatric Noonan syndrome-associated hypertrophic myocardial tissue slices."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Improvement of Ca2+ handling, as depicted by a more positive
          force-frequency relationship and enhanced post-pause potentiation
          (31.2%), was noted in the trametinib-treated slice.
        explanation: >-
          Reports the calcium-handling measurement that grounds this readout.
computational_models:
- name: LZTR1-RIT1 Recruitment Docking and Molecular-Dynamics Model
  description: >-
    Integrated structural model of the near-full-length human CUL3 substrate
    adaptor LZTR1 (modeled residues 35-833) binding substrate RIT1. A
    multi-template LZTR1 homology model was combined with consensus
    protein-protein docking, FoldX calculations and duplicate 200-ns atomistic
    simulations of wild-type LZTR1 and the disease-associated G248R, R283Q and
    R412C variants in free and RIT1-bound states. The deposited artifact
    preserves wild-type static structures, not the mutant trajectories used for
    the published comparisons.
  model_type: MOLECULAR_DOCKING
  repository_url: https://zenodo.org/records/4593670
  model_id: LZTR1-RIT1.pdb
  base_model: HHpred multi-template LZTR1 model using PDB 5A10 and 4J8Z
  model_software: >-
    MODELLER 9.23, HHpred, Maestro 2019-4, ClusPro, ZDOCK, PatchDock,
    FRODOCK, FoldX, GROMACS 5.1.5 with Amber03/TIP3P, and VMD
  model_format: PDB
  publication: PMID:33792302
  modeled_mechanisms:
  - target: LZTR1-Mediated RAS Proteostasis Defect
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Models the LZTR1-RIT1 recognition step that precedes CUL3-mediated
      ubiquitination and degradation, and tests how three LZTR1 substitutions
      alter the predicted interface or propagate conformational effects.
    limitations: >-
      The study did not measure ubiquitination, RIT1 turnover, RAS abundance or
      MAPK signaling, and performed no new experimental validation. LZTR1 was
      assembled from low-identity domain templates, the clinical annotation of
      R283Q was conflicting, and the deposit lacks mutant coordinates,
      trajectories, topologies, run parameters, docking outputs and random
      seeds. The static wild-type structures therefore support visualization,
      not end-to-end replay of the disease simulations.
    readouts:
    - name: Predicted LZTR1-RIT1 electrostatic interface network
      target: LZTR1-Mediated RAS Proteostasis Defect
      interpretation: >-
        A consensus interaction pose places an electrostatic contact network at
        the putative substrate-recognition surface; it is a computational
        hypothesis rather than an experimentally solved complex in this study.
      evidence:
      - reference: PMID:33792302
        reference_title: "Structural Model for Recruitment of RIT1 to the LZTR1 E3 Ligase: Evidences from an Integrated Computational Approach."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          We observe that the interaction model LZTR1-RIT1 is stabilized by an
          electrostatic bond network established between the two protein surfaces
        explanation: >-
          Identifies the principal structural feature reported by the docking
          model.
    - name: Variant-specific LZTR1 recognition and allosteric dynamics
      target: LZTR1-Mediated RAS Proteostasis Defect
      direction: ALTERED
      interpretation: >-
        G248R and R283Q altered the predicted substrate-recognition surface,
        whereas R412C was interpreted as a possible allosteric perturbation
        linking the Kelch and C-terminal BTB regions.
      evidence:
      - reference: PMID:33792302
        reference_title: "Structural Model for Recruitment of RIT1 to the LZTR1 E3 Ligase: Evidences from an Integrated Computational Approach."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          We identify G248R and R283Q as damaging mutations involved in the
          recognition process of the substrate RIT1 and R412C as a possible
          allosteric mutation
        explanation: >-
          Reports the variant-specific interpretations from the docking and
          molecular-dynamics analyses.
    evidence:
    - reference: PMID:33792302
      reference_title: "Structural Model for Recruitment of RIT1 to the LZTR1 E3 Ligase: Evidences from an Integrated Computational Approach."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Here, we address the interaction model between adaptor LZTR1 and
        substrate RIT1 by applying an integrated computational approach,
        including molecular modeling and docking techniques.
      explanation: >-
        Establishes the model's LZTR1-RIT1 recruitment scope and computational
        methods.
  variables:
  - name: LZTR1-RIT1 interface contacts
    description: Electrostatic and hydrogen-bond contacts in the consensus docked complex.
  - name: LZTR1 backbone displacement
    dataset_identifier: RMSD
    description: Molecular-dynamics deviation from the starting conformation.
    unit: nm
  - name: LZTR1 residue fluctuation
    dataset_identifier: RMSF
    description: Per-residue conformational fluctuation across each simulation.
    unit: nm
  findings:
  - statement: >-
      The consensus complex predicts an electrostatic LZTR1-RIT1 recognition
      surface resembling substrate interfaces in homologous ubiquitin ligases.
    evidence:
    - reference: PMID:33792302
      reference_title: "Structural Model for Recruitment of RIT1 to the LZTR1 E3 Ligase: Evidences from an Integrated Computational Approach."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        We observe that the interaction model LZTR1-RIT1 is stabilized by an
        electrostatic bond network established between the two protein surfaces,
        which is reminiscent of homologous ubiquitin ligases complexes.
      explanation: >-
        States the model's central interface prediction and its structural
        comparator.
  evidence:
  - reference: PMID:33792302
    reference_title: "Structural Model for Recruitment of RIT1 to the LZTR1 E3 Ligase: Evidences from an Integrated Computational Approach."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Then, running MD simulations, we characterize differential conformational
      dynamics of the multi-domain LZTR1, offering interesting implications on
      the mechanistic role of specific point mutations.
    explanation: >-
      Establishes that atomistic simulations were used to compare the
      variant-specific conformational behavior.
  notes: >-
    Zenodo record 4593670 (DOI 10.5281/zenodo.4593670) is immutable and CC BY
    4.0. Curator smoke checks
    confirmed both PDB files parse as single-model coordinate sets and match the
    deposited checksums: LZTR1-RIT1.pdb SHA256
    e8d6ccd42ed610ae23f490f4e0d5b274a5cb2eb09413b3243a72d058df704a29 and
    full-lengthLZTR1.pdb SHA256
    05fabfd85279a69056e95244ea94ef561d66c5b604a5b4f4ff76f7226082a891.
    The latter begins at residue 35 and ends at 833 despite its filename. The
    bundled predict_pathogenicity.pl is actually a shell-style ANNOVAR command,
    fails Perl syntax checking, and depends on separately obtained databases;
    it is not part of a runnable molecular-dynamics workflow. A later
    experimental LZTR1 Kelch-RIT1 structure (PMID:40934300; PDB 9MEY) supersedes
    this model for current interface geometry; the 2021 model is retained as a
    historical, variant-dynamics hypothesis with LOW fidelity.
- name: LZTR1 L580P AlphaFold-Multimer Polymerization Model
  description: >-
    ColabFold/AlphaFold-Multimer comparison of wild-type and homozygous Noonan
    syndrome LZTR1 L580P trimers. The highest-ranked wild-type arrangement
    contained a BACK2-BACK2 dimer plus a monomer, whereas the L580P arrangement
    added a BACK1-BACK1 interface to form a linear trimer, providing a structural
    hypothesis for the higher-order polymers observed experimentally.
  model_type: STRUCTURAL_PREDICTION
  model_software: >-
    ColabFold version 02c53 with AlphaFold-Multimer v2; six recycles, no
    templates, NVIDIA A5000 24 GB, two independent runs
  publication: PMID:39003740
  modeled_mechanisms:
  - target: LZTR1-Mediated RAS Proteostasis Defect
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Predicts an allele-specific change in LZTR1 self-association that offers a
      structural explanation for impaired LZTR1 complex function and consequent
      loss of RAS-family protein turnover.
    limitations: >-
      AlphaFold-Multimer was not trained to resolve single-residue variant
      effects, only three chains could be modeled, and none of the predicted
      coordinates, PAE matrices, inputs or seeds was deposited. Endogenous
      polymers could not be imaged without overexpression. The patient-derived
      cardiomyocytes and CRISPR rescue strongly validate the broader mechanism,
      but polymer geometry itself was not solved experimentally and the model
      does not simulate ubiquitination, degradation or downstream signaling.
    readouts:
    - name: Predicted LZTR1 homotrimer chain topology
      target: LZTR1-Mediated RAS Proteostasis Defect
      direction: ALTERED
      interpretation: >-
        L580P changes the top-ranked assembly from a dimer-plus-monomer
        configuration to a linear trimer with an additional BACK1-BACK1
        interface.
      evidence:
      - reference: PMID:39003740
        reference_title: Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: COMPUTATIONAL
        snippet: >-
          The variant is predicted to alter the binding affinity of the
          dimerization domains facilitating the formation of linear LZTR1 polymers.
        explanation: >-
          Supports the linear-polymer prediction, but not the more detailed
          BACK1/BACK2 topology reported in the article body.
    evidence:
    - reference: PMID:39003740
      reference_title: Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        The variant is predicted to alter the binding affinity of the
        dimerization domains facilitating the formation of linear LZTR1 polymers.
      explanation: >-
        Supports the model's partial representation of the LZTR1 proteostasis
        mechanism.
  variables:
  - name: Predicted local-distance difference test
    dataset_identifier: pLDDT
    description: Per-residue AlphaFold confidence score.
    unit: score
  - name: Predicted aligned error
    dataset_identifier: PAE
    description: Pairwise confidence in relative residue positions across chains.
    unit: angstrom
  - name: LZTR1 multimer interface topology
    description: BACK1 and BACK2 domain contacts joining the predicted chains.
  findings:
  - statement: >-
      Uni- or biallelic correction of LZTR1 L580P rescued the molecular and
      cellular disease phenotype surrounding the structural prediction.
    evidence:
    - reference: PMID:39003740
      reference_title: Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Uni- or biallelic genetic correction of the LZTR1L580P missense variant
        rescues the molecular and cellular disease phenotype
      explanation: >-
        Provides isogenic rescue of the disease mechanism surrounding the
        structural prediction, while not independently resolving the modeled
        interfaces.
  evidence:
  - reference: PMID:39003740
    reference_title: Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Molecular, cellular, and functional phenotyping in combination with in
      silico prediction identify an LZTR1L580P-specific disease mechanism
      provoking cardiac hypertrophy.
    explanation: >-
      Establishes that in-silico structure prediction was integrated into the
      allele-specific mechanistic study.
  notes: >-
    The article is CC BY-NC 4.0 and explicitly reports no original code. It
    provides no reusable paper-specific coordinates or prediction metadata;
    PXD038425 and PXD038417 are proteomics deposits, not model archives. The
    generic mutable ColabFold notebook is therefore not recorded as this
    model's repository. Evidence comes from one homozygous patient and family;
    iPSC-cardiomyocytes are developmentally immature and engineered heart muscle
    does not reproduce whole-organ physiology.
- name: RIT1 A57G-RAF1 Interface Structural Model
  description: >-
    Active-state structural models of wild-type and Noonan-associated RIT1 A57G
    bound to the RAF1 RAS-binding domain, compared with the solved KRAS-RAF1
    complex and annotated with NMR chemical-shift perturbations. The model
    localizes a shared switch-I interface and proposes that A57G increases local
    backbone flexibility and RAF1 affinity.
  model_type: STRUCTURAL_PREDICTION
  base_model: KRAS-RAF1-RBD crystal structure PDB 6VJJ
  publication: PMID:37450595
  modeled_mechanisms:
  - target: RIT1-Mediated RAF Recruitment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Represents the RIT1 switch-I contact surface with RAF1 and predicts an
      allele-specific interface change that was tested by binding assays and
      interface mutagenesis.
    limitations: >-
      The paper does not identify the model-building engine or release the
      modeled coordinates. The structure is a static template-based complex,
      while cellular assays use ectopic protein expression. A57G enhances direct
      RAF1 binding but that interaction is weak and insufficient for MAPK
      activation without membrane localization and classical RAS. The in-vivo
      trametinib rescue used a different RIT1 allele, M90I, and does not validate
      A57G-specific model geometry.
    readouts:
    - name: RIT1 A57G binding affinity for RAF1-RBD
      target: RIT1-Mediated RAF Recruitment
      direction: INCREASED
      interpretation: >-
        Isothermal titration calorimetry and cellular BRET provide experimental
        correspondence for the modeled A57G interface, but do not establish the
        complete activation mechanism.
      evidence:
      - reference: PMID:37450595
        reference_title: RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          bound approximately five times more tightly to RAF1-RBD compared with
          WT
        explanation: >-
          Reports the allele-specific binding difference used to test the
          structural interpretation.
    evidence:
    - reference: PMID:37450595
      reference_title: RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Perturbed residues were then mapped onto modeled structures of WT and
        A57G mutants of RIT1 in the active state
      explanation: >-
        Establishes the disease-variant structural comparison and its NMR-based
        interface mapping.
  variables:
  - name: RIT1-RAF1 interface residues
    description: Modeled switch-I and RAF1-RBD contacts annotated by NMR perturbations.
  - name: RIT1-RAF1 dissociation constant
    dataset_identifier: KD
    description: Experimental affinity used to assess the modeled interface.
    unit: micromolar
  findings:
  - statement: >-
      The A57G interface model and NMR mapping predict differential engagement
      of RAF1-RBD around RIT1 switch I, consistent with higher measured affinity.
    evidence:
    - reference: PMID:37450595
      reference_title: RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        These data suggest that the switch I of RIT1A57G differentially engages
        RAF1-RBD, potentially providing the enhanced stability exhibited by the
        pathogenic variant.
      explanation: >-
        States the structural inference supported by the modeled complex and
        NMR comparison.
  - statement: >-
      Direct RAF binding does not let pathogenic RIT1 bypass classical RAS;
      classical RAS remains necessary for MAPK activation.
    evidence:
    - reference: PMID:37450595
      reference_title: RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Although mutant RIT1 binds to RAF kinases directly, it fails to activate
        MAPK signaling in the absence of classical RAS proteins.
      explanation: >-
        Defines the experimentally tested sufficiency boundary for the structural
        recruitment model.
  evidence:
  - reference: PMID:37450595
    reference_title: RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Perturbed residues were then mapped onto modeled structures of WT and A57G
      mutants of RIT1 in the active state
    explanation: >-
      Establishes the disease-variant structural comparison used for the
      interface model.
  notes: >-
    The article is CC BY 4.0. Neither model coordinates nor code were deposited;
    GEO GSE207187 and GSE207188 contain RNA-seq rather than model artifacts. PDB
    6VJJ is an experimental KRAS-RAF1 template, not the modeled RIT1 complex.
    The paper does not report the model-building engine or output format; PyMOL
    was used only to map NMR perturbations. Consequently, the published geometry
    cannot be independently rebuilt from the reported methods alone. Inefficient
    RAF1 cysteine-rich-domain engagement is an author hypothesis, not an output
    of the modeled RIT1-RAF1-RBD complex.
- name: SHP2 N308S Molecular-Dynamics and Interaction-Network Model
  description: >-
    Molecular-dynamics and protein-interaction-network analysis of the
    PTPN11 N308S variant that co-segregated with Noonan syndrome in seven
    affected relatives. The integrated model predicts loss of stabilizing
    hydrogen bonds, greater conformational heterogeneity and a shift toward an
    activated open SHP2 state, followed by stronger predicted interactions with
    signaling hubs including GRB2 and SRC.
  publication: PMID:41843963
  modeled_mechanisms:
  - target: SHP2 Gain-of-Function Activation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Represents an allele-specific conformational route from N308S to reduced
      autoinhibitory stability and a qualitative shift toward an activated open
      state.
    limitations: >-
      The result comes from one related pedigree and has no independent family
      replication. The article does not expose model coordinates, trajectories,
      simulation duration, force field, code or a reusable configuration, and
      validation used HEK293T cells rather than developmental tissues. The
      inferred GRB2/SRC and ERK-to-chromatin axis combines separate network,
      phosphoproteomic and cellular layers and is not a single prospectively
      validated simulation.
    readouts:
    - name: SHP2 conformational heterogeneity
      target: SHP2 Gain-of-Function Activation
      direction: INCREASED
      interpretation: >-
        Broader modeled conformational sampling is interpreted as destabilization
        of the autoinhibited state rather than a quantitative clinical predictor.
      evidence:
      - reference: PMID:41843963
        reference_title: Phosphoproteomics elucidates the functional impact of the PTPN11 p.Asn308Ser variant in a Noonan syndrome pedigree.
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          This change enhances conformational heterogeneity and shifts the
          protein into an activated "open" state.
        explanation: >-
          Reports the direction of the principal molecular-dynamics readout.
    - name: Predicted shift toward an activated open state
      target: SHP2 Gain-of-Function Activation
      direction: ALTERED
      interpretation: >-
        The qualitative modeled shift toward open SHP2 provides structural
        support for gain of function; no open-state fraction or patient-specific
        threshold was reported.
      evidence:
      - reference: PMID:41843963
        reference_title: Phosphoproteomics elucidates the functional impact of the PTPN11 p.Asn308Ser variant in a Noonan syndrome pedigree.
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          This change enhances conformational heterogeneity and shifts the
          protein into an activated "open" state.
        explanation: >-
          Connects the modeled conformational shift directly to the SHP2
          activation node.
    evidence:
    - reference: PMID:41843963
      reference_title: Phosphoproteomics elucidates the functional impact of the PTPN11 p.Asn308Ser variant in a Noonan syndrome pedigree.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        This revealed that the mutation disrupts critical hydrogen bonds and
        remodels the interaction network.
      explanation: >-
        Supports the modeled structural perturbation underlying the activation
        link.
  variables:
  - name: SHP2 hydrogen-bond network
    description: Intramolecular contacts altered by N308S in the structural analysis.
  - name: SHP2 conformational-state shift
    description: Qualitative modeled shift from the closed toward an activated open conformation.
  - name: Predicted SHP2 interaction network
    description: Variant-associated protein interactions including GRB2 and SRC.
  findings:
  - statement: >-
      N308S was predicted to disrupt hydrogen bonds, increase conformational
      heterogeneity and favor an open SHP2 conformation.
    evidence:
    - reference: PMID:41843963
      reference_title: Phosphoproteomics elucidates the functional impact of the PTPN11 p.Asn308Ser variant in a Noonan syndrome pedigree.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        This revealed that the mutation disrupts critical hydrogen bonds and
        remodels the interaction network. This change enhances conformational
        heterogeneity and shifts the protein into an activated "open" state.
      explanation: >-
        Summarizes the atomistic prediction without extending it to clinical
        outcome prediction.
  evidence:
  - reference: PMID:41843963
    reference_title: Phosphoproteomics elucidates the functional impact of the PTPN11 p.Asn308Ser variant in a Noonan syndrome pedigree.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Using a multi-level approach that integrated experimental structural
      analysis, molecular dynamics simulations, protein-protein interaction
      network analysis, quantitative phosphoproteomics, and functional
      validation in cellular models
    explanation: >-
      Establishes the computational components and the distinct experimental
      validation layers.
  notes: >-
    This 2026 study is a pedigree-specific mechanistic model, not a longitudinal
    digital twin. The article is not openly licensed and no model repository was
    identified. PXD068242/IPX0011703000 contains the phosphoproteomics data, not
    the molecular-dynamics model, and has no stated reusable model license. The
    model-building engine, force field, duration, trajectory files and output
    format are not publicly reported. `model_type` is omitted because the
    current enum has no category for disease-variant molecular dynamics without
    docking.
- name: SOS1 R1131K Transfer-Entropy Signaling Model
  description: >-
    Information-theoretic model of bidirectional predictive dependence between
    SOS1 and RAF from simultaneous single-cell membrane-translocation
    trajectories. A Gaussian covariance approximation estimates time-resolved
    transfer entropy in wild-type and Noonan-associated SOS1 R1131K cells with
    or without MEK inhibition, revealing phase-specific effective regulation
    consistent with feedback changes or shared hidden inputs.
  repository_url: https://archive.softwareheritage.org/swh:1:rev:7ff6a1cfdef5163ae98a663381e12cc4f065d3f6
  model_id: TE_by_Gaussian_Approximation_2.ipynb
  base_model: Gaussian-approximation transfer-entropy method of Imaizumi et al. 2022
  model_software: Python 3.9.7, Jupyter, NumPy, pandas, matplotlib, and seaborn
  model_format: Jupyter Notebook and CSV single-cell time series
  publication: PMID:40047537
  modeled_mechanisms:
  - target: SOS-Family-Mediated RAS-GTP Loading
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Uses SOS1 and RAF membrane-translocation dynamics to measure how R1131K
      changes effective information flow through the SOS-RAF signaling system.
      This is an indirect functional readout of the SOS node; RAS-GTP loading is
      not measured.
    limitations: >-
      Transfer entropy quantifies predictive dependence and does not identify a
      unique biochemical path or prove molecular causality; hidden or common
      inputs can generate backward information flow. The acute EGF experiment
      uses SOS1-knockout HeLa cells with ectopic Halo-SOS1 and GFP-RAF, retains
      endogenous SOS2, pools cells across independent measurements, and does not
      model development or patient phenotypes. The Gaussian approximation is a
      first-order treatment of noisy, potentially non-Gaussian trajectories.
    readouts:
    - name: Early RAF-to-SOS backward transfer entropy
      target: SOS-Family-Mediated RAS-GTP Loading
      direction: INCREASED
      interpretation: >-
        R1131K increases the early backward information-flow peak, indicating an
        altered effective feedback regime rather than increased RAS-GTP itself.
      evidence:
      - reference: PMID:40047537
        reference_title: Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements.
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          Similar to the MEK inhibitor, R1131K significantly increased the early
          bw-TE peak.
        explanation: >-
          Reports the direction of the early transfer-entropy effect.
    - name: Late RAF-to-SOS backward transfer entropy
      target: SOS-Family-Mediated RAS-GTP Loading
      direction: DECREASED
      interpretation: >-
        R1131K decreases the late backward information-flow peak without MEK
        inhibition, showing that the same allele has opposite phase-specific
        effects.
      evidence:
      - reference: PMID:40047537
        reference_title: Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements.
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          In addition, R1131K specifically decreased the late bw-TE peak.
        explanation: >-
          Reports the direction of the late transfer-entropy effect.
    - name: Late-phase transfer-entropy abnormality after MEK inhibition
      target: SOS-Family-Mediated RAS-GTP Loading
      direction: RESTORED
      interpretation: >-
        Trametinib removed the late-phase abnormality but did not normalize the
        early phase, so the rescue is explicitly phase-specific.
      evidence:
      - reference: PMID:40047537
        reference_title: Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements.
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          MEK inhibition rescued the abnormality in the late phase but not in
          the early phase.
        explanation: >-
          Defines the limited temporal scope of the perturbation rescue.
    evidence:
    - reference: PMID:40047537
      reference_title: Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Furthermore, TE analysis identified the functional disorder of a SOS
        mutation associated with Noonan syndrome
      explanation: >-
        Establishes the allele-specific application of the transfer-entropy
        model.
  variables:
  - name: SOS1 membrane-translocation trajectory
    dataset_identifier: X(t)
    description: One-minute single-cell Halo-SOS1 response sequence after EGF stimulation.
  - name: RAF membrane-translocation trajectory
    dataset_identifier: Y(t)
    description: Simultaneously measured single-cell GFP-RAF response sequence.
  - name: SOS-to-RAF transfer entropy
    dataset_identifier: fw-TE
    description: Forward predictive information flow from SOS to RAF.
    unit: nat
  - name: RAF-to-SOS transfer entropy
    dataset_identifier: bw-TE
    description: Backward predictive information flow reflecting feedback or shared hidden inputs.
    unit: nat
  findings:
  - statement: >-
      R1131K raises early backward transfer entropy and lowers late backward
      transfer entropy, revealing a signaling defect not evident from RAF
      activation or translocation amplitude alone.
    evidence:
    - reference: PMID:40047537
      reference_title: Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        The information flow was perturbed in Noonan cells carrying the R1131K
        mutation. The mutation had opposite impacts on the early and late phases
        in cells without the MEK inhibitor
      explanation: >-
        Summarizes the principal allele-specific dynamic result.
  - statement: >-
      Trametinib restores the late-phase transfer-entropy abnormality but not the
      early-phase abnormality.
    evidence:
    - reference: PMID:40047537
      reference_title: Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        MEK inhibition rescued the abnormality in the late phase but not in the
        early phase.
      explanation: >-
        States the phase-specific perturbation result without treating it as
        clinical therapeutic efficacy.
  evidence:
  - reference: PMID:40047537
    reference_title: Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      TE analysis allows for model-free assessment of the timing, direction, and
      strength of the information flow regulating the system response.
    explanation: >-
      Defines the computational method and its explicitly model-free scope.
  - reference: PMID:40047537
    reference_title: Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The information flow was perturbed in Noonan cells carrying the R1131K
      mutation.
    explanation: >-
      Ties the model to Noonan syndrome: the analysis was applied to cells
      carrying the Noonan-associated SOS1 R1131K variant.
  notes: >-
    `model_type` is deliberately omitted: information-theoretic network
    inference fits none of the current enum values and is not a kinetic,
    machine-learning or Boolean model. The paper-pinned Software Heritage
    revision is 7ff6a1cfdef5163ae98a663381e12cc4f065d3f6; the mutable repository
    home is https://github.com/YasushiSako/transfer_entropy_2. That revision has
    no software-license file; repository HEAD
    3467850de2e45dfc2b7766ba4dce0d7af8839a00 only adds the MIT LICENSE. The
    README licenses the 16 CSV data files under CC BY-NC-SA 4.0. Curator static
    inspection confirmed that all wild-type and R1131K, vehicle and MEK-inhibitor
    CSVs are present. The seeded notebook has no environment lock and expects
    selected input pairs to be copied or renamed to SOStotal.csv and
    RAFtotal.csv. It also uses the removed pandas `set_axis(inplace=True)` API
    and fails under pandas 3.0.3 without a small compatibility edit, so it is not
    a one-command reproduction.
datasets:
- accession: geo:GSE213798
  title: Aberrant cortical layer development of brain organoids developed from Noonan syndrome-iPSCs
  description: >-
    Human induced pluripotent stem cell-derived cortical organoid transcriptomic
    resource profiling neurodevelopmental abnormalities in Noonan syndrome and
    matched isogenic corrected controls across developmental time points.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 9
  conditions:
  - Noonan syndrome iPSC-derived cortical organoids
  - isogenic corrected control cortical organoids
  platform: GPL24676
  publication: GEO:GSE213798
  evidence:
  - reference: GEO:GSE213798
    reference_title: "Aberrant cortical layer development of brain organoids developed from Noonan syndrome-iPSCs"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      single-cell transcriptomic analysis represented increment of EN population
      and overexpression of cortical layer markers in NS-COs.
    explanation: >-
      Provides disease-relevant human neurodevelopmental transcriptomic evidence
      for cortical-layer and neuronal-connectivity abnormalities in Noonan syndrome.
- accession: geo:GSE188238
  title: Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome
  description: >-
    Bulk transcriptomic dataset integrating left ventricular myocardial tissue
    and patient-derived PTPN11N308S/+ iPSC-cardiomyocyte modeling to define
    mechanisms of Noonan syndrome-associated childhood cardiomyopathy.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 11
  conditions:
  - Noonan syndrome-associated cardiomyopathy
  - sarcomeric hypertrophic cardiomyopathy comparator
  - non-diseased cardiac control
  platform: GPL20301
  publication: PMID:34988410
  evidence:
  - reference: GEO:GSE188238
    reference_title: "Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gene expression in left ventricular myocardial tissue from NS-CM, HCM and
      normal hearts
    explanation: >-
      Supports human myocardial tissue evidence for transcriptomic distinctions
      between Noonan cardiomyopathy and sarcomeric HCM.
  - reference: GEO:GSE188238
    reference_title: "Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      complemented with disease modeling in cardiomyocytes differentiated from
      patient-derived PTPN11N308S/+ induced pluripotent stem cells
    explanation: >-
      Supports complementary in vitro iPSC-cardiomyocyte modeling of Noonan
      cardiomyopathy mechanisms.
- accession: geo:GSE131069
  title: Differential gene expression in human RAF1 S257L/+ and isogenic corrected iPSC-derived cardiomyocytes
  description: >-
    Bulk RNA-seq dataset from human RAF1 S257L/+ Noonan syndrome iPSC-derived
    cardiomyocytes and isogenic corrected controls, including pathway-perturbation
    conditions targeting MEK/ERK signaling.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 12
  conditions:
  - RAF1 S257L/+ Noonan syndrome iPSC-derived cardiomyocytes
  - isogenic corrected control cardiomyocytes
  - MEK/ERK pathway inhibition perturbation
  platform: GPL23934
  publication: PMID:31163979
  evidence:
  - reference: GEO:GSE131069
    reference_title: "Differential gene expression in human RAF1 S257L/+ and isogenic corrected iPSC-derived cardiomyocytes"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hence, to gain insights into the transcriptional alterations induced by
      the NS-associated RAF1S257L/+ mutation in human iPSC-derived
      cardiomyocytes, we performed quantitative transcriptome profiling by
      RNA-sequencing.
    explanation: >-
      Supports a mutation-specific human cardiomyocyte transcriptomic resource
      linking RAF1-driven signaling dysregulation to Noonan cardiac phenotypes.
discussions:
- discussion_id: noonan_erk_magnitude_vs_neural_crest_phenotype
  prompt: >-
    Does the magnitude of ERK activation produced by a PTPN11 variant predict
    its neural crest phenotype and clinical severity, or can a variant perturb
    neural crest development without measurably raising ERK phosphorylation?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#SHP2 Gain-of-Function Activation
  - pathophysiology#ERK Cascade Hyperactivation
  - pathophysiology#Neural Crest Cell Developmental Dysregulation
  rationale: >-
    The entry models Noonan syndrome as convergent RAS-MAPK hyperactivation, and
    for the craniofacial arm that model is well supported: neural-crest-restricted
    SHP2 Q79R causes the defects and MEK inhibition prevents them. But ERK
    magnitude is not obviously the whole story, and this matters practically
    because "how much does it raise pERK" is the assay a functional lab would
    reach for when classifying a variant of uncertain significance.

    Two independent lines argue the assay is incomplete. Peer-reviewed zebrafish
    work already showed SHP2 has a phosphatase- and Erk-independent function in
    neural crest, mediated through its SH2 domains, which is what reconciles
    catalytically impaired NSML alleles with catalytically enhanced Noonan
    alleles causing overlapping disease. A recent preprint then reported a
    Noonan-spectrum variant of uncertain significance, c.1282G>A (V428M), that
    did not raise ERK phosphorylation in cells yet drove excessive neural crest
    migration in chick embryos, and reported that ERK activation did not track
    clinical severity across an 18-patient cohort.

    This is deliberately recorded as an open question rather than curated as a
    mechanism. The V428M observation is preprint-only, from an overexpression
    assay, and is not sole support for anything in this entry. What would settle
    it is whether the ERK-independent arm is the same SH2-domain function the
    zebrafish work identified, and whether it operates in human cranial neural
    crest rather than avian trunk neural crest.
  evidence:
  - reference: PMID:20493809
    reference_title: "Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We also identify an unexpected phosphatase- and Erk-independent function,
      mediated through its SH2 domains, which is evolutionarily conserved and
      prevents p53-mediated apoptosis in the brain and neural crest.
    explanation: >-
      Peer-reviewed precedent that SHP2 has a neural crest function which an
      ERK-phosphorylation readout cannot see — this is what makes the question
      well-posed rather than speculative.
  - reference: PPR:PPR1278294
    reference_title: "An integrated computational, clinical, and functional framework for assessing  <i>PTPN11</i>  (SHP2) variant effects on ERK signaling and neural crest cell behavior in Noonan spectrum disorders"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      variants stratify beyond simple gain/loss-of-function dichotomies into
      strong ERK-dependent hyperactivation, moderate ERK activation with
      variable protein stability and the paradoxical c.1282G>A variant, which
      did not increase ERK phosphorylation
    explanation: >-
      Biochemical profiling in HEK293T cells reporting the variant class that
      motivates the question. Preprint, not peer reviewed.
  - reference: PPR:PPR1278294
    reference_title: "An integrated computational, clinical, and functional framework for assessing  <i>PTPN11</i>  (SHP2) variant effects on ERK signaling and neural crest cell behavior in Noonan spectrum disorders"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In vivo, this variant drove excessive neural crest cell migration in chick
      embryos, suggesting that its effects on NCC migration may involve
      ERK-independent mechanisms or context-dependent signaling not captured by
      steady-state assays.
    explanation: >-
      The in vivo half of the observation, and the reason the migration modifier
      on the neural crest node is DYSREGULATED rather than directional. Note the
      authors state it as a suggestion, not a demonstration.
  - reference: PPR:PPR1278294
    reference_title: "An integrated computational, clinical, and functional framework for assessing  <i>PTPN11</i>  (SHP2) variant effects on ERK signaling and neural crest cell behavior in Noonan spectrum disorders"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ERK activation did not strictly correlate with clinical severity, yet
      these functional differences were associated with distinct growth,
      cardiac, pigmentation, and neurodevelopmental outcomes.
    explanation: >-
      The clinical-cohort half (18 pediatric patients). A negative correlational
      result in a small cohort — suggestive of the gap, not a refutation of the
      ERK model.
  proposed_experiments:
  - experiment_id: noonan_sh2_domain_requirement_for_erk_independent_ncc_effect
    name: Test whether the ERK-independent neural crest effect requires the SHP2 SH2 domains
    description: >-
      Assay the paradoxical variant class alongside SH2-domain mutants in the
      same neural crest system, to determine whether the ERK-independent
      migration effect is the SH2-mediated function already identified in
      zebrafish or a distinct one.
  - experiment_id: noonan_endogenous_level_human_ncc_replication
    name: Replicate the migration phenotype at endogenous expression levels in human neural crest
    description: >-
      Knock the variant in at the endogenous locus in human iPSC-derived neural
      crest cells rather than overexpressing it in avian trunk neural crest,
      which would separate allele-specific effects from SHP2 dosage effects and
      test the human cranial lineage that generates the Noonan facial skeleton.
  - experiment_id: noonan_perk_vs_phenotype_powered_cohort
    name: Correlate pERK with phenotype in a cohort powered for it
    description: >-
      A variant-stratified cohort large enough to test whether ERK activation
      magnitude predicts craniofacial, cardiac, and neurodevelopmental outcome,
      rather than the 18-patient exploratory series the question arose from.
  notes: >-
    Raised from monarch-initiative/dismech#6513 (preprint scan). Preprint
    findings are recorded here as an open question, not curated as mechanism.
- discussion_id: noonan_erk5_not_erk1_2_drives_raf1_cm_hypertrophy
  prompt: >-
    Is ERK1/2 hyperactivation, rather than ERK5 signaling, the correct driver
    to assert for RAF1-associated cardiomyocyte hypertrophy in Noonan syndrome?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Cardiomyocyte Hypertrophy
  - pathophysiology#ERK Cascade Hyperactivation
  - experimental_models#Noonan syndrome iPSC-cardiomyocyte model
  rationale: >-
    The entry's ERK Cascade Hyperactivation node asserts a downstream edge to
    Cardiomyocyte Hypertrophy on the strength of a mouse RIT1 study showing
    that MAPK-pathway inhibition alleviates cardiac hypertrophy. A RAF1
    S257L/+ iPSC-cardiomyocyte model directly tested the ERK1/2 arm of that
    pathway and found the opposite: MEK1/2 inhibitors that strongly reduced
    ERK1/2 phosphorylation had no effect on cell size, while a distinct
    pathway, ERK5, drove the hypertrophic phenotype. ERK5 is not otherwise
    modeled anywhere in this entry. The mismatch may reflect a genuine
    genotype-specific difference (RIT1 vs. RAF1) rather than a wrong edge, but
    the entry currently cannot distinguish those possibilities because it has
    no ERK5 node to attach the RAF1 finding to.
  evidence:
  - reference: PMID:31163979
    reference_title: "Inducible Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1-Associated Noonan Syndrome."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, although ERK1/2 activation was strongly reduced, there
      was no significant effect on hypertrophy in RAF1S257L/+ iCMs in
      response to treatment with either PD98059 or Trametinib (Fig.4C–D),
      suggesting that MEK1/2-ERK1/2 activation is not the principal driver
      of hypertrophy in NS-associated RAF1 mutations.
    explanation: The human-model evidence behind the mismatch.
  - reference: DOI:10.1126/sciadv.adf4766
    reference_title: "RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with aberrant RAF/MAPK activation as a driver of disease, we
      show that pathway inhibition alleviates cardiac hypertrophy in a mouse
      model of RIT1 mutant Noonan syndrome.
    explanation: The mouse-model evidence the entry's existing edge is built on, which this discussion contrasts against the human iPSC-cardiomyocyte result.
  proposed_experiments:
  - experiment_id: noonan_erk5_selective_inhibition_raf1_icm
    name: Test ERK5-selective inhibition of RAF1-mutant cardiomyocyte hypertrophy directly
    description: >-
      Confirm the ERK5 dependence reported for RAF1 S257L/+ iCMs (BIX02189
      and dominant-negative ERK5 both reduced cell size) in an independent
      RAF1 patient line, and test whether the same rescue holds for RIT1
      mutant human iPSC-cardiomyocytes to determine whether the RIT1 mouse
      and RAF1 human results reflect one pathway or two genotype-specific
      ones.
  notes: >-
    Raised while adding modeled_mechanisms links for the Noonan iPSC-cardiomyocyte
    model (monarch-initiative/dismech#10432).

- discussion_id: noonan_mek_therapeutic_window_vs_cardiotoxicity
  prompt: >-
    Does the MEK inhibition that reverses RAF1-driven hypertrophic
    cardiomyopathy also impose the cardiomyocyte injury that MEK inhibition
    causes in cancer patients, and if so at what dose, duration and age is the
    net effect still favourable?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#MEK Inhibitor Therapy
  - pathophysiology#ERK Cascade Hyperactivation
  - pathophysiology#Cardiomyocyte Hypertrophy
  rationale: >-
    The same pharmacology appears in this knowledge base twice, in opposite
    directions. Here, abrogating ERK signalling is the intended benefit. In
    kb/modules/mek_inhibition_cardiac_mitochondrial_injury.yaml it is the
    initiating injury: loss of ERK-dependent mitochondrial STAT3 serine-727
    phosphorylation, respiratory chain failure and reversible cardiac
    hypocontractility, curated from oncology cohorts and mouse work.

    The two bodies of evidence do not overlap in what they measured. Every
    therapeutic result cited in this entry reads out echocardiographic wall
    thickness, outflow gradient (the only measure that moved in the adult RAF1
    case), cardiac mass or fetal gene expression over weeks to months; none
    assessed mitochondrial respiration or STAT3
    serine-727. The toxicity module is not reported in a RAS-MAPK-variant
    background. So the directions are unreconciled rather than contradictory,
    and neither body of work refutes the other.

    One dataset touches both. In paediatric RASopathy myocardial slices
    (PMID:39573843) trametinib lowered developed force while improving
    sarcoplasmic reticulum calcium handling in the same tissue. Reduced force
    is the direction of the toxicity module's terminal node, measured for once
    in a Noonan-variant context, and it sits beside a calcium result pointing
    the other way. That is a single patient's tissue under acute exposure, so
    it frames the question rather than answering it.

    This matters for how the treatment is read off the entry. A reader who sees
    only the case reports will take MEK inhibition to be straightforwardly
    corrective, and the entry currently gives them no route to the account of
    what the same drug does to cardiomyocytes. There is no schema slot that
    would carry that link: Treatment has no adverse-effect or adverse-mechanism
    field, which is recorded in dismech#12664.

    It is deliberately not curated as a conforms_to link. Noonan syndrome's own
    pathophysiology does not instantiate MEK-inhibition injury; the injury is a
    property of a treatment given for it, and the module's conformer is the
    drug-toxicity entry MEK_Inhibitor_Induced_Cardiomyopathy.
  proposed_experiments:
  - experiment_id: noonan_mek_force_and_mitochondrial_readout
    name: Paired contractile and mitochondrial readout of MEK inhibition in RASopathy myocardium
    description: >-
      Extend the myocardial slice protocol that measured force and calcium
      handling so that it also reports the quantities the cardiotoxicity module
      is built on, in the same tissue and the same exposure. Measure developed
      force, force-frequency relationship and post-pause potentiation alongside
      mitochondrial respiration and STAT3 serine-727 phosphorylation, across a
      trametinib dose range and a culture duration longer than an acute
      exposure, in slices or engineered heart tissue from several RASopathy
      genotypes with non-RASopathy hypertrophic myocardium as comparator.
    would_support:
    - pathophysiology#Cardiomyocyte Hypertrophy
    supporting_outcome:
    - >-
        Developed force falls while mitochondrial respiration and STAT3
        serine-727 phosphorylation are preserved, and the hypertrophic
        transcriptional programme regresses. The force change would then be a
        consequence of reduced hypertrophic signalling rather than the
        mitochondrial injury the module describes, and the two directions would
        be reconciled.
    refuting_outcome:
    - >-
        Mitochondrial respiration and STAT3 serine-727 phosphorylation fall in
        RASopathy myocardium as they do in the oncology setting, with the same
        dose dependence. The toxicity mechanism would then be operating
        concurrently with the benefit, making the therapeutic window a real
        constraint rather than a theoretical one, and the dose and duration at
        which it opens would become the clinical question.
references:
- reference: PMID:20301303
  title: "Noonan Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1159/000545410
  title: Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders
  findings: []
- reference: DOI:10.1007/s00431-026-06764-2
  title: Noonan syndrome spectrum disorders in real life patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort
  findings: []
- reference: DOI:10.1002/ajmga.70060
  title: 'Neuropathic Pain and Enlarged Nerves in Adult Noonan Syndrome and Noonan Syndrome With Multiple Lentigines: Health-Related Quality of Life and Neurologic Symptoms'
  findings: []
- reference: DOI:10.1097/MD.0000000000046340
  title: 'Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report'
  findings: []
- reference: DOI:10.1016/j.jaccas.2026.107006
  title: Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy
  findings: []
- reference: DOI:10.1007/s00431-023-05263-y
  title: Novel therapeutic perspectives in Noonan syndrome and RASopathies
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.1007/s10557-022-07324-0
  title: An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.1016/j.jacc.2019.01.066
  title: Hypertrophic Cardiomyopathy in Noonan Syndrome Treated by MEK-Inhibition
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.1126/sciadv.adf4766
  title: RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome–associated cardiac hypertrophy
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.1158/1078-0432.ccr-24-1611
  title: Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.1172/jci.insight.182382
  title: Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome–like phenotypes in mice
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.1172/jci172839
  title: 'Central conducting lymphatic anomaly: from bench to bedside'
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.3389/fped.2025.1475143
  title: Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.3390/children11111342
  title: 'Refractory Chylothorax and Ventricular Hypertrophy Treated with Trametinib in a Patient with Noonan Syndrome: 18-Month Follow-Up'
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.3390/genes15081015
  title: Cardiac Phenotype and Gene Mutations in RASopathies
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.3390/ijms26083515
  title: 'Update on the Clinical and Molecular Characterization of Noonan Syndrome and Other RASopathies: A Retrospective Study and Systematic Review'
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.3390/life14060731
  title: 'Exploring New Drug Repurposing Opportunities for MEK Inhibitors in RASopathies: A Comprehensive Review of Safety, Efficacy, and Future Perspectives of Trametinib and Selumetinib'
  found_in:
  - Noonan_Syndrome-deep-research-falcon.md
  - Noonan_Syndrome-deep-research-cyberian-codex.md
  findings: []

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References & Deep Research