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

2

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.

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Discussions and Knowledge Gaps

2

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

"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

"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.

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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

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

Downstream

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

Show evidence (1 reference)

PMID:17143285 SUPPORT In Vitro

"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

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

RIT1 gain-of-function mutations cause aberrant membrane localization and RAF recruitment, bypassing normal RAS regulation and driving excessive MAPK pathway activation.

RIT1 hgnc:10023

Ras protein signal transduction GO:0007265

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 (1 reference)

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.

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

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

"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.

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

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.

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 (1 reference)

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.

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

"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:0001837 heart valve morphogenesis GO:0003179

pulmonary valve UBERON:0002146 heart UBERON:0000948

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.

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.

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.

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Pathograph

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Phenotypes

40

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 1

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, so the mechanism converges here rather than this being one arm of a generic 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.

🧬

Genetic Associations

17

PTPN11 (Pathogenic Variants)

Gene: PTPN11 hgnc:9644

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

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

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

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

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

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

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

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 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.

+ 1 more reference

MRAS (Pathogenic Variants)

Gene: MRAS hgnc:7227

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 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.

MAP2K2 (Pathogenic Variants)

Gene: MAP2K2 hgnc:6842

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

Balloon valvuloplasty or surgical valvotomy for pulmonary valve stenosis; septal myectomy or alcohol ablation for severe hypertrophic cardiomyopathy.

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

Show evidence (1 reference)

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."

Demonstrates feasibility of staged surgical management for structural heart disease in severe Noonan-associated cardiomyopathy.

MEK Inhibitor Therapy

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

Agent: trametinib CHEBI:75998

Trametinib (MEK1/2 inhibitor) has shown promising results in case reports for treatment-refractory hypertrophic cardiomyopathy and lymphatic complications. MEK inhibition can reverse cardiomyocyte hypertrophy in animal models.

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.

Target Phenotypes: Hypertrophic cardiomyopathy HP:0001639 Lymphedema HP:0001004

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."

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

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

Birth Prevalence 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)

Birth Prevalence 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 (1 reference)

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.

📊

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

"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

"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

"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

2

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

"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

"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

"NS-COs also exhibited reduced synaptic connectivity."

Directly reports the synaptic connectivity readout.

Show evidence (1 reference)

PMID:36430334 SUPPORT In Vitro

"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

"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

"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

"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

"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

"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

"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

"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

"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

"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.

🐁

Animal Models

4

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.

{ }

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: 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: 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: >-
    RIT1 gain-of-function mutations cause aberrant membrane localization and
    RAF recruitment, bypassing normal RAS regulation and driving excessive
    MAPK pathway activation.
  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.

- name: LZTR1-Mediated RAS Proteostasis Defect
  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.
  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
  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.

- 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:0001837
      label: epithelial to mesenchymal transition
  - 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.

- 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, so the mechanism converges here rather than
    this being one arm of a generic 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: 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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  gene_term:
    preferred_term: LZTR1
    term:
      id: hgnc:6742
      label: LZTR1
  association: Pathogenic Variants
  frequency: OCCASIONAL
  notes: >-
    Can cause both autosomal dominant and autosomal recessive forms.
    Acts as a CUL3 adaptor controlling RAS proteostasis through ubiquitination.
    Dominant mutations act in a dominant-negative manner.
  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.
  - 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 LZTR1-Noonan syndrome gene-disease relationship as definitive with autosomal recessive inheritance.
- name: MRAS
  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
  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: 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.
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: >-
    Balloon valvuloplasty or surgical valvotomy for pulmonary valve stenosis;
    septal myectomy or alcohol ablation for severe hypertrophic cardiomyopathy.
  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: >-
      Demonstrates feasibility of staged surgical management for structural
      heart disease in severe Noonan-associated cardiomyopathy.
- name: MEK Inhibitor Therapy
  description: >-
    Trametinib (MEK1/2 inhibitor) has shown promising results in case reports
    for treatment-refractory hypertrophic cardiomyopathy and lymphatic complications.
    MEK inhibition can reverse cardiomyocyte hypertrophy in animal models.
  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_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  - preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  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.
- 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.
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.
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).

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