Noonan Syndrome 11

Genetic MONDO:0032786 Pathograph 11 Show in embeddings browser RASopathy Noonan Syndrome

Noonan syndrome 11 (NS11) is the MRAS-related form of Noonan syndrome, an autosomal dominant RASopathy caused by germline activating missense variants in MRAS, which encodes the RAS-family GTPase M-Ras. Mutant M-Ras has impaired intrinsic GTPase activity and is constitutively GTP-loaded and membrane targeted; it binds SHOC2 and PPP1CB more avidly, promoting assembly of the MRAS-SHOC2-PP1 holophosphatase that dephosphorylates the inhibitory RAF S259 site and drives RAF-MEK-ERK, with variably increased PI3K-AKT signalling. Clinically the entry is defined within the Noonan spectrum by a strong, variant-restricted association with hypertrophic cardiomyopathy: the reported cases cluster on a narrow set of codons (Gly23, Thr68, Gln71) and nearly all have had HCM, frequently severe, early onset and obstructive, with several neonatal or infant deaths. The phenotype is not uniform, however — a single adult with the recurrent p.Thr68Ile substitution presented instead with mild, late-onset left ventricular hypertrophy — so HCM severity should not be treated as an obligate feature. NS11 is an ultra-rare cause of Noonan syndrome: only a handful of unrelated patients have been reported since MRAS was implicated in 2017. General Noonan syndrome features (short stature, characteristic facies, developmental delay/intellectual disability) are present but are shared with the parent entry, Noonan Syndrome, which this entry cross-references rather than duplicates.

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2
Mappings
1
Inheritance
7
Pathophys.
1
Histopath.
25
Phenotypes
2
Gaps
11
Pathograph
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Genes
4
Medical Actions
2
Differentials
1
Trials
2
Models
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References
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Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE CARDIOVASCULAR
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Mappings

MONDO
MONDO:0032786 Noonan syndrome 11
skos:exactMatch MONDO
Primary disease term for this entry.
MONDO:0018997 Noonan syndrome DisMech
skos:broadMatch MONDO
MONDO records Noonan syndrome 11 as a child of Noonan syndrome; the dismech umbrella entry Noonan Syndrome carries that broader term.
👪

Inheritance

1
Autosomal Dominant HP:0000006
NS11 is inherited in an autosomal dominant manner, in keeping with Noonan syndrome generally. Every reported MRAS-related case has arisen de novo, which is expected given the severity of the associated cardiomyopathy and the resulting limited reproductive fitness; no familial transmission of an MRAS variant has been described.
Autosomal dominant inheritance
Show evidence (3 references)
CGGV:assertion_04ca29c1-6b44-474c-b54b-1c8be52de172-2022-12-14T170000.000Z SUPPORT Other
"MRAS | HGNC:7227 | Noonan syndrome | MONDO:0018997 | AD | Moderate"
ClinGen records the mode of inheritance for MRAS-related Noonan syndrome as autosomal dominant.
PMID:31108500 SUPPORT Human Clinical
"Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events."
Documents the de novo occurrence of the heterozygous MRAS variants in unaffected-parent trios.
PMID:20301303 SUPPORT Human Clinical
"Each child of an individual with autosomal dominant NS has a 50% chance of inheriting the pathogenic variant"
GeneReviews gives the transmission risk for autosomal dominant Noonan syndrome. The risk follows from the mode of inheritance rather than from the causal gene, so it applies to NS11 even though every reported MRAS proband to date has been a de novo case.
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Discussions and Knowledge Gaps

2
Do germline activating MRAS variants confer an increased cancer risk, as the corresponding hotspot substitutions in other RAS homologs do?
KNOWLEDGE GAP ns11_mras_cancer_risk
Attached to
pathophysiology#Constitutive M-Ras GTP Loading
p.Gln71Arg is a recurrent oncogenic substitution in RAS homologs across various cancers, and other RASopathies carry defined tumour predisposition. No NS11 patient has been reported with a malignancy, but the reported cohort is tiny and several patients died in infancy, so the question is unanswerable from current data rather than answered in the negative.
Proposed experiments
Longitudinal tumour surveillance of a molecularly ascertained MRAS cohort
ns11_tumour_surveillance_cohort
Prospective, protocol-driven oncological follow-up of all surviving individuals with pathogenic MRAS variants, pooled internationally given the small numbers.
Show evidence (1 reference)
PMID:34080768 SUPPORT Human Clinical
"Therefore, long-term follow-up of these individuals and further descriptions are required to fully understand the complete phenotypic spectrum of NS associated with MRAS germline variants, including if these individuals present an increased risk for cancer."
Explicitly names the cancer-risk question as unresolved for MRAS-related Noonan syndrome.
What accounts for the wide variation in cardiac severity among carriers of the same recurrent MRAS substitution?
KNOWLEDGE GAP ns11_cardiac_severity_variability
Attached to
pathophysiology#Hypertrophic Cardiomyopathy with Outflow Tract Obstruction
p.Thr68Ile is the most frequently recurrent NS11 variant and has been reported both in a neonate who died of cardiac failure and in an adult with only mild, late-onset left ventricular hypertrophy. Identical genotype with opposite cardiac trajectories implies modifiers, mosaicism, or ascertainment bias towards severe paediatric cases, and the distinction matters directly for counselling and for whether early myectomy is offered.
Proposed experiments
Genotype-stratified natural history study with modifier analysis
ns11_genotype_stratified_natural_history
Serial echocardiography in all reported and newly ascertained MRAS carriers, stratified by substitution, combined with exome-wide modifier screening and assessment of somatic mosaicism.
Show evidence (1 reference)
PMID:36734411 SUPPORT Human Clinical
"The present case provides evidence that HCM does not represent an obligatory, early-onset and severe complication in subjects with MRAS variants."
Establishes the intra-genotype discrepancy in cardiac severity that this gap concerns.
⚙

Pathophysiology

7
MRAS Activating Missense Variant
NS11 is initiated by a germline heterozygous missense substitution in MRAS, almost always at one of a narrow set of codons — Gly23 (p.Gly23Val, p.Gly23Arg), Thr68 (p.Thr68Ile) or Gln71 (p.Gln71Arg) — that correspond to known RASopathy and oncogenic hotspots in other RAS-family GTPases. The substitutions lie in or adjacent to the P-loop, switch regions and GTP-binding site, and are predicted to perturb effector-interaction surfaces and nucleotide handling.
MRAS hgnc:7227 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MRAS (hgnc:7227). hgnc:7227 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
MRAS p.Gly23Val CRISPR knock-in iPSC line IPSC DERIVED MODEL Introduces the disease-causing allele into a human pluripotent background, providing the genetic perturbation from which disease-relevant cell types can be derived.
Downstream
Constitutive M-Ras GTP Loading Hotspot substitutions impair intrinsic GTP hydrolysis, locking M-Ras in its active, GTP-bound state.
Show evidence (2 references)
PMID:28289718 SUPPORT Computational
"Mutation analysis using in silico mutation prediction tools and molecular dynamics simulations predicted the identified variant, p.Gly23Val-MRAS, to be damaging to normal protein function and adversely affect effector interaction regions and the GTP-binding site."
In silico prediction and molecular dynamics simulation localizing the founding NS11 variant to the effector-interaction and GTP-binding surfaces of M-Ras. Computational arm of a mixed-source paper.
PMID:31108500 SUPPORT Human Clinical
"Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins."
Establishes that the NS11 variant spectrum is confined to conserved RASopathy hotspot codons rather than being distributed across the gene.
Constitutive M-Ras GTP Loading
Impaired intrinsic GTP hydrolysis leaves mutant M-Ras persistently GTP-bound. Activation is quantitatively large: ectopic expression of p.Gly23Val-MRAS produced an approximately 40-fold increase in M-Ras activation relative to wild type. The GTP-loaded mutant is also constitutively targeted to the plasma membrane and dwells abnormally long in non-raft microdomains, so the active protein is retained where its effectors are engaged.
Ras protein signal transduction GO:0007265 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Ras protein signal transduction (GO:0007265). GO:0007265 is a biological process from the Gene Ontology. ↑ INCREASED constitutive plasma membrane targeting of M-Ras GO:0072659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased constitutive plasma membrane targeting of M-Ras, annotated with protein localization to plasma membrane (GO:0072659). GO:0072659 is a biological process from the Gene Ontology. ↑ INCREASED
M-Ras GTP hydrolysis GO:0003924 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased M-Ras GTP hydrolysis, annotated with GTPase activity (GO:0003924). GO:0003924 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Enhanced MRAS-SHOC2-PP1 Holophosphatase Assembly Persistently active, membrane-anchored M-Ras binds SHOC2 and the PP1 catalytic subunit PPP1CB more avidly, promoting formation of the heterotrimeric holophosphatase.
Show evidence (2 references)
PMID:28289718 SUPPORT In Vitro
"Subsequent ectopic expression experiments revealed a 40-fold increase in MRAS activation for p.Gly23Val-MRAS compared with WT-MRAS."
Quantifies the gain of function at the level of M-Ras activation state.
PMID:31108500 SUPPORT In Vitro
"Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK..."
Supports both the impaired GTPase activity and the constitutive membrane localization of NS11 mutants.
Enhanced MRAS-SHOC2-PP1 Holophosphatase Assembly
M-Ras, the leucine-rich-repeat scaffold SHOC2 and protein phosphatase 1 assemble into a heterotrimeric holoenzyme in which M-Ras and SHOC2 act as regulatory subunits conferring specificity for RAF, and M-Ras additionally acts as the membrane-targeting subunit. Noonan-causing substitutions in any of the three components — MRAS, SHOC2 or PPP1CB — promote assembly of this complex, which is the shared biochemical lesion linking NS11 to SHOC2-related and PPP1CB-related Noonan-spectrum disease.
PP1 holoenzyme serine/threonine phosphatase activity GO:0004722 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased PP1 holoenzyme serine/threonine phosphatase activity, annotated with protein serine/threonine phosphatase activity (GO:0004722). GO:0004722 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
RAF S259 Dephosphorylation and RAF Activation The assembled holophosphatase removes the inhibitory S259 phosphate from CRAF (S365 on BRAF), relieving 14-3-3-mediated autoinhibition and permitting RAF activation.
Show evidence (2 references)
PMID:30348783 SUPPORT In Vitro
"The MRAS GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase 1 (PP1) to form a heterotrimeric holoenzyme that dephosphorylates this S259 RAF site."
Defines the holophosphatase and its substrate, the inhibitory RAF S259 site.
PMID:36175670 SUPPORT In Vitro
"The SMP complex forms only when MRAS is in an active state and is dependent on SHOC2 functioning as a scaffolding protein in the complex by bringing PP1C and MRAS together."
The crystal structure shows the holophosphatase assembles only around active, GTP-bound M-Ras, which is why a constitutively active NS11 mutant drives complex formation.
RAF S259 Dephosphorylation and RAF Activation
Dephosphorylation of the inhibitory S259 site on CRAF (S365 on BRAF) by the MRAS-SHOC2-PP1 holophosphatase is a rate-limiting step in RAF activation. With mutant M-Ras driving complex assembly, this brake is released more readily and RAF signalling into MEK-ERK is potentiated.
RAF S259 dephosphorylation GO:0006470 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased RAF S259 dephosphorylation, annotated with protein dephosphorylation (GO:0006470). GO:0006470 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
RAS-MAPK and PI3K-AKT Pathway Hyperactivation Released RAF drives increased MEK-ERK signal flux; NS11 mutants additionally raise PI3K-AKT output to a variable degree.
Show evidence (1 reference)
PMID:30348783 SUPPORT In Vitro
"Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations is likely driven at the biochemical level by enhanced ternary complex formation and highlights the crucial role of this phosphatase holoenzyme in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human development."
States the mechanistic model connecting MRAS mutation, holophosphatase assembly and RAF S259 dephosphorylation to Noonan syndrome.
RAS-MAPK and PI3K-AKT Pathway Hyperactivation
The convergent cellular consequence of activating MRAS variants is upregulated signal flow through the RAF-MEK-ERK cascade, with variably increased PI3K-AKT signalling. This is the shared final common pathway of the RASopathies, and it accounts for the Noonan-spectrum craniofacial, growth and neurodevelopmental features that NS11 shares with the parent Noonan Syndrome entry.
ERK1 and ERK2 cascade GO:0070371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ERK1 and ERK2 cascade (GO:0070371). GO:0070371 is a biological process from the Gene Ontology. ↑ INCREASED PI3K-AKT signalling GO:0043491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased PI3K-AKT signalling, annotated with phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491). GO:0043491 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cardiomyocyte Hypertrophy and Calcium Handling Abnormality Pathway hyperactivation in cardiomyocytes produces cell enlargement, a hypertrophic gene-expression programme and disturbed calcium handling.
Show evidence (2 references)
PMID:31108500 SUPPORT In Vitro
"Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation."
Establishes that both MAPK and PI3K-AKT arms are engaged by MRAS functional upregulation.
PMID:28289718 SUPPORT In Vitro
"Additional biochemical assays demonstrated enhanced activation of both RAS/MAPK pathway signaling and downstream gene expression in cells expressing p.Gly23Val-MRAS."
Independent demonstration of RAS/MAPK hyperactivation by an NS11 variant.
Cardiomyocyte Hypertrophy and Calcium Handling Abnormality
In patient-derived and CRISPR-engineered isogenic iPSC-derived cardiomyocytes, p.Gly23Val-MRAS is both necessary and sufficient to produce increased cell size, a cardiac hypertrophy gene-expression signature, and impaired calcium handling with an increased frequency of irregular calcium transients and altered kinetics. This is the cell-level substrate of the hypertrophic cardiomyopathy that defines NS11 clinically.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac muscle hypertrophy GO:0003300 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cardiac muscle hypertrophy (GO:0003300). GO:0003300 is a biological process from the Gene Ontology. ↑ INCREASED intracellular calcium ion homeostasis GO:0006874 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intracellular calcium ion homeostasis (GO:0006874). GO:0006874 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
MRAS p.Gly23Val patient-derived and isogenic iPSC-derived cardiomyocytes IPSC DERIVED MODEL Reproduces cardiomyocyte enlargement, a hypertrophic gene-expression programme and abnormal calcium handling in a human genetic background, with isogenic controls on both sides.
Downstream
Hypertrophic Cardiomyopathy with Outflow Tract Obstruction Cardiomyocyte hypertrophy at tissue scale produces ventricular wall thickening that in most reported NS11 patients obstructs the left ventricular outflow tract.
Show evidence (2 references)
PMID:31638832 SUPPORT In Vitro
"p.Gly23Val-MRAS is both necessary and sufficient to elicit a cardiac hypertrophy phenotype in iPSC-CMs that includes increased cell size, changes in cardiac gene expression, and abnormal calcium handling"
Isogenic-control experiments establish necessity and sufficiency of the NS11 variant for the cardiomyocyte phenotype.
PMID:31638832 SUPPORT In Vitro
"Additionally, patient and disease modeled iPSC-CMs displayed impaired Ca2+ handling, including increased frequency of irregular Ca2+ transients and changes in Ca2+ handling kinetics."
Documents the calcium-handling component of the cellular phenotype.
Hypertrophic Cardiomyopathy with Outflow Tract Obstruction
The organ-level lesion that distinguishes NS11 within the Noonan spectrum. Reported patients have shown hypertrophic cardiomyopathy far more consistently than Noonan syndrome overall, in which HCM affects roughly 20-30%; the MRAS cases are additionally weighted towards early onset, outflow tract obstruction, and poor prognosis, with deaths in the neonatal and infant periods. The severity is nonetheless not invariant — an adult with the recurrent p.Thr68Ile substitution had only mild, late-onset left ventricular hypertrophy — so obligate early severe HCM is not a safe inference from genotype.
Show evidence (2 references)
PMID:34080768 SUPPORT Human Clinical
"This report reinforces the high frequency of HCM among individuals harboring MRAS variants, contrasting to the 20% overall prevalence of this cardiac anomaly in NS."
Contrasts the near-universal HCM of MRAS-related disease against the much lower background rate in Noonan syndrome generally.
PMID:36734411 SUPPORT Human Clinical
"The present case provides evidence that HCM does not represent an obligatory, early-onset and severe complication in subjects with MRAS variants."
Qualifies the severity claim: the cardiac phenotype is variable, and a mild late-onset course occurs.
✶

Histopathology

1
Myocardial hypertrophy with obliterative portal venopathy and lymphangiectasia
Autopsy of the antenatally diagnosed eighth patient showed the cardiac hypertrophy expected of NS11 together with two findings not previously described in MRAS-related disease: obliterative portal venopathy (with portal-tract widening, hypoplastic or absent portal vein branches and increased hepatic arterial branches) and pulmonary lymphangiectasia. The reporting authors judged the hepatic and portal abnormalities to be manifestations of MRAS-related Noonan syndrome rather than incidental.
Show evidence (1 reference)
PMID:41866303 SUPPORT Human Clinical
"Histopathology revealed HCM, obliterative portal venopathy and lymphangiectasia, consistent with NS pathology."
Reports the microscopic findings at autopsy in the single NS11 patient examined histopathologically.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Noonan Syndrome 11 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

25
Cardiovascular 4
Hypertrophic Cardiomyopathy VERY_FREQUENT HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41866303 SUPPORT Human Clinical
"These findings suggest that pathogenic MRAS variants confer a high risk of severe HCM (100% of cases)."
A literature review of all reported NS11 cases quantifies HCM at 100% of cases, supporting the VERY_FREQUENT band.
PMID:31108500 SUPPORT Human Clinical
"This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM."
Independent case series placing MRAS among the HCM-predisposing RASopathy genes.
Left Ventricular Hypertrophy HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36734411 SUPPORT Human Clinical
"We report on the natural history of the first adult subject with NS carrying the recurrent pathogenic p.Thr68Ile amino acid substitution. Different from what had previously been observed, he presented with a mild, late-onset left ventricular hypertrophy, and a constellation of additional..."
Documents late-onset left ventricular hypertrophy as the cardiac manifestation in the reported adult NS11 patient.
Pulmonic Stenosis HP:0001642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonic stenosis (HP:0001642). HP:0001642 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28289718 SUPPORT Human Clinical
"Cardiac hypertrophy, pulmonary valve stenosis, ASD, facial dysmorphisms, ptosis, and developmental delays"
The patient summary table records pulmonary valve stenosis in the p.Thr68Ile NS11 patient.
Atrial Septal Defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28289718 SUPPORT Human Clinical
"Cardiac hypertrophy, pulmonary valve stenosis, ASD, facial dysmorphisms, ptosis, and developmental delays"
The patient summary table records an atrial septal defect (ASD) in the p.Thr68Ile NS11 patient.
Ear 1
Low-Set Ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
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."
Records low-set posteriorly rotated ears in a molecularly confirmed MRAS patient.
Eye 2
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31173466 SUPPORT Human Clinical
"The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy."
Documents hypertelorism in the MRAS p.Gln71Arg patient.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28289718 SUPPORT Human Clinical
"Cardiac hypertrophy, pulmonary valve stenosis, ASD, facial dysmorphisms, ptosis, and developmental delays"
The patient summary table records ptosis in the p.Thr68Ile NS11 patient.
Head and Neck 2
Downslanted Palpebral Fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31173466 SUPPORT Human Clinical
"The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy."
Documents downslanting palpebral fissures in the MRAS p.Gln71Arg patient.
Relative Macrocephaly HP:0004482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Relative macrocephaly (HP:0004482). HP:0004482 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31173466 SUPPORT Human Clinical
"The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy."
Documents relative macrocephaly in the MRAS p.Gln71Arg patient.
Metabolism 1
Hydrops Fetalis HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41866303 SUPPORT Human Clinical
"At clinical examination, the weight was 2726 g (> 95th percentile for gestational age) in a context of hydrops fetalis"
Documents hydrops fetalis in the antenatally diagnosed MRAS-related patient.
Musculoskeletal 3
Pectus Excavatum HP:0000767 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus excavatum (HP:0000767). HP:0000767 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28289718 SUPPORT Human Clinical
"She had low set and mildly posteriorly angulated ears, very mild pectus excavatum, numerous wrinkles in her palms with slight redundancy of the soft tissue"
Records pectus excavatum on clinical examination of the p.Thr68Ile NS11 patient.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28289718 SUPPORT Human Clinical
"of her small joints, and hypotonia"
The examination findings for the p.Thr68Ile NS11 patient record hypotonia.
Joint Hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28289718 SUPPORT Human Clinical
"mild hyperexten- sibility of her small joints, and hypotonia"
Records mild hyperextensibility of the small joints in the p.Thr68Ile NS11 patient. The word is transcribed with the source's line-break hyphenation (`hyperexten- sibility`) because the cached full text splits it across a line; the quote is otherwise verbatim.
Nervous System 2
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36734411 SUPPORT Human Clinical
"Gain of function pathogenic variants in MRAS have been found in a small subset of pediatric subjects presenting with Noonan syndrome (NS) associated with hypertrophic cardiomyopathy (HCM) and moderate to severe intellectual disability."
Reports moderate to severe intellectual disability as part of the described NS11 phenotype.
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28289718 SUPPORT Human Clinical
"She walked independently at 2.5 years, used signs at around 15 months and spoken words at age 4 years, and was not fully toilet trained until age 6."
Documents delayed acquisition of motor, language and self-care milestones in the p.Thr68Ile NS11 patient.
Prenatal and Birth 1
Polyhydramnios HP:0001561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyhydramnios (HP:0001561). HP:0001561 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41866303 SUPPORT Human Clinical
"A cesarean section was performed at 33 weeks' gestation due to worsening fetal pleural effusions and maternal intolerance to polyhydramnios."
Documents polyhydramnios in the antenatally diagnosed NS11 pregnancy.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (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."
Records short stature in a molecularly confirmed MRAS p.Thr68Ile patient.
Other 8
Left Ventricular Outflow Tract Obstruction HP:0032092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular outflow tract obstruction (HP:0032092). HP:0032092 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34080768 SUPPORT Human Clinical
"Thus, these preliminary data suggest that variants in MRAS per se are high risk factors for the development of an early, severe HCM, mostly of them with left ventricle outflow tract obstruction, with poor prognosis."
States that most reported MRAS cases have outflow tract obstruction.
PMID:41517739 SUPPORT Human Clinical
"Echocardiography demonstrated obstructive hypertrophic cardiomyopathy with vegetation located in the left ventricular outflow tract."
Documents outflow tract obstruction in an adult NS11 patient.
Depressed Nasal Ridge HP:0000457 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depressed nasal bridge, annotated with Depressed nasal ridge (HP:0000457). HP:0000457 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31173466 SUPPORT Human Clinical
"The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy."
Documents a depressed nasal bridge in the MRAS p.Gln71Arg patient.
Posteriorly Rotated Ears HP:0000358 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posteriorly rotated ears (HP:0000358). HP:0000358 is a phenotype from the Human Phenotype Ontology.
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."
Records posteriorly rotated ears in a molecularly confirmed MRAS patient.
Broad Forehead HP:0000337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad forehead (HP:0000337). HP:0000337 is a phenotype from the Human Phenotype Ontology.
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."
Records a broad forehead in a molecularly confirmed MRAS patient.
Broad Neck HP:0000475 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad neck (HP:0000475). HP:0000475 is a phenotype from the Human Phenotype Ontology.
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."
Records a broad neck in a molecularly confirmed MRAS patient.
Increased Nuchal Translucency HP:0010880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased nuchal translucency (HP:0010880). HP:0010880 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41866303 SUPPORT Human Clinical
"The fetus exhibited increased nuchal translucency, agenesis of the ductus venosus, pulmonary lymphangiectasia, and complex hepatic vascular anomalies."
Documents increased nuchal translucency in the first antenatally diagnosed NS11 case.
Pulmonary Lymphangiectasia HP:0006521 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary lymphangiectasia (HP:0006521). HP:0006521 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41866303 SUPPORT Human Clinical
"The fetus exhibited increased nuchal translucency, agenesis of the ductus venosus, pulmonary lymphangiectasia, and complex hepatic vascular anomalies."
Names pulmonary lymphangiectasia specifically in the antenatally diagnosed NS11 case, supporting the HP:0006521 binding.
PMID:41866303 SUPPORT Human Clinical
"Histopathology revealed HCM, obliterative portal venopathy and lymphangiectasia, consistent with NS pathology."
Histopathological confirmation of lymphangiectasia in the fetal NS11 case.
Fetal Pleural Effusion HP:0025676 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fetal pleural effusion (HP:0025676). HP:0025676 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41866303 SUPPORT Human Clinical
"A cesarean section was performed at 33 weeks' gestation due to worsening fetal pleural effusions and maternal intolerance to polyhydramnios."
Documents fetal pleural effusions in the antenatally diagnosed NS11 case.
🧬

Genetic Associations

1
MRAS (Pathogenic Variants)
Gene: MRAS hgnc:7227 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MRAS (hgnc:7227). hgnc:7227 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (5 references)
PMID:28289718 SUPPORT Human Clinical
"Herein, we describe the discovery of mutations in MRAS in patients with NS and cardiac hypertrophy, establishing MRAS as the newest NS with cardiac hypertrophy-susceptibility gene."
The founding report establishing MRAS as a Noonan syndrome gene.
PMID:31108500 SUPPORT Human Clinical
"Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events."
Identifies two of the recurrent de novo pathogenic MRAS variants.
PMID:31173466 SUPPORT Human Clinical
"Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers."
Adds p.Gln71Arg to the pathogenic MRAS variant spectrum.
+ 2 more references
💊

Medical Actions

4
Cardiac surveillance and management of hypertrophic cardiomyopathy
Action: Therapeutic ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. NCIT:C49236
Because hypertrophic cardiomyopathy is present in essentially every reported NS11 patient and can be obstructive from infancy or emerge late in adulthood, echocardiographic surveillance is the central management task. Cardiovascular anomalies in Noonan syndrome are otherwise treated as in the general population. A recognized complication of outflow tract obstruction in this group is infective endocarditis, which prompted a call for careful cardiac surveillance in RASopathy patients.
Show evidence (2 references)
PMID:20301303 SUPPORT Human Clinical
"Cardiovascular anomalies in NS are usually treated as in the general population."
GeneReviews management guidance for the cardiac manifestations of Noonan syndrome.
PMID:41517739 SUPPORT Human Clinical
"It also identifies infective endocarditis as a previously unreported complication in MRAS-associated NS with outflow tract obstruction, highlighting the importance of careful cardiac surveillance in patients with RASopathies."
Motivates cardiac surveillance specifically in MRAS-associated Noonan syndrome.
Surgical septal myectomy
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Myectomy has been used to relieve outflow tract obstruction in NS11, including in the index patient at age 8. Outcomes have not been uniformly good — a 2-month-old infant died after myectomy — so the balance of risk in early infancy is unsettled.
Show evidence (1 reference)
PMID:34080768 SUPPORT Human Clinical
"We report on a 2-month-old infant boy also presenting this cardiac anomaly that evolved to a fatal outcome after a surgical myectomy."
Documents myectomy being performed in NS11 and its poor outcome in this infant, supporting the treatment's use while qualifying its risk.
Growth hormone therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: somatropin (recombinant human growth hormone) NCIT:C837 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses somatropin (recombinant human growth hormone), annotated with Somatropin (NCIT:C837). NCIT:C837 is a therapeutic agent from the NCI Thesaurus.
Growth hormone is used for the short stature of Noonan syndrome generally. No MRAS-specific growth hormone outcome data exist; this is inherited from the parent entry's management and should be applied with the usual caution in a patient with hypertrophic cardiomyopathy.
Show evidence (1 reference)
PMID:20301303 SUPPORT Human Clinical
"Growth hormone (GH) treatment increases growth velocity."
GeneReviews establishes growth hormone as standard management for the short stature of Noonan syndrome.
MEK inhibition
Action: Targeted TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Targeted Therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. NCIT:C93352
Because NS11 acts through RAF-MEK-ERK hyperactivation, MEK inhibitors are the mechanistically aligned targeted therapy and have been proposed for MRAS-related disease. This is a rationale, not established care: no MRAS -specific interventional trial has been reported.
Mechanism Target:
INHIBITS RAS-MAPK and PI3K-AKT Pathway Hyperactivation — MEK inhibitors block the MEK-ERK arm downstream of the activated MRAS-SHOC2-PP1/RAF axis.
Show evidence (1 reference)
PMID:41866303 SUPPORT Other
"Moreover, emerging targeted therapies, such as MEK inhibitors, offer potential for treatment."
Identifies MEK inhibition as the emerging targeted approach for MRAS-related Noonan syndrome; evidence source is OTHER because this is a review/case-report proposal rather than a reported intervention.
Show evidence (1 reference)
PMID:41866303 SUPPORT Other
"Moreover, emerging targeted therapies, such as MEK inhibitors, offer potential for treatment."
Supports MEK inhibition only as an emerging, proposed option for MRAS-related Noonan syndrome, not as established therapy.
🔬

Diagnosis

1
Molecular genetic testing on a RASopathy panel
NS11 is a molecular diagnosis. Because the MRAS-associated cardiac phenotype overlaps sarcomeric hypertrophic cardiomyopathy, the index case was identified only by trio whole exome sequencing after negative clinical testing of the standard Noonan and myofilament HCM gene panels; MRAS is now included on RASopathy panels. A confirmed heterozygous pathogenic MRAS variant in a proband with suggestive findings establishes the diagnosis.
Show evidence (3 references)
PMID:28289718 SUPPORT Human Clinical
"Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS-encoded RAS-related protein 3 as the cause of her disease."
Describes the trio exome approach that established the first molecular diagnosis of NS11.
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."
A second worked example of exome-based molecular confirmation of NS11.
PMID:20301303 SUPPORT Human Clinical
"The diagnosis of Noonan is established in a proband with suggestive findings and a heterozygous pathogenic variant in BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 or either a heterozygous variant or biallelic pathogenic variants in LZTR1 identified by molecular..."
GeneReviews states the diagnostic criterion this section curates: a heterozygous pathogenic MRAS variant in a proband with suggestive findings establishes the molecular diagnosis.
📈

Progression

2
Prenatal and neonatal severe cardiac disease
Age: fetal life to early infancy
Most reported NS11 patients have had early-onset, rapidly progressive and often obstructive hypertrophic cardiomyopathy, with deaths antenatally, in the neonatal period, and after infant myectomy.
Show evidence (2 references)
PMID:34080768 SUPPORT Human Clinical
"We report on a 2-month-old infant boy also presenting this cardiac anomaly that evolved to a fatal outcome after a surgical myectomy."
Documents the severe, fatal early-infancy end of the NS11 cardiac natural history.
PMID:41866303 SUPPORT Human Clinical
"Based on available follow-up data, the mortality rate reached 37.5% (three of eight individuals)."
Quantifies mortality across the whole reported MRAS series. The denominator is eight published patients, so this is a case-series figure and not a population survival estimate.
Mild adult-onset left ventricular hypertrophy
Age: adulthood
The severe early course is not obligate: the single reported adult with the recurrent p.Thr68Ile substitution had mild, late-onset left ventricular hypertrophy, so anticipatory guidance is needed across the whole age range.
Show evidence (1 reference)
PMID:36734411 SUPPORT Human Clinical
"It also adds new data about late-onset features suggesting that other unexpected complications might be observed in adult subjects providing anticipatory guidance for individuals of all age."
Documents the mild adult-onset end of the NS11 cardiac natural history.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
Eight unrelated patients with pathogenic MRAS variants had been reported as of the February 2025 literature review; MRAS accounts for a very small minority of molecularly solved Noonan syndrome.
Show evidence (1 reference)
PMID:41866303 SUPPORT Human Clinical
"This article includes a review of the literature on NS with pathogenic MRAS variants and describes an eighth case, the first documented with early and severe antenatal manifestations."
A targeted narrative literature review (the authors explicitly preferred this to a PRISMA systematic review) counts a total of eight reported patients, establishing the ultra-rare, case-report-level occurrence of NS11.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Noonan Syndrome 11:

Sarcomeric hypertrophic cardiomyopathy
Overlapping Features NS11 presenting as isolated early severe hypertrophic cardiomyopathy is readily mistaken for a sarcomeric HCM; the index NS11 patient had already been screened negative on myofilament HCM gene panels before exome sequencing found the MRAS variant. Extracardiac Noonan features (dysmorphism, short stature, developmental delay) discriminate.
Show evidence (1 reference)
PMID:28289718 SUPPORT Human Clinical
"Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS-encoded RAS-related protein 3 as the cause of her disease."
The case was reached by exome sequencing after standard cardiomyopathy and Noonan panels were uninformative.
Other RASopathies with hypertrophic cardiomyopathy
Overlapping Features RAF1-, RIT1- and PTPN11-related Noonan syndrome, Noonan syndrome with multiple lentigines, and Costello syndrome all include hypertrophic cardiomyopathy, and SHOC2- and PPP1CB-related disease shares the same MRAS-SHOC2-PP1 biochemical axis. Discrimination is molecular.
Show evidence (1 reference)
PMID:31108500 SUPPORT Human Clinical
"This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM."
Places MRAS alongside the other HCM-predisposing RASopathy genes from which it must be distinguished.
🔬

Clinical Trials

1
NCT06555237 PHASE_II RECRUITING
MEKinRAS, a randomised phase 2 trial of the MEK inhibitor trametinib added to standard therapy for hypertrophic cardiomyopathy in children with a genetically confirmed RASopathy. It is the trial most directly relevant to the NS11 cardiac phenotype, but eligibility is defined at the RAS/MAPK pathway level: the registry entry does not name MRAS or document MRAS-positive enrolment, so this is not MRAS-specific interventional evidence.
Target Phenotypes: Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT06555237 SUPPORT Other
"The goal of this study is to evaluate the effectiveness of trametinib treatment in patients with Hyperthropic cardiomyopathy and a genetic mutation in the RAS/MAPK pathway."
Establishes an active MEK-inhibitor trial for RASopathy-associated hypertrophic cardiomyopathy; support is PARTIAL because eligibility is pathway-level rather than MRAS-specific.
🧫

Experimental Models

2
MRAS p.Gly23Val patient-derived and isogenic iPSC-derived cardiomyocytes IPSC_DERIVED_MODEL
Patient-derived iPSCs carrying MRAS p.Gly23Val, a CRISPR/Cas9-corrected isogenic control, and an unrelated control line into which the variant was introduced, differentiated to cardiomyocytes. The bidirectional design establishes both necessity and sufficiency of the variant for the hypertrophic phenotype.
Publication
PMID:31638832
Pathograph links
Cardiomyocyte Hypertrophy and Calcium Handling Abnormality recapitulates fidelity: high Reproduces cardiomyocyte enlargement, a hypertrophic gene-expression programme and abnormal calcium handling in a human genetic background, with isogenic controls on both sides.
Limitations: iPSC-derived cardiomyocytes are structurally and metabolically immature and cultured without haemodynamic load or the non-myocyte cell types of the myocardium, so ventricular remodelling and outflow tract obstruction cannot be modelled.
Readouts
Cardiomyocyte cell size
Direction: INCREASED
Interpretation: Cell enlargement is the defining in vitro correlate of the hypertrophy node.
Show evidence (1 reference)
PMID:31638832 SUPPORT In Vitro
"Compared with controls, both patient and disease modeled iPSC-CMs were significantly larger and demonstrated changes in gene expression and intracellular pathway signaling characteristic of cardiac hypertrophy."
Reports the cell-size measurement in both patient and disease-modelled lines.
Frequency of irregular calcium transients
Direction: INCREASED
Interpretation: Disturbed calcium handling accompanies the hypertrophic phenotype and is a plausible arrhythmic substrate.
Show evidence (1 reference)
PMID:31638832 SUPPORT In Vitro
"Additionally, patient and disease modeled iPSC-CMs displayed impaired Ca2+ handling, including increased frequency of irregular Ca2+ transients and changes in Ca2+ handling kinetics."
Reports the calcium-transient measurement.
Show evidence (1 reference)
PMID:31638832 SUPPORT In Vitro
"p.Gly23Val-MRAS is both necessary and sufficient to elicit a cardiac hypertrophy phenotype in iPSC-CMs that includes increased cell size, changes in cardiac gene expression, and abnormal calcium handling"
Supports treating this model as informative for the cardiomyocyte hypertrophy node.
Show evidence (1 reference)
PMID:31638832 SUPPORT In Vitro
"CRISPR/Cas9 gene editing was used to correct the pathogenic p.Gly23Val-MRAS variant in patient cells (isogenic control) and to introduce the pathogenic variant into unrelated control cells (disease modeled) to determine the necessity and sufficiency of the p.Gly23Val-MRAS variant to elicit the..."
Describes the bidirectional isogenic design of this model system.
MRAS p.Gly23Val CRISPR knock-in iPSC line IPSC_DERIVED_MODEL
A human iPSC line into which the NS11-associated MRAS p.Gly23Val variant was introduced by CRISPR/Cas9, distributed as a resource for studying MRAS-specific pathomechanisms and candidate therapies in disease-relevant lineages.
Publication
PMID:37141804
Pathograph links
MRAS Activating Missense Variant perturbs fidelity: moderate Introduces the disease-causing allele into a human pluripotent background, providing the genetic perturbation from which disease-relevant cell types can be derived.
Limitations: This is a reagent report: the undifferentiated line itself carries no characterized disease phenotype, and downstream phenotypes must be established in each derived lineage.
Show evidence (1 reference)
PMID:37141804 SUPPORT In Vitro
"The established MRASG23V iPSC line allows to study MRAS-specific pathomechanisms and to test novel therapeutic strategies in various disease-relevant cell types and tissues."
States the intended use of the line as a model of the MRAS variant.
Show evidence (1 reference)
PMID:37141804 SUPPORT In Vitro
"Here, we describe the generation of a human iPSC line harboring the Noonan syndrome-associated MRAS p.G23V variant by using CRISPR/Cas9 technology."
Establishes the existence and genotype of this model line.
{ }

Source YAML

click to show 
name: Noonan Syndrome 11
creation_date: "2026-08-18T00:00:00Z"
description: >-
  Noonan syndrome 11 (NS11) is the MRAS-related form of Noonan syndrome, an
  autosomal dominant RASopathy caused by germline activating missense variants
  in MRAS, which encodes the RAS-family GTPase M-Ras. Mutant M-Ras has impaired
  intrinsic GTPase activity and is constitutively GTP-loaded and membrane
  targeted; it binds SHOC2 and PPP1CB more avidly, promoting assembly of the
  MRAS-SHOC2-PP1 holophosphatase that dephosphorylates the inhibitory RAF S259
  site and drives RAF-MEK-ERK, with variably increased PI3K-AKT signalling.
  Clinically the entry is defined within the Noonan spectrum by a strong,
  variant-restricted association with hypertrophic cardiomyopathy: the reported
  cases cluster on a narrow set of codons (Gly23, Thr68, Gln71) and nearly all
  have had HCM, frequently severe, early onset and obstructive, with several
  neonatal or infant deaths. The phenotype is not uniform, however — a single
  adult with the recurrent p.Thr68Ile substitution presented instead with mild,
  late-onset left ventricular hypertrophy — so HCM severity should not be
  treated as an obligate feature. NS11 is an ultra-rare cause of Noonan
  syndrome: only a handful of unrelated patients have been reported since MRAS
  was implicated in 2017. General Noonan syndrome features (short stature,
  characteristic facies, developmental delay/intellectual disability) are
  present but are shared with the parent entry, Noonan Syndrome, which this
  entry cross-references rather than duplicates.
category: Genetic
parents:
- RASopathy
- Noonan Syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0032786
      label: Noonan syndrome 11
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary disease term for this entry.
  - term:
      id: MONDO:0018997
      label: Noonan syndrome
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO records Noonan syndrome 11 as a child of Noonan syndrome; the
      dismech umbrella entry Noonan Syndrome carries that broader term.
disease_term:
  preferred_term: Noonan syndrome 11
  description: >-
    The MRAS-related form of Noonan syndrome, caused by germline activating
    missense variants in MRAS and strongly associated with hypertrophic
    cardiomyopathy.
  term:
    id: MONDO:0032786
    label: Noonan syndrome 11
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Eight unrelated patients with pathogenic MRAS variants had been reported as
    of the February 2025 literature review; MRAS accounts for a very small
    minority of molecularly solved Noonan syndrome.
  evidence:
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This article includes a review of the literature on NS with pathogenic
      MRAS variants and describes an eighth case, the first documented with
      early and severe antenatal manifestations.
    explanation: >-
      A targeted narrative literature review (the authors explicitly preferred
      this to a PRISMA systematic review) counts a total of eight reported
      patients, establishing the ultra-rare, case-report-level occurrence of
      NS11.
pathophysiology:
- name: MRAS Activating Missense Variant
  description: >-
    NS11 is initiated by a germline heterozygous missense substitution in MRAS,
    almost always at one of a narrow set of codons — Gly23 (p.Gly23Val,
    p.Gly23Arg), Thr68 (p.Thr68Ile) or Gln71 (p.Gln71Arg) — that correspond to
    known RASopathy and oncogenic hotspots in other RAS-family GTPases. The
    substitutions lie in or adjacent to the P-loop, switch regions and
    GTP-binding site, and are predicted to perturb effector-interaction surfaces
    and nucleotide handling.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: MRAS
    term:
      id: hgnc:7227
      label: MRAS
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Mutation analysis using in silico mutation prediction tools and molecular
      dynamics simulations predicted the identified variant, p.Gly23Val-MRAS, to
      be damaging to normal protein function and adversely affect effector
      interaction regions and the GTP-binding site.
    explanation: >-
      In silico prediction and molecular dynamics simulation localizing the
      founding NS11 variant to the effector-interaction and GTP-binding
      surfaces of M-Ras. Computational arm of a mixed-source paper.
  - reference: PMID:31108500
    reference_title: "Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gly23 and Thr68 are highly conserved residues, and the corresponding
      codons are known hotspots for RASopathy-associated mutations in other RAS
      proteins.
    explanation: >-
      Establishes that the NS11 variant spectrum is confined to conserved
      RASopathy hotspot codons rather than being distributed across the gene.
  downstream:
  - target: Constitutive M-Ras GTP Loading
    causal_link_type: DIRECT
    description: >-
      Hotspot substitutions impair intrinsic GTP hydrolysis, locking M-Ras in
      its active, GTP-bound state.
    evidence:
    - reference: PMID:31108500
      reference_title: "Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Functional analyses documented high level of activation of MRAS mutants
        due to impaired GTPase activity, which was associated with constitutive
        plasma membrane targeting, prolonged localization in non-raft
        microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably
        increased MAPK and PI3K-AKT activation.
      explanation: >-
        Directly attributes the activation of the mutant protein to loss of
        GTPase activity.
- name: Constitutive M-Ras GTP Loading
  description: >-
    Impaired intrinsic GTP hydrolysis leaves mutant M-Ras persistently
    GTP-bound. Activation is quantitatively large: ectopic expression of
    p.Gly23Val-MRAS produced an approximately 40-fold increase in M-Ras
    activation relative to wild type. The GTP-loaded mutant is also
    constitutively targeted to the plasma membrane and dwells abnormally long in
    non-raft microdomains, so the active protein is retained where its effectors
    are engaged.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: M-Ras GTP hydrolysis
    term:
      id: GO:0003924
      label: GTPase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: Ras protein signal transduction
    term:
      id: GO:0007265
      label: Ras protein signal transduction
    modifier: INCREASED
  - preferred_term: constitutive plasma membrane targeting of M-Ras
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
    modifier: INCREASED
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Subsequent ectopic expression experiments revealed a 40-fold increase in
      MRAS activation for p.Gly23Val-MRAS compared with WT-MRAS.
    explanation: >-
      Quantifies the gain of function at the level of M-Ras activation state.
  - reference: PMID:31108500
    reference_title: "Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analyses documented high level of activation of MRAS mutants
      due to impaired GTPase activity, which was associated with constitutive
      plasma membrane targeting, prolonged localization in non-raft
      microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably
      increased MAPK and PI3K-AKT activation.
    explanation: >-
      Supports both the impaired GTPase activity and the constitutive membrane
      localization of NS11 mutants.
  downstream:
  - target: Enhanced MRAS-SHOC2-PP1 Holophosphatase Assembly
    causal_link_type: DIRECT
    description: >-
      Persistently active, membrane-anchored M-Ras binds SHOC2 and the PP1
      catalytic subunit PPP1CB more avidly, promoting formation of the
      heterotrimeric holophosphatase.
    evidence:
    - reference: PMID:30348783
      reference_title: "SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        MRAS, SHOC2, and PPP1CB are mutated in Noonan syndrome, and we show that
        syndromic mutations invariably promote complex formation with each
        other, but not necessarily with other interactors.
      explanation: >-
        Shows that Noonan-causing MRAS mutations act by enhancing ternary
        complex formation with SHOC2 and PPP1CB.
- name: Enhanced MRAS-SHOC2-PP1 Holophosphatase Assembly
  description: >-
    M-Ras, the leucine-rich-repeat scaffold SHOC2 and protein phosphatase 1
    assemble into a heterotrimeric holoenzyme in which M-Ras and SHOC2 act as
    regulatory subunits conferring specificity for RAF, and M-Ras additionally
    acts as the membrane-targeting subunit. Noonan-causing substitutions in any
    of the three components — MRAS, SHOC2 or PPP1CB — promote assembly of this
    complex, which is the shared biochemical lesion linking NS11 to
    SHOC2-related and PPP1CB-related Noonan-spectrum disease.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: PP1 holoenzyme serine/threonine phosphatase activity
    term:
      id: GO:0004722
      label: protein serine/threonine phosphatase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:30348783
    reference_title: "SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The MRAS GTPase, a close relative of RAS oncoproteins, interacts with
      SHOC2 and protein phosphatase 1 (PP1) to form a heterotrimeric holoenzyme
      that dephosphorylates this S259 RAF site.
    explanation: >-
      Defines the holophosphatase and its substrate, the inhibitory RAF S259
      site.
  - reference: PMID:36175670
    reference_title: "Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The SMP complex forms only when MRAS is in an active state and is
      dependent on SHOC2 functioning as a scaffolding protein in the complex by
      bringing PP1C and MRAS together.
    explanation: >-
      The crystal structure shows the holophosphatase assembles only around
      active, GTP-bound M-Ras, which is why a constitutively active NS11 mutant
      drives complex formation.
  downstream:
  - target: RAF S259 Dephosphorylation and RAF Activation
    causal_link_type: DIRECT
    description: >-
      The assembled holophosphatase removes the inhibitory S259 phosphate from
      CRAF (S365 on BRAF), relieving 14-3-3-mediated autoinhibition and
      permitting RAF activation.
    evidence:
    - reference: PMID:30348783
      reference_title: "SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        MRAS also functions as a targeting subunit as membrane localization is
        required for efficient RAF dephosphorylation and ERK pathway regulation
        in cells.
      explanation: >-
        Links the membrane-localized complex to RAF dephosphorylation and ERK
        pathway output.
- name: RAF S259 Dephosphorylation and RAF Activation
  description: >-
    Dephosphorylation of the inhibitory S259 site on CRAF (S365 on BRAF) by the
    MRAS-SHOC2-PP1 holophosphatase is a rate-limiting step in RAF activation.
    With mutant M-Ras driving complex assembly, this brake is released more
    readily and RAF signalling into MEK-ERK is potentiated.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: RAF S259 dephosphorylation
    term:
      id: GO:0006470
      label: protein dephosphorylation
    modifier: INCREASED
  evidence:
  - reference: PMID:30348783
    reference_title: "SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations
      is likely driven at the biochemical level by enhanced ternary complex
      formation and highlights the crucial role of this phosphatase holoenzyme
      in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human
      development.
    explanation: >-
      States the mechanistic model connecting MRAS mutation, holophosphatase
      assembly and RAF S259 dephosphorylation to Noonan syndrome.
  downstream:
  - target: RAS-MAPK and PI3K-AKT Pathway Hyperactivation
    causal_link_type: DIRECT
    description: >-
      Released RAF drives increased MEK-ERK signal flux; NS11 mutants
      additionally raise PI3K-AKT output to a variable degree.
    evidence:
    - reference: PMID:28289718
      reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Additional biochemical assays demonstrated enhanced activation of both
        RAS/MAPK pathway signaling and downstream gene expression in cells
        expressing p.Gly23Val-MRAS.
      explanation: >-
        Demonstrates increased MAPK pathway output downstream of the NS11
        variant.
- name: RAS-MAPK and PI3K-AKT Pathway Hyperactivation
  description: >-
    The convergent cellular consequence of activating MRAS variants is
    upregulated signal flow through the RAF-MEK-ERK cascade, with variably
    increased PI3K-AKT signalling. This is the shared final common pathway of
    the RASopathies, and it accounts for the Noonan-spectrum craniofacial,
    growth and neurodevelopmental features that NS11 shares with the parent
    Noonan Syndrome entry.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: INCREASED
  - preferred_term: PI3K-AKT signalling
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  evidence:
  - reference: PMID:31108500
    reference_title: "Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, our findings further emphasize the relevance of the
      MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the
      contribution of both MAPK and PI3K-AKT pathways in MRAS functional
      upregulation.
    explanation: >-
      Establishes that both MAPK and PI3K-AKT arms are engaged by MRAS
      functional upregulation.
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Additional biochemical assays demonstrated enhanced activation of both
      RAS/MAPK pathway signaling and downstream gene expression in cells
      expressing p.Gly23Val-MRAS.
    explanation: >-
      Independent demonstration of RAS/MAPK hyperactivation by an NS11 variant.
  downstream:
  - target: Cardiomyocyte Hypertrophy and Calcium Handling Abnormality
    causal_link_type: DIRECT
    description: >-
      Pathway hyperactivation in cardiomyocytes produces cell enlargement, a
      hypertrophic gene-expression programme and disturbed calcium handling.
    evidence:
    - reference: PMID:31638832
      reference_title: "MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Compared with controls, both patient and disease modeled iPSC-CMs were
        significantly larger and demonstrated changes in gene expression and
        intracellular pathway signaling characteristic of cardiac hypertrophy.
      explanation: >-
        Directly links the NS11 variant, via altered intracellular pathway
        signalling, to a cardiomyocyte hypertrophy phenotype.
- name: Cardiomyocyte Hypertrophy and Calcium Handling Abnormality
  description: >-
    In patient-derived and CRISPR-engineered isogenic iPSC-derived
    cardiomyocytes, p.Gly23Val-MRAS is both necessary and sufficient to produce
    increased cell size, a cardiac hypertrophy gene-expression signature, and
    impaired calcium handling with an increased frequency of irregular calcium
    transients and altered kinetics. This is the cell-level substrate of the
    hypertrophic cardiomyopathy that defines NS11 clinically.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  - preferred_term: intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31638832
    reference_title: "MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      p.Gly23Val-MRAS is both necessary and sufficient to elicit a cardiac
      hypertrophy phenotype in iPSC-CMs that includes increased cell size,
      changes in cardiac gene expression, and abnormal calcium handling
    explanation: >-
      Isogenic-control experiments establish necessity and sufficiency of the
      NS11 variant for the cardiomyocyte phenotype.
  - reference: PMID:31638832
    reference_title: "MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Additionally, patient and disease modeled iPSC-CMs displayed impaired Ca2+
      handling, including increased frequency of irregular Ca2+ transients and
      changes in Ca2+ handling kinetics.
    explanation: >-
      Documents the calcium-handling component of the cellular phenotype.
  downstream:
  - target: Hypertrophic Cardiomyopathy with Outflow Tract Obstruction
    causal_link_type: DIRECT
    description: >-
      Cardiomyocyte hypertrophy at tissue scale produces ventricular wall
      thickening that in most reported NS11 patients obstructs the left
      ventricular outflow tract.
    evidence:
    - reference: PMID:34080768
      reference_title: "Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thus, these preliminary data suggest that variants in MRAS per se are
        high risk factors for the development of an early, severe HCM, mostly of
        them with left ventricle outflow tract obstruction, with poor prognosis.
      explanation: >-
        Connects MRAS variants specifically to obstructive, early and severe
        hypertrophic cardiomyopathy.
- name: Hypertrophic Cardiomyopathy with Outflow Tract Obstruction
  description: >-
    The organ-level lesion that distinguishes NS11 within the Noonan spectrum.
    Reported patients have shown hypertrophic cardiomyopathy far more
    consistently than Noonan syndrome overall, in which HCM affects roughly
    20-30%; the MRAS cases are additionally weighted towards early onset,
    outflow tract obstruction, and poor prognosis, with deaths in the neonatal
    and infant periods. The severity is nonetheless not invariant — an adult
    with the recurrent p.Thr68Ile substitution had only mild, late-onset left
    ventricular hypertrophy — so obligate early severe HCM is not a safe
    inference from genotype.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:34080768
    reference_title: "Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report reinforces the high frequency of HCM among individuals
      harboring MRAS variants, contrasting to the 20% overall prevalence of this
      cardiac anomaly in NS.
    explanation: >-
      Contrasts the near-universal HCM of MRAS-related disease against the much
      lower background rate in Noonan syndrome generally.
  - reference: PMID:36734411
    reference_title: "Natural history of MRAS-related Noonan syndrome: Evidence of mild adult-onset left ventricular hypertrophy and neuropsychiatric features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present case provides evidence that HCM does not represent an
      obligatory, early-onset and severe complication in subjects with MRAS
      variants.
    explanation: >-
      Qualifies the severity claim: the cardiac phenotype is variable, and a
      mild late-onset course occurs.
phenotypes:
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  description: >-
    The cardinal and near-universal feature of MRAS-related Noonan syndrome. All
    unrelated patients reported to date have had HCM, most with early onset and
    a severe, often obstructive course; a minority present with mild late-onset
    left ventricular hypertrophy instead.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that pathogenic MRAS variants confer a high risk of
      severe HCM (100% of cases).
    explanation: >-
      A literature review of all reported NS11 cases quantifies HCM at 100% of
      cases, supporting the VERY_FREQUENT band.
  - reference: PMID:31108500
    reference_title: "Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report provides additional evidence that a narrow spectrum of
      activating mutations in MRAS represents another rare cause of NS, and that
      MRAS has to be counted among the RASopathy genes predisposing to HCM.
    explanation: >-
      Independent case series placing MRAS among the HCM-predisposing RASopathy
      genes.
- category: Cardiovascular
  name: Left Ventricular Outflow Tract Obstruction
  description: >-
    Asymmetric hypertrophy in reported NS11 patients frequently obstructs the
    left ventricular outflow tract, prompting surgical myectomy; obstruction has
    been documented from infancy through adulthood.
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:34080768
    reference_title: "Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, these preliminary data suggest that variants in MRAS per se are high
      risk factors for the development of an early, severe HCM, mostly of them
      with left ventricle outflow tract obstruction, with poor prognosis.
    explanation: >-
      States that most reported MRAS cases have outflow tract obstruction.
  - 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: >-
      Documents outflow tract obstruction in an adult NS11 patient.
- category: Cardiovascular
  name: Left Ventricular Hypertrophy
  description: >-
    Left ventricular hypertrophy is the measurable structural expression of the
    cardiomyopathy and may be the only cardiac finding in the mild, adult-onset
    end of the NS11 spectrum.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:36734411
    reference_title: "Natural history of MRAS-related Noonan syndrome: Evidence of mild adult-onset left ventricular hypertrophy and neuropsychiatric features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on the natural history of the first adult subject with NS
      carrying the recurrent pathogenic p.Thr68Ile amino acid substitution.
      Different from what had previously been observed, he presented with a
      mild, late-onset left ventricular hypertrophy, and a constellation of
      additional symptoms rarely seen in NS.
    explanation: >-
      Documents late-onset left ventricular hypertrophy as the cardiac
      manifestation in the reported adult NS11 patient.
- category: Growth
  name: Short Stature
  description: >-
    Short stature, a cardinal Noonan syndrome feature, is present in reported
    NS11 patients from the index case onwards.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  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: >-
      Records short stature in a molecularly confirmed MRAS p.Thr68Ile patient.
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Ocular hypertelorism is part of the RASopathy facial gestalt seen in
    MRAS-related Noonan syndrome.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:31173466
    reference_title: "Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's dysmorphic features included relative macrocephaly, a
      down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge,
      and low-set ears with thick lobes; these facial features are strongly
      associated with RASopathy.
    explanation: >-
      Documents hypertelorism in the MRAS p.Gln71Arg patient.
- category: Craniofacial
  name: Downslanted Palpebral Fissures
  description: >-
    Downward-slanting palpebral fissures contribute to the characteristic
    Noonan facies in NS11.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:31173466
    reference_title: "Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's dysmorphic features included relative macrocephaly, a
      down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge,
      and low-set ears with thick lobes; these facial features are strongly
      associated with RASopathy.
    explanation: >-
      Documents downslanting palpebral fissures in the MRAS p.Gln71Arg patient.
- category: Craniofacial
  name: Depressed Nasal Ridge
  description: >-
    A depressed nasal bridge is reported among the dysmorphic features of
    MRAS-related Noonan syndrome.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0000457
      label: Depressed nasal ridge
  evidence:
  - reference: PMID:31173466
    reference_title: "Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's dysmorphic features included relative macrocephaly, a
      down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge,
      and low-set ears with thick lobes; these facial features are strongly
      associated with RASopathy.
    explanation: >-
      Documents a depressed nasal bridge in the MRAS p.Gln71Arg patient.
- category: Craniofacial
  name: Low-Set Ears
  description: >-
    Low-set, posteriorly rotated ears are a recurrent finding across the
    reported NS11 patients.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  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: >-
      Records low-set posteriorly rotated ears in a molecularly confirmed MRAS
      patient.
- category: Craniofacial
  name: Posteriorly Rotated Ears
  description: >-
    Posterior rotation of the ears accompanies the low ear position in reported
    NS11 patients.
  phenotype_term:
    preferred_term: Posteriorly rotated ears
    term:
      id: HP:0000358
      label: Posteriorly rotated ears
  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: >-
      Records posteriorly rotated ears in a molecularly confirmed MRAS patient.
- category: Craniofacial
  name: Broad Forehead
  description: >-
    A broad forehead is part of the Noonan facial gestalt documented in NS11.
  phenotype_term:
    preferred_term: Broad forehead
    term:
      id: HP:0000337
      label: Broad forehead
  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: >-
      Records a broad forehead in a molecularly confirmed MRAS patient.
- category: Craniofacial
  name: Relative Macrocephaly
  description: >-
    Relative macrocephaly was documented in the patient with the severe
    p.Gln71Arg phenotype.
  phenotype_term:
    preferred_term: Relative macrocephaly
    term:
      id: HP:0004482
      label: Relative macrocephaly
  evidence:
  - reference: PMID:31173466
    reference_title: "Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's dysmorphic features included relative macrocephaly, a
      down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge,
      and low-set ears with thick lobes; these facial features are strongly
      associated with RASopathy.
    explanation: >-
      Documents relative macrocephaly in the MRAS p.Gln71Arg patient.
- category: Musculoskeletal
  name: Broad Neck
  description: >-
    A broad neck, the milder end of the Noonan short/webbed neck spectrum, is
    documented in an adult NS11 patient.
  phenotype_term:
    preferred_term: Broad neck
    term:
      id: HP:0000475
      label: Broad neck
  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: >-
      Records a broad neck in a molecularly confirmed MRAS patient.
- category: Neurological
  name: Intellectual Disability
  description: >-
    Moderate to severe intellectual disability has been reported in the
    paediatric NS11 cohort, alongside globally delayed developmental milestones
    in the index case.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36734411
    reference_title: "Natural history of MRAS-related Noonan syndrome: Evidence of mild adult-onset left ventricular hypertrophy and neuropsychiatric features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gain of function pathogenic variants in MRAS have been found in a small
      subset of pediatric subjects presenting with Noonan syndrome (NS)
      associated with hypertrophic cardiomyopathy (HCM) and moderate to severe
      intellectual disability.
    explanation: >-
      Reports moderate to severe intellectual disability as part of the
      described NS11 phenotype.
- category: Prenatal
  name: Increased Nuchal Translucency
  description: >-
    Prenatal presentation of NS11 was first documented in the eighth reported
    case, which showed increased nuchal translucency among other severe
    antenatal findings.
  phenotype_term:
    preferred_term: Increased nuchal translucency
    term:
      id: HP:0010880
      label: Increased nuchal translucency
  evidence:
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The fetus exhibited increased nuchal translucency, agenesis of the ductus
      venosus, pulmonary lymphangiectasia, and complex hepatic vascular
      anomalies.
    explanation: >-
      Documents increased nuchal translucency in the first antenatally
      diagnosed NS11 case.
- category: Respiratory
  name: Pulmonary Lymphangiectasia
  description: >-
    Pulmonary lymphangiectasia, a manifestation of the lymphatic dysplasia seen
    across Noonan syndrome, was present antenatally and confirmed
    histopathologically in the severe fetal NS11 case.
  phenotype_term:
    preferred_term: Pulmonary lymphangiectasia
    term:
      id: HP:0006521
      label: Pulmonary lymphangiectasia
  evidence:
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The fetus exhibited increased nuchal translucency, agenesis of the ductus
      venosus, pulmonary lymphangiectasia, and complex hepatic vascular
      anomalies.
    explanation: >-
      Names pulmonary lymphangiectasia specifically in the antenatally
      diagnosed NS11 case, supporting the HP:0006521 binding.
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathology revealed HCM, obliterative portal venopathy and
      lymphangiectasia, consistent with NS pathology.
    explanation: >-
      Histopathological confirmation of lymphangiectasia in the fetal NS11 case.
- category: Prenatal
  name: Fetal Pleural Effusion
  description: >-
    Worsening fetal pleural effusions, a serosal-effusion manifestation of
    lymphatic dysplasia, prompted preterm delivery in the antenatally diagnosed
    NS11 case.
  phenotype_term:
    preferred_term: Fetal pleural effusion
    term:
      id: HP:0025676
      label: Fetal pleural effusion
  evidence:
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A cesarean section was performed at 33 weeks' gestation due to worsening
      fetal pleural effusions and maternal intolerance to polyhydramnios.
    explanation: >-
      Documents fetal pleural effusions in the antenatally diagnosed NS11 case.
- category: Prenatal
  name: Polyhydramnios
  description: >-
    Polyhydramnios accompanied the effusions in the antenatally diagnosed NS11
    pregnancy.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A cesarean section was performed at 33 weeks' gestation due to worsening
      fetal pleural effusions and maternal intolerance to polyhydramnios.
    explanation: >-
      Documents polyhydramnios in the antenatally diagnosed NS11 pregnancy.
- category: Cardiovascular
  name: Pulmonic Stenosis
  description: >-
    Pulmonary valve stenosis, the commonest congenital heart lesion of Noonan
    syndrome generally, was present alongside the hypertrophic cardiomyopathy in
    the second reported NS11 patient (p.Thr68Ile).
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac hypertrophy, pulmonary valve stenosis, ASD, facial dysmorphisms,
      ptosis, and developmental delays
    explanation: >-
      The patient summary table records pulmonary valve stenosis in the
      p.Thr68Ile NS11 patient.
- category: Cardiovascular
  name: Atrial Septal Defect
  description: >-
    An atrial septal defect accompanied the cardiomyopathy and pulmonary valve
    stenosis in the second reported NS11 patient.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac hypertrophy, pulmonary valve stenosis, ASD, facial dysmorphisms,
      ptosis, and developmental delays
    explanation: >-
      The patient summary table records an atrial septal defect (ASD) in the
      p.Thr68Ile NS11 patient.
- category: Craniofacial
  name: Ptosis
  description: >-
    Ptosis, a core component of the Noonan facial gestalt, is documented in the
    p.Thr68Ile NS11 patient.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac hypertrophy, pulmonary valve stenosis, ASD, facial dysmorphisms,
      ptosis, and developmental delays
    explanation: >-
      The patient summary table records ptosis in the p.Thr68Ile NS11 patient.
- category: Musculoskeletal
  name: Pectus Excavatum
  description: >-
    Mild pectus excavatum was among the skeletal findings in the p.Thr68Ile NS11
    patient, consistent with the chest-wall deformity typical of Noonan
    syndrome.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had low set and mildly posteriorly angulated ears, very mild pectus
      excavatum, numerous wrinkles in her palms with slight redundancy of the
      soft tissue
    explanation: >-
      Records pectus excavatum on clinical examination of the p.Thr68Ile NS11
      patient.
- category: Neurological
  name: Global Developmental Delay
  description: >-
    Both originally reported NS11 patients had globally delayed developmental
    milestones; the p.Thr68Ile patient walked independently at 2.5 years, used
    signs at 15 months and spoken words at 4 years.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She walked independently at 2.5 years, used signs at around 15 months and
      spoken words at age 4 years, and was not fully toilet trained until age 6.
    explanation: >-
      Documents delayed acquisition of motor, language and self-care milestones
      in the p.Thr68Ile NS11 patient.
- category: Neurological
  name: Hypotonia
  description: >-
    Hypotonia was documented on examination of the p.Thr68Ile NS11 patient, in
    keeping with the reduced muscle tone commonly seen across the RASopathies.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      of her small joints, and hypotonia
    explanation: >-
      The examination findings for the p.Thr68Ile NS11 patient record hypotonia.
- category: Musculoskeletal
  name: Joint Hypermobility
  description: >-
    Mild hyperextensibility of the small joints was recorded in the p.Thr68Ile
    NS11 patient, alongside the redundant palmar soft tissue and pectus
    excavatum of the same examination.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild hyperexten- sibility of her small joints, and hypotonia"
    explanation: >-
      Records mild hyperextensibility of the small joints in the p.Thr68Ile NS11
      patient. The word is transcribed with the source's line-break hyphenation
      (`hyperexten- sibility`) because the cached full text splits it across a
      line; the quote is otherwise verbatim.
- category: Prenatal
  name: Hydrops Fetalis
  description: >-
    The eighth reported patient, an MRAS-related fetus with severe antenatal
    disease, was hydropic at birth, the end stage of the serosal effusions and
    lymphatic drainage failure that dominated the prenatal course.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At clinical examination, the weight was 2726 g (> 95th percentile for
      gestational age) in a context of hydrops fetalis
    explanation: >-
      Documents hydrops fetalis in the antenatally diagnosed MRAS-related
      patient.
histopathology:
- name: Myocardial hypertrophy with obliterative portal venopathy and lymphangiectasia
  description: >-
    Autopsy of the antenatally diagnosed eighth patient showed the cardiac
    hypertrophy expected of NS11 together with two findings not previously
    described in MRAS-related disease: obliterative portal venopathy (with
    portal-tract widening, hypoplastic or absent portal vein branches and
    increased hepatic arterial branches) and pulmonary lymphangiectasia. The
    reporting authors judged the hepatic and portal abnormalities to be
    manifestations of MRAS-related Noonan syndrome rather than incidental.
  evidence:
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathology revealed HCM, obliterative portal venopathy and
      lymphangiectasia, consistent with NS pathology.
    explanation: >-
      Reports the microscopic findings at autopsy in the single NS11 patient
      examined histopathologically.
  notes: >-
    A single autopsy, so this is a description rather than a frequency claim; no
    other reported MRAS patient has had a published histopathological
    examination.
genetic:
- name: MRAS
  notes: >-
    MRAS encodes M-Ras (RAS-related protein 3, R-Ras3), a RAS-family small
    GTPase that transmits signal to RAF through the SHOC2-PP1 holophosphatase.
    NS11 is caused by heterozygous germline missense variants at a narrow set of
    conserved hotspot codons. Reported pathogenic changes are c.68G>T
    (p.Gly23Val), c.67G>C (p.Gly23Arg), c.203C>T (p.Thr68Ile — the most
    frequently recurrent) and c.212A>G (p.Gln71Arg); all reported occurrences
    have been de novo.
  gene_term:
    preferred_term: MRAS
    term:
      id: hgnc:7227
      label: MRAS
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we describe the discovery of mutations in MRAS in patients with NS
      and cardiac hypertrophy, establishing MRAS as the newest NS with cardiac
      hypertrophy-susceptibility gene.
    explanation: >-
      The founding report establishing MRAS as a Noonan syndrome gene.
  - reference: PMID:31108500
    reference_title: "Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Targeted sequencing revealed de novo MRAS variants, c.203C > T
      (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events.
    explanation: >-
      Identifies two of the recurrent de novo pathogenic MRAS variants.
  - reference: PMID:31173466
    reference_title: "Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a patient with a severe Noonan syndrome phenotype
      associated with a germline Q71R MRAS variant, which represents a recurrent
      substitution in RAS homologs in various cancers.
    explanation: >-
      Adds p.Gln71Arg to the pathogenic MRAS variant spectrum.
  - 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: >-
      The ClinGen RASopathy Gene Curation Expert Panel classifies the
      MRAS-Noonan syndrome gene-disease relationship as Moderate with autosomal
      dominant inheritance.
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Noonan is established in a proband with suggestive
      findings and a heterozygous pathogenic variant in BRAF, KRAS, MAP2K1,
      MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 or either a
      heterozygous variant or biallelic pathogenic variants in LZTR1 identified
      by molecular genetic testing.
    explanation: >-
      GeneReviews lists MRAS among the genes in which a heterozygous pathogenic
      variant establishes a molecular diagnosis of Noonan syndrome.
inheritance:
- name: Autosomal Dominant
  description: >-
    NS11 is inherited in an autosomal dominant manner, in keeping with Noonan
    syndrome generally. Every reported MRAS-related case has arisen de novo,
    which is expected given the severity of the associated cardiomyopathy and
    the resulting limited reproductive fitness; no familial transmission of an
    MRAS variant has been described.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - 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 records the mode of inheritance for MRAS-related Noonan syndrome
      as autosomal dominant.
  - reference: PMID:31108500
    reference_title: "Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Targeted sequencing revealed de novo MRAS variants, c.203C > T
      (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events.
    explanation: >-
      Documents the de novo occurrence of the heterozygous MRAS variants in
      unaffected-parent trios.
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with autosomal dominant NS has a 50% chance of
      inheriting the pathogenic variant
    explanation: >-
      GeneReviews gives the transmission risk for autosomal dominant Noonan
      syndrome. The risk follows from the mode of inheritance rather than from
      the causal gene, so it applies to NS11 even though every reported MRAS
      proband to date has been a de novo case.
diagnosis:
- name: Molecular genetic testing on a RASopathy panel
  description: >-
    NS11 is a molecular diagnosis. Because the MRAS-associated cardiac phenotype
    overlaps sarcomeric hypertrophic cardiomyopathy, the index case was
    identified only by trio whole exome sequencing after negative clinical
    testing of the standard Noonan and myofilament HCM gene panels; MRAS is now
    included on RASopathy panels. A confirmed heterozygous pathogenic MRAS
    variant in a proband with suggestive findings establishes the diagnosis.
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing (WES) and trio-based genomic triangulation of a
      15-year-old female with a clinical diagnosis of NS and concomitant cardiac
      hypertrophy and her unaffected parents identified a de novo variant in
      MRAS-encoded RAS-related protein 3 as the cause of her disease.
    explanation: >-
      Describes the trio exome approach that established the first molecular
      diagnosis of NS11.
  - 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: >-
      A second worked example of exome-based molecular confirmation of NS11.
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Noonan is established in a proband with suggestive
      findings and a heterozygous pathogenic variant in BRAF, KRAS, MAP2K1,
      MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 or either a
      heterozygous variant or biallelic pathogenic variants in LZTR1 identified
      by molecular genetic testing.
    explanation: >-
      GeneReviews states the diagnostic criterion this section curates: a
      heterozygous pathogenic MRAS variant in a proband with suggestive findings
      establishes the molecular diagnosis.
differential_diagnoses:
- name: Sarcomeric hypertrophic cardiomyopathy
  description: >-
    NS11 presenting as isolated early severe hypertrophic cardiomyopathy is
    readily mistaken for a sarcomeric HCM; the index NS11 patient had already
    been screened negative on myofilament HCM gene panels before exome
    sequencing found the MRAS variant. Extracardiac Noonan features
    (dysmorphism, short stature, developmental delay) discriminate.
  evidence:
  - reference: PMID:28289718
    reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing (WES) and trio-based genomic triangulation of a
      15-year-old female with a clinical diagnosis of NS and concomitant cardiac
      hypertrophy and her unaffected parents identified a de novo variant in
      MRAS-encoded RAS-related protein 3 as the cause of her disease.
    explanation: >-
      The case was reached by exome sequencing after standard cardiomyopathy and
      Noonan panels were uninformative.
- name: Other RASopathies with hypertrophic cardiomyopathy
  description: >-
    RAF1-, RIT1- and PTPN11-related Noonan syndrome, Noonan syndrome with
    multiple lentigines, and Costello syndrome all include hypertrophic
    cardiomyopathy, and SHOC2- and PPP1CB-related disease shares the same
    MRAS-SHOC2-PP1 biochemical axis. Discrimination is molecular.
  evidence:
  - reference: PMID:31108500
    reference_title: "Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report provides additional evidence that a narrow spectrum of
      activating mutations in MRAS represents another rare cause of NS, and that
      MRAS has to be counted among the RASopathy genes predisposing to HCM.
    explanation: >-
      Places MRAS alongside the other HCM-predisposing RASopathy genes from
      which it must be distinguished.
progression:
- phase: Prenatal and neonatal severe cardiac disease
  age_range: fetal life to early infancy
  notes: >-
    Most reported NS11 patients have had early-onset, rapidly progressive and
    often obstructive hypertrophic cardiomyopathy, with deaths antenatally, in
    the neonatal period, and after infant myectomy.
  evidence:
  - reference: PMID:34080768
    reference_title: "Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a 2-month-old infant boy also presenting this cardiac anomaly
      that evolved to a fatal outcome after a surgical myectomy.
    explanation: >-
      Documents the severe, fatal early-infancy end of the NS11 cardiac natural
      history.
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on available follow-up data, the mortality rate reached 37.5% (three
      of eight individuals).
    explanation: >-
      Quantifies mortality across the whole reported MRAS series. The denominator
      is eight published patients, so this is a case-series figure and not a
      population survival estimate.
- phase: Mild adult-onset left ventricular hypertrophy
  age_range: adulthood
  notes: >-
    The severe early course is not obligate: the single reported adult with the
    recurrent p.Thr68Ile substitution had mild, late-onset left ventricular
    hypertrophy, so anticipatory guidance is needed across the whole age range.
  evidence:
  - reference: PMID:36734411
    reference_title: "Natural history of MRAS-related Noonan syndrome: Evidence of mild adult-onset left ventricular hypertrophy and neuropsychiatric features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It also adds new data about late-onset features suggesting that other
      unexpected complications might be observed in adult subjects providing
      anticipatory guidance for individuals of all age.
    explanation: >-
      Documents the mild adult-onset end of the NS11 cardiac natural history.
treatments:
- name: Cardiac surveillance and management of hypertrophic cardiomyopathy
  description: >-
    Because hypertrophic cardiomyopathy is present in essentially every reported
    NS11 patient and can be obstructive from infancy or emerge late in
    adulthood, echocardiographic surveillance is the central management task.
    Cardiovascular anomalies in Noonan syndrome are otherwise treated as in the
    general population. A recognized complication of outflow tract obstruction
    in this group is infective endocarditis, which prompted a call for careful
    cardiac surveillance in RASopathy patients.
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiovascular anomalies in NS are usually treated as in the general
      population.
    explanation: >-
      GeneReviews management guidance for the cardiac manifestations of 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: >-
      It also identifies infective endocarditis as a previously unreported
      complication in MRAS-associated NS with outflow tract obstruction,
      highlighting the importance of careful cardiac surveillance in patients
      with RASopathies.
    explanation: >-
      Motivates cardiac surveillance specifically in MRAS-associated Noonan
      syndrome.
- name: Surgical septal myectomy
  description: >-
    Myectomy has been used to relieve outflow tract obstruction in NS11,
    including in the index patient at age 8. Outcomes have not been uniformly
    good — a 2-month-old infant died after myectomy — so the balance of risk in
    early infancy is unsettled.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:34080768
    reference_title: "Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a 2-month-old infant boy also presenting this cardiac anomaly
      that evolved to a fatal outcome after a surgical myectomy.
    explanation: >-
      Documents myectomy being performed in NS11 and its poor outcome in this
      infant, supporting the treatment's use while qualifying its risk.
- name: Growth hormone therapy
  description: >-
    Growth hormone is used for the short stature of Noonan syndrome generally.
    No MRAS-specific growth hormone outcome data exist; this is inherited from
    the parent entry's management and should be applied with the usual caution
    in a patient with hypertrophic cardiomyopathy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin (recombinant human growth hormone)
      term:
        id: NCIT:C837
        label: Somatropin
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth hormone (GH) treatment increases growth velocity.
    explanation: >-
      GeneReviews establishes growth hormone as standard management for the
      short stature of Noonan syndrome.
- name: MEK inhibition
  description: >-
    Because NS11 acts through RAF-MEK-ERK hyperactivation, MEK inhibitors are
    the mechanistically aligned targeted therapy and have been proposed for
    MRAS-related disease. This is a rationale, not established care: no MRAS
    -specific interventional trial has been reported.
  treatment_term:
    preferred_term: Targeted Therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: RAS-MAPK and PI3K-AKT Pathway Hyperactivation
    treatment_effect: INHIBITS
    description: >-
      MEK inhibitors block the MEK-ERK arm downstream of the activated
      MRAS-SHOC2-PP1/RAF axis.
    evidence:
    - reference: PMID:41866303
      reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Moreover, emerging targeted therapies, such as MEK inhibitors, offer
        potential for treatment.
      explanation: >-
        Identifies MEK inhibition as the emerging targeted approach for
        MRAS-related Noonan syndrome; evidence source is OTHER because this is
        a review/case-report proposal rather than a reported intervention.
  evidence:
  - reference: PMID:41866303
    reference_title: "Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Moreover, emerging targeted therapies, such as MEK inhibitors, offer
      potential for treatment.
    explanation: >-
      Supports MEK inhibition only as an emerging, proposed option for
      MRAS-related Noonan syndrome, not as established therapy.
clinical_trials:
- name: NCT06555237
  phase: PHASE_II
  status: RECRUITING
  description: >-
    MEKinRAS, a randomised phase 2 trial of the MEK inhibitor trametinib added
    to standard therapy for hypertrophic cardiomyopathy in children with a
    genetically confirmed RASopathy. It is the trial most directly relevant to
    the NS11 cardiac phenotype, but eligibility is defined at the RAS/MAPK
    pathway level: the registry entry does not name MRAS or document
    MRAS-positive enrolment, so this is not MRAS-specific interventional
    evidence.
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT06555237
    reference_title: "MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies (MEKinRAS) - Randomized Controlled Trial"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The goal of this study is to evaluate the effectiveness of trametinib
      treatment in patients with Hyperthropic cardiomyopathy and a genetic
      mutation in the RAS/MAPK pathway.
    explanation: >-
      Establishes an active MEK-inhibitor trial for RASopathy-associated
      hypertrophic cardiomyopathy; support is PARTIAL because eligibility is
      pathway-level rather than MRAS-specific.
experimental_models:
- name: MRAS p.Gly23Val patient-derived and isogenic iPSC-derived cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Patient-derived iPSCs carrying MRAS p.Gly23Val, a CRISPR/Cas9-corrected
    isogenic control, and an unrelated control line into which the variant was
    introduced, differentiated to cardiomyocytes. The bidirectional design
    establishes both necessity and sufficiency of the variant for the
    hypertrophic phenotype.
  publication: PMID:31638832
  evidence:
  - reference: PMID:31638832
    reference_title: "MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CRISPR/Cas9 gene editing was used to correct the pathogenic
      p.Gly23Val-MRAS variant in patient cells (isogenic control) and to
      introduce the pathogenic variant into unrelated control cells (disease
      modeled) to determine the necessity and sufficiency of the p.Gly23Val-MRAS
      variant to elicit the disease phenotype in iPSC-derived cardiomyocytes
      (iPSC-CMs).
    explanation: >-
      Describes the bidirectional isogenic design of this model system.
  modeled_mechanisms:
  - target: Cardiomyocyte Hypertrophy and Calcium Handling Abnormality
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces cardiomyocyte enlargement, a hypertrophic gene-expression
      programme and abnormal calcium handling in a human genetic background,
      with isogenic controls on both sides.
    limitations: >-
      iPSC-derived cardiomyocytes are structurally and metabolically immature
      and cultured without haemodynamic load or the non-myocyte cell types of
      the myocardium, so ventricular remodelling and outflow tract obstruction
      cannot be modelled.
    readouts:
    - name: Cardiomyocyte cell size
      target: Cardiomyocyte Hypertrophy and Calcium Handling Abnormality
      direction: INCREASED
      interpretation: >-
        Cell enlargement is the defining in vitro correlate of the hypertrophy
        node.
      evidence:
      - reference: PMID:31638832
        reference_title: "MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Compared with controls, both patient and disease modeled iPSC-CMs were
          significantly larger and demonstrated changes in gene expression and
          intracellular pathway signaling characteristic of cardiac hypertrophy.
        explanation: >-
          Reports the cell-size measurement in both patient and disease-modelled
          lines.
    - name: Frequency of irregular calcium transients
      target: Cardiomyocyte Hypertrophy and Calcium Handling Abnormality
      direction: INCREASED
      interpretation: >-
        Disturbed calcium handling accompanies the hypertrophic phenotype and is
        a plausible arrhythmic substrate.
      evidence:
      - reference: PMID:31638832
        reference_title: "MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Additionally, patient and disease modeled iPSC-CMs displayed impaired
          Ca2+ handling, including increased frequency of irregular Ca2+
          transients and changes in Ca2+ handling kinetics.
        explanation: >-
          Reports the calcium-transient measurement.
    evidence:
    - reference: PMID:31638832
      reference_title: "MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        p.Gly23Val-MRAS is both necessary and sufficient to elicit a cardiac
        hypertrophy phenotype in iPSC-CMs that includes increased cell size,
        changes in cardiac gene expression, and abnormal calcium handling
      explanation: >-
        Supports treating this model as informative for the cardiomyocyte
        hypertrophy node.
- name: MRAS p.Gly23Val CRISPR knock-in iPSC line
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    A human iPSC line into which the NS11-associated MRAS p.Gly23Val variant was
    introduced by CRISPR/Cas9, distributed as a resource for studying
    MRAS-specific pathomechanisms and candidate therapies in disease-relevant
    lineages.
  publication: PMID:37141804
  modeled_mechanisms:
  - target: MRAS Activating Missense Variant
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Introduces the disease-causing allele into a human pluripotent background,
      providing the genetic perturbation from which disease-relevant cell types
      can be derived.
    limitations: >-
      This is a reagent report: the undifferentiated line itself carries no
      characterized disease phenotype, and downstream phenotypes must be
      established in each derived lineage.
    evidence:
    - reference: PMID:37141804
      reference_title: "Generation of a genetically-modified induced pluripotent stem cell line harboring a Noonan syndrome-associated gene variant MRAS p.G23V."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The established MRASG23V iPSC line allows to study MRAS-specific
        pathomechanisms and to test novel therapeutic strategies in various
        disease-relevant cell types and tissues.
      explanation: >-
        States the intended use of the line as a model of the MRAS variant.
  evidence:
  - reference: PMID:37141804
    reference_title: "Generation of a genetically-modified induced pluripotent stem cell line harboring a Noonan syndrome-associated gene variant MRAS p.G23V."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we describe the generation of a human iPSC line harboring the Noonan
      syndrome-associated MRAS p.G23V variant by using CRISPR/Cas9 technology.
    explanation: >-
      Establishes the existence and genotype of this model line.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:28289718
      reference_title: "Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a
        member of a family of developmental disorders termed "RASopathies,"
        which are caused mainly by gain-of-function mutations in genes encoding
        RAS/MAPK signaling pathway proteins.
      explanation: >-
        Places NS11 in the inherited, gain-of-function signalling-disorder class.
  - classification_value: CARDIOVASCULAR
    evidence:
    - reference: PMID:34080768
      reference_title: "Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This report reinforces the high frequency of HCM among individuals
        harboring MRAS variants, contrasting to the 20% overall prevalence of
        this cardiac anomaly in NS.
      explanation: >-
        The defining clinical burden of NS11 is cardiovascular.
discussions:
- discussion_id: ns11_mras_cancer_risk
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do germline activating MRAS variants confer an increased cancer risk, as the
    corresponding hotspot substitutions in other RAS homologs do?
  rationale: >-
    p.Gln71Arg is a recurrent oncogenic substitution in RAS homologs across
    various cancers, and other RASopathies carry defined tumour predisposition.
    No NS11 patient has been reported with a malignancy, but the reported cohort
    is tiny and several patients died in infancy, so the question is
    unanswerable from current data rather than answered in the negative.
  attaches_to:
  - pathophysiology#Constitutive M-Ras GTP Loading
  proposed_experiments:
  - experiment_id: ns11_tumour_surveillance_cohort
    name: Longitudinal tumour surveillance of a molecularly ascertained MRAS cohort
    description: >-
      Prospective, protocol-driven oncological follow-up of all surviving
      individuals with pathogenic MRAS variants, pooled internationally given
      the small numbers.
  evidence:
  - reference: PMID:34080768
    reference_title: "Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, long-term follow-up of these individuals and further
      descriptions are required to fully understand the complete phenotypic
      spectrum of NS associated with MRAS germline variants, including if these
      individuals present an increased risk for cancer.
    explanation: >-
      Explicitly names the cancer-risk question as unresolved for MRAS-related
      Noonan syndrome.
- discussion_id: ns11_cardiac_severity_variability
  kind: KNOWLEDGE_GAP
  prompt: >-
    What accounts for the wide variation in cardiac severity among carriers of
    the same recurrent MRAS substitution?
  rationale: >-
    p.Thr68Ile is the most frequently recurrent NS11 variant and has been
    reported both in a neonate who died of cardiac failure and in an adult with
    only mild, late-onset left ventricular hypertrophy. Identical genotype with
    opposite cardiac trajectories implies modifiers, mosaicism, or ascertainment
    bias towards severe paediatric cases, and the distinction matters directly
    for counselling and for whether early myectomy is offered.
  attaches_to:
  - pathophysiology#Hypertrophic Cardiomyopathy with Outflow Tract Obstruction
  proposed_experiments:
  - experiment_id: ns11_genotype_stratified_natural_history
    name: Genotype-stratified natural history study with modifier analysis
    description: >-
      Serial echocardiography in all reported and newly ascertained MRAS
      carriers, stratified by substitution, combined with exome-wide modifier
      screening and assessment of somatic mosaicism.
  evidence:
  - reference: PMID:36734411
    reference_title: "Natural history of MRAS-related Noonan syndrome: Evidence of mild adult-onset left ventricular hypertrophy and neuropsychiatric features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present case provides evidence that HCM does not represent an
      obligatory, early-onset and severe complication in subjects with MRAS
      variants.
    explanation: >-
      Establishes the intra-genotype discrepancy in cardiac severity that this
      gap concerns.
references:
- reference: PMID:20301303
  title: "Noonan Syndrome."
  tags:
  - GeneReviews
notes: >-
  Scope note: this entry deliberately models only the MRAS-specific arm of
  Noonan syndrome. Features shared with the wider Noonan spectrum (pulmonary
  valve stenosis, coagulation defects, cryptorchidism, lymphatic dysplasia in
  general, feeding difficulties, and the full management and surveillance
  protocol) are curated on the parent entry, Noonan Syndrome, which this entry
  lists under `parents` rather than duplicating. Pulmonary valve stenosis and
  the prenatal lymphatic findings are the deliberate exceptions: they are
  curated here because they are directly documented in the reported MRAS
  patients themselves, not inherited from the general Noonan description.

  Frequency note: the GeneReviews entry (PMID:20301303) is cited for
  genotype-independent statements only — diagnostic criteria, transmission risk
  and management. Its frequency bands ("50%-80% of individuals", "found in
  20%-50% of individuals") describe Noonan syndrome as a whole and were
  deliberately NOT inherited by this entry, because assigning general
  Noonan/RASopathy prevalence figures to the eight published MRAS patients would
  be unsupported. The single `frequency:` value in this file is the one figure
  reported for MRAS specifically (HCM in 100% of reported cases).

  Curation provenance note: the first falcon deep-research run for this entry
  resolved "Noonan syndrome 11" to autosomal dominant LZTR1-related Noonan
  syndrome (NS10, OMIM 616564) — a Named Entity Confusion within the numbered
  Noonan series. `just preflight-dr` returned WARN with LZTR1 mentioned 61 times
  against 5 for MRAS, and the report's own OMIM identifiers (605275, 616564)
  disagreed with the MONDO:0032786 xref (618499). That report was discarded and
  not cherry-picked; the entry was built from primary literature anchored on the
  OAK-verified causal gene MRAS (HGNC:7227).
📚

References & Deep Research

References

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

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 17 citations 2026-08-18T09:52:49.898789

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

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

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

Disease Characteristics Research Template

Target Disease

  • Disease Name: Noonan Syndrome 11 NS11 the MRAS-related form of Noonan syndrome OMIM 618499 MONDO:0032786 caused by germline activating missense variants in the MRAS gene encoding the RAS-family GTPase M-Ras. NOT LZTR1-related Noonan syndrome and NOT any other numbered Noonan syndrome type.
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Noonan Syndrome 11 NS11 the MRAS-related form of Noonan syndrome OMIM 618499 MONDO:0032786 caused by germline activating missense variants in the MRAS gene encoding the RAS-family GTPase M-Ras. NOT LZTR1-related Noonan syndrome and NOT any other numbered Noonan syndrome type. covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

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

1. Disease Information

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

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

2. Etiology

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

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

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

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

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

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

5. Environmental Information

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

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

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

    Search first: CDC databases, WHO, PubMed, NHANES

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

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

6. Mechanism / Pathophysiology

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

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

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

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

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

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

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

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

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

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

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

    Search first: PubMed, Gene Ontology, Reactome

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

7. Anatomical Structures Affected

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

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

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

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

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

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

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

8. Temporal Development

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

    Search first: OMIM, Orphanet, HPO, PubMed

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

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

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

9. Inheritance and Population

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

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

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

10. Diagnostics

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

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

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

11. Outcome/Prognosis

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

12. Treatment

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

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

13. Prevention

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

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

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

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

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

    Search first: NSGC resources, ACMG guidelines, GeneReviews

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

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

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

    Search first: VBO (Vertebrate Breed Ontology)

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

    Search first: NCBI Gene

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Noonan syndrome 11 (MRAS-related): disease-characteristics report

Scope and evidence standard

This report concerns only Noonan syndrome 11 (NS11) caused by germline activating MRAS variants. It does not describe LZTR1-related Noonan syndrome or any other numbered Noonan syndrome. NS11 is exceptionally rare; consequently, the evidence base consists primarily of a few human cases, cell-functional studies, and structural/biochemical work. Statements labeled “general Noonan/RASopathy care” are clinical extrapolations, not MRAS-specific outcome evidence.

domain MRAS-specific established finding evidence type/source certainty or key limitation
Disease identity Noonan syndrome 11 is the MRAS-related Noonan syndrome entity; key identifiers include OMIM 618499 and MONDO:0032786 Aggregated disease-gene resource plus literature-linked target-disease evidence (OpenTargets Search: Noonan syndrome 11-MRAS) High confidence for disease-gene mapping; sparse primary patient literature compared with other Noonan genes
Causal gene The causal gene is MRAS (muscle RAS oncogene homolog), encoding the RAS-family small GTPase M-Ras Human gene-disease association evidence and primary case reports (OpenTargets Search: Noonan syndrome 11-MRAS, higgins2017elucidationofmrasmediated pages 1-2) High confidence
Reported pathogenic variants Reported NS11 missense activating variants include p.Gly23Val, p.Thr68Ile, and p.Gln71Arg Human case report and mechanistic/structural studies referencing NS variants (higgins2017elucidationofmrasmediated pages 1-2, bonsor2024rasandshoc2 pages 6-8, young2018shoc2–mras–pp1complexpositively pages 5-6) p.Gly23Val and p.Thr68Ile are directly documented in the 2017 human report; p.Gln71Arg is strongly supported by later mechanistic literature but was not detailed in the retrieved human case excerpt
Inheritance Reported human cases were de novo; disease mechanism is consistent with autosomal dominant transmission if inherited Human trio/genotype-negative cohort evidence (higgins2017elucidationofmrasmediated pages 1-2, higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 9-11) Very small number of directly retrieved patients limits penetrance/segregation estimates
Molecular effect NS11 is caused by germline activating missense variants producing gain-of-function/constitutive activation of MRAS Human functional studies and structural/biochemical studies (higgins2017elucidationofmrasmediated pages 1-2, bonsor2024rasandshoc2 pages 6-8, higgins2017elucidationofmrasmediated pages 9-11, young2018shoc2–mras–pp1complexpositively pages 5-6) High confidence for GOF mechanism
Core phenotype Phenotype is dominated by congenital or early-onset cardiac hypertrophy/HCM, often with additional congenital heart disease, plus classic Noonan features such as distinctive facies, short stature, hypotonia/developmental delay, and learning difficulties Direct human clinical evidence from reported patients (higgins2017elucidationofmrasmediated pages 1-2, higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 2-4, higgins2017elucidationofmrasmediated pages 9-11) High confidence that cardiac disease is prominent; exact frequency estimates remain uncertain because very few cases are available
Cardiac manifestations Reported findings include biventricular/left ventricular hypertrophy, outflow tract obstruction, pulmonary valve stenosis, and atrial septal defect; one patient required surgical myectomy in childhood Direct human clinical case data (higgins2017elucidationofmrasmediated pages 2-4, higgins2017elucidationofmrasmediated pages 11-12, higgins2017elucidationofmrasmediated pages 9-11) Strong case-level evidence, but no MRAS-specific natural-history cohort
Development/growth Reported non-cardiac findings include short stature, global developmental delay, delayed walking/language, intellectual/learning difficulties, joint hypermobility, pectus excavatum, hypotonia, and characteristic facies Direct human clinical evidence (higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 2-4, higgins2017elucidationofmrasmediated pages 6-8) Frequencies cannot be robustly estimated from retrieved data
Signaling mechanism Pathogenic MRAS variants enhance formation/function of the SHOC2-MRAS-PP1C holophosphatase complex, promoting RAF inhibitory-site (S259/CR2-pS) dephosphorylation, RAF activation, and downstream ERK/MAPK signaling Biochemical, structural, and cell-based mechanistic evidence (bonsor2024rasandshoc2 pages 6-8, higgins2017elucidationofmrasmediated pages 9-11, young2018shoc2–mras–pp1complexpositively pages 5-6) High mechanistic confidence; much evidence derives from in vitro/structural systems rather than patient tissue
Diagnostic approach Diagnosis is established by sequencing-based molecular testing: WES/trio analysis identified one de novo case, and targeted sequencing of genotype-negative RASopathy patients with cardiac hypertrophy found another Human diagnostic evidence (higgins2017elucidationofmrasmediated pages 1-2, higgins2017elucidationofmrasmediated pages 2-4, higgins2017elucidationofmrasmediated pages 9-11) High confidence that MRAS should be included in RASopathy/HCM genomic testing; no MRAS-specific biomarker beyond genotype
Population frequency Reported pathogenic variants are ultra-rare/absent in population databases; one 2017 report noted absence from >280,000 gnomAD alleles Human genetic case evidence (higgins2017elucidationofmrasmediated pages 2-4) Variant-level rarity supported; disease prevalence/incidence for MRAS-NS11 specifically is not established
Epidemiology No established MRAS-specific prevalence, incidence, sex ratio, founder effect, anticipation, or mosaicism data were identified in retrieved evidence Evidence-gap assessment from available literature context (higgins2017elucidationofmrasmediated pages 1-2, higgins2017elucidationofmrasmediated pages 9-11) Major limitation: ultra-rare condition with only a handful of published cases in retrieved sources
Treatment No established MRAS-specific targeted therapy has been proven in clinical practice; current care is syndrome-/phenotype-directed, especially cardiac management Human case outcomes plus general RASopathy management context (higgins2017elucidationofmrasmediated pages 2-4, faienza2024cardiacphenotypeand pages 7-8) Important limitation: treatment evidence is extrapolated largely from broader RASopathy/Noonan care, not MRAS-only cohorts
Trial landscape MEKinRAS (NCT06555237) is a recruiting phase 2 trial of trametinib for RASopathy-associated HCM, but the registry does not explicitly state MRAS-related NS11-specific eligibility or enrollment ClinicalTrials.gov registry evidence (NCT06555237 chunk 1) Potential relevance to MRAS-HCM is indirect; not an MRAS-specific interventional study
Evidence base overall The MRAS-specific evidence base remains small but coherent: rare de novo activating missense variants, recurrent severe cardiac phenotype, and a convergent SHOC2-MRAS-PP1C/RAF-ERK mechanism Integrated human genetic, functional, structural, and registry evidence (higgins2017elucidationofmrasmediated pages 1-2, higgins2017elucidationofmrasmediated pages 9-11, bonsor2024rasandshoc2 pages 6-8, young2018shoc2–mras–pp1complexpositively pages 5-6, NCT06555237 chunk 1) Main limitation is very limited patient count and lack of MRAS-specific long-term outcome studies

Table: This table summarizes the compact, MRAS-specific evidence base for Noonan syndrome 11, emphasizing what is directly established versus what remains uncertain. It is useful for separating firm gene/mechanism/phenotype findings from gaps in prevalence and treatment data.

1. Disease information

Definition. NS11 is a congenital, lifelong RASopathy caused by heterozygous activating missense variants in MRAS, encoding the small RAS-family GTPase M-Ras. It combines a Noonan-pattern developmental phenotype—characteristic craniofacial appearance, growth impairment, skeletal findings and neurodevelopmental delay—with particularly prominent congenital or early-childhood cardiac hypertrophy/hypertrophic cardiomyopathy (HCM). Open Targets links MONDO:0032786 specifically to MRAS (ENSG00000158186), supported by the primary MRAS literature (including PMID 28289718). (OpenTargets Search: Noonan syndrome 11-MRAS)

Identifiers and names.

  • OMIM: 618499, Noonan syndrome 11.
  • MONDO: MONDO:0032786, Noonan syndrome 11.
  • Causal-gene identity: MRAS; Open Targets approved name “muscle RAS oncogene homolog.” (OpenTargets Search: Noonan syndrome 11-MRAS)
  • Common synonyms: MRAS-related Noonan syndrome; MRAS-mediated Noonan syndrome; Noonan syndrome associated with MRAS; NS11.
  • Orphanet/MeSH/ICD: no retrieved subtype-specific Orphanet, MeSH, ICD-10 or ICD-11 code was established. Coding generally falls under broader Noonan-syndrome/congenital-malformation categories; such codes do not uniquely identify MRAS-NS11.

The evidence combines individual-level case reports/series with aggregated disease resources. It is not derived from an EHR-scale cohort or population registry.

2. Etiology, risk and protective factors

The primary and sufficient cause is a germline heterozygous activating MRAS missense variant. The initially reported affected individuals carried de novo p.Gly23Val or p.Thr68Ile substitutions; later mechanistic literature recognizes p.Gln71Arg as another NS-associated constitutively active allele. (higgins2017elucidationofmrasmediated pages 1-2, bonsor2024rasandshoc2 pages 6-8)

The first p.Gly23Val case was identified through trio whole-exome sequencing (WES), and the variant was absent from more than 280,000 gnomAD alleles. Screening 109 unrelated genotype-negative patients with suspected RASopathy and cardiac hypertrophy identified the second de novo variant, p.Thr68Ile—approximately 0.9% of that highly selected cohort, not a population prevalence estimate. (higgins2017elucidationofmrasmediated pages 2-4, higgins2017elucidationofmrasmediated pages 9-11, higgins2017elucidationofmrasmediated pages 6-8)

Risk factors. The relevant risk is genetic: a pathogenic MRAS allele in the germline. Most directly documented cases were de novo, so absence of family history does not materially reduce risk in a clinically suggestive child. If an affected person transmits the allele, the expected Mendelian recurrence risk is 50% per pregnancy, although MRAS-specific penetrance cannot yet be quantified. Parental germline mosaicism remains theoretically possible but has not been quantified.

Environmental, lifestyle, infectious and gene–environment factors. No evidence establishes toxins, diet, smoking, occupation, infection, parental age or other environmental exposures as causes or modifiers of NS11. There are likewise no validated genetic or environmental protective factors. These are evidence gaps, not evidence of absolute absence.

3. Phenotypes

MRAS-specific human observations

The directly documented phenotype is dominated by early cardiac disease. One female with p.Gly23Val had biventricular/left-ventricular hypertrophy beginning in infancy, biventricular outflow obstruction and surgical myectomy at age eight. She also had short stature, a long/dysmorphic face, low-set posteriorly rotated ears, global developmental delay and cognitive disability. (higgins2017elucidationofmrasmediated pages 2-4)

The p.Thr68Ile-positive female had cardiac hypertrophy, pulmonary-valve stenosis and an atrial septal defect, with ptosis, low-set posteriorly angulated ears, pectus excavatum, redundant palmar soft tissue/wrinkling, joint hypermobility and hypotonia. Development was delayed: independent walking at 2.5 years, sign language at 15 months, spoken words at four years and special-education support by kindergarten. (higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 11-12)

Suggested phenotype annotations include:

Phenotype Type/course Suggested HPO term
Hypertrophic cardiomyopathy/cardiac hypertrophy Congenital or infantile; severity variable and potentially progressive/obstructive HP:0001639; cardiac hypertrophy HP:0001712
Left/biventricular outflow obstruction Clinical/imaging sign; may require surgery HP:0001698 or more specific obstruction term
Pulmonary-valve stenosis Congenital structural cardiac sign HP:0001642
Atrial septal defect Congenital structural cardiac sign HP:0001631
Short stature Growth manifestation, childhood HP:0004322
Global developmental delay Neurodevelopmental sign, early childhood HP:0001263
Intellectual/learning disability Cognitive/functional manifestation HP:0001249; HP:0001328 where appropriate
Hypotonia Neuromuscular sign, infancy/childhood HP:0001252
Ptosis/hypertelorism/low-set ears Dysmorphic signs HP:0000508; HP:0000316; HP:0000369
Pectus excavatum Skeletal manifestation HP:0000767
Joint hypermobility Musculoskeletal sign HP:0001382

Because the published denominator is extremely small, percentages should not be calculated as stable NS11 frequencies. The strongest qualitative association is cardiac hypertrophy/HCM, while developmental, facial, growth and skeletal findings show variable expression. Disease-specific EQ-5D, SF-36, PROMIS or caregiver-burden data do not exist. Nevertheless, obstructive HCM, surgery, developmental delay and special-education needs plainly create substantial functional burden at the individual level. (higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 2-4)

4. Genetic and molecular information

Gene. MRAS is the sole established causal gene for NS11. Open Targets identifies only MRAS as an associated target for MONDO:0032786. (OpenTargets Search: Noonan syndrome 11-MRAS)

Variant class and origin. Established disease alleles are germline, heterozygous missense variants with gain-of-function effects—not truncating loss-of-function alleles, chromosomal rearrangements or somatic-only mutations. Directly reported variants include:

  • p.Gly23Val, reported as c.68G>T in detailed text; de novo and absent from >280,000 population alleles. The retrieved source contained one inconsistent predicted cDNA notation, so clinical reporting should use the transcript-specific laboratory HGVS record rather than infer it from the protein change. (higgins2017elucidationofmrasmediated pages 1-2, higgins2017elucidationofmrasmediated pages 2-4)
  • c.203C>T (p.Thr68Ile); de novo. (higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 11-12)
  • p.Gln71Arg (Q71R); recognized in later structural/mechanistic studies as a constitutively active NS allele. (bonsor2024rasandshoc2 pages 6-8)

ClinVar classifications should be checked against the current transcript and submission date during implementation. Functional evidence strongly supports pathogenic/gain-of-function interpretation for these recurrent mechanistically coherent alleles, but this report should not substitute for current laboratory ACMG/AMP adjudication.

Modifiers, epigenetics and chromosome abnormalities. No validated modifier gene, MRAS-NS11 episignature, disease-specific methylation profile or recurrent large chromosomal abnormality has been established. No founder allele, anticipation or carrier-frequency estimate is available.

5. Environmental information

NS11 is not an infectious, toxic or lifestyle-mediated disease. No causal pathogen, occupational exposure, pollutant, radiation exposure, diet, alcohol or smoking association is known. Routine healthy lifestyle measures remain relevant to general cardiovascular health but do not prevent the germline disorder.

6. Mechanism and pathophysiology

Upstream causal chain

  1. A germline activating substitution changes MRAS nucleotide-state regulation and/or effector interactions.
  2. G23V, T68I and Q71R favor the constitutively active, GTP-bound state. Wild-type MRAS shares about 50% sequence identity with canonical RAS proteins but normally binds/activates RAF less efficiently; the disease alleles overcome normal control. (bonsor2024rasandshoc2 pages 6-8)
  3. GTP-bound MRAS assembles the SHOC2–MRAS–PP1C holophosphatase at the plasma membrane. SHOC2 acts as scaffold and PP1C as catalytic phosphatase.
  4. The complex dephosphorylates RAF’s conserved inhibitory CR2 site—classically CRAF Ser259/BRAF Ser365—releasing 14-3-3-mediated inhibition and facilitating RAF activation/dimerization.
  5. RAF activates MEK and ERK, changing developmental gene expression, cell proliferation, differentiation and growth.
  6. Dysregulated signaling in developing myocardium and other embryonic tissues produces HCM/structural heart disease, dysmorphism, impaired linear growth and neurodevelopmental abnormalities.

Cell experiments showed p.Gly23Val produced approximately fourfold greater GTP loading at five minutes and 40-fold greater loading at 30 minutes after EGF stimulation than wild-type MRAS, with increased ERK phosphorylation and serum-response-element transcription. (higgins2017elucidationofmrasmediated pages 1-2, higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 9-11)

Young et al. summarized the biochemical result directly: germline MRAS/SHOC2/PPP1CB mutations enhance ternary-complex formation, which “specifically dephosphorylates an inhibitory site on RAF kinases, activating downstream signaling.” Their experiments further distinguish G23V, which can promote direct RAF binding and holophosphatase assembly, from T68I, which preferentially enhances SHOC2–PP1 interaction/RAF-phosphatase function. (young2018shoc2–mras–pp1complexpositively pages 5-6)

The 2024 structural review concludes that G23V, T68I and Q71R place MRAS in a constitutively active GTP-bound state, with Q71R adding contacts to SHOC2; measured complex affinities are in the low-nanomolar range. (bonsor2024rasandshoc2 pages 6-8, bonsor2024rasandshoc2 pages 19-20)

Suggested GO annotations: small GTPase-mediated signal transduction (GO:0007264); Ras protein signal transduction (GO:0007265); MAPK cascade (GO:0000165); positive regulation of ERK1/2 cascade (GO:0070374); protein dephosphorylation (GO:0006470); regulation of protein serine/threonine phosphatase activity; heart development (GO:0007507); cardiac muscle-cell development and proliferation.

Likely relevant cell types: cardiomyocyte (CL:0000746), cardiac fibroblast (CL:0000746-adjacent ontology mapping should be verified), endocardial/endothelial cells, neural progenitors and growth-plate chondrocytes. Direct NS11 single-cell evidence is absent; these are mechanistically plausible annotation targets, not demonstrated cell-selective lesions.

Subcellular components: plasma membrane (GO:0005886), cytosol (GO:0005829), protein-containing complex (GO:0032991), SHOC2–MRAS–PP1C complex where a dedicated ontology term is unavailable.

No NS11-specific metabolic, immune, inflammatory, oxidative-stress, transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic or multi-omic signature has been established. The available molecular profiling consists principally of targeted signaling assays and protein structures.

7. Anatomical structures affected

The heart is the best-supported primary organ, involving ventricular myocardium and potentially pulmonary valve/septa/outflow tracts. Suggested annotations are heart (UBERON:0000948), myocardium (UBERON:0002349), cardiac ventricle (UBERON:0002082), interventricular/atrial septal structures, pulmonary valve and ventricular outflow tract.

Secondary systems include craniofacial structures, skeleton/chest wall, joints, central nervous system/neurodevelopment and the somatic growth axis. No consistent lateralization is described. At subcellular level, disease originates in membrane-associated RAS signaling rather than a primary mitochondrial, lysosomal or endoplasmic-reticulum disorder.

8. Temporal development and natural history

Onset is prenatal/congenital or early pediatric, even if molecular diagnosis occurs later. Cardiac hypertrophy may be recognized in infancy and can progress to obstruction requiring childhood intervention. Developmental delay becomes apparent as milestones are missed; short stature emerges over childhood. (higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 2-4)

NS11 is lifelong. There is no validated staging system, remission pattern, median progression rate or MRAS-specific longitudinal cohort. Critical windows include prenatal cardiac development, infancy for detection of HCM/feeding and developmental difficulties, early childhood for intervention, and later childhood/adulthood for arrhythmia, obstruction and heart-failure surveillance.

9. Inheritance and population

Inheritance is autosomal dominant, with most published cases arising de novo. Expressivity is variable, but penetrance cannot be estimated. Genetic anticipation is not expected for a missense RASopathy and has not been reported. Germline mosaicism, founder effects, consanguinity effects and geographic clustering have not been demonstrated.

There is no reliable NS11-specific prevalence, incidence, sex ratio, age distribution or ancestry enrichment. Both initially described patients were female and of European descent, but that observation is far too small and ascertainment-biased to infer demographic risk. (higgins2017elucidationofmrasmediated pages 9-11)

General Noonan/RASopathy prevalence estimates must not be assigned to NS11. The 109-person selected screening cohort yielded one additional MRAS case, but it consisted specifically of genotype-negative RASopathy patients with cardiac hypertrophy and therefore cannot estimate prevalence. (higgins2017elucidationofmrasmediated pages 6-8)

10. Diagnostics

Clinical evaluation

Suspect NS11 when a child has Noonan-pattern dysmorphism and developmental/growth abnormalities together with early or severe HCM, particularly after common RASopathy genes are negative. Baseline evaluation should include physical/dysmorphology examination, three-generation pedigree, growth parameters, developmental assessment, ECG and echocardiography. Cardiac MRI/Holter monitoring is selected according to HCM severity, rhythm symptoms and image quality.

Molecular confirmation

Preferred testing is a comprehensive RASopathy panel including MRAS, or an HCM/congenital-heart-disease panel that includes MRAS when syndromic features are present. Trio WES is useful when panel testing is negative and proved diagnostic in the discovery case. Genome sequencing can detect coding variants plus classes missed by exome/panel testing, but no recurrent NS11 structural variant is known. Sanger/orthogonal confirmation and parental testing establish de novo status. (higgins2017elucidationofmrasmediated pages 1-2, higgins2017elucidationofmrasmediated pages 2-4)

CMA, karyotype and FISH are not confirmatory for an MRAS missense disorder, but CMA may be appropriate when developmental anomalies suggest a copy-number differential. Mitochondrial, repeat-expansion and liquid-biopsy testing are not indicated for NS11 itself. There is no validated serum, enzyme, metabolomic or epigenomic diagnostic biomarker beyond the molecular variant.

Differential diagnosis

Differentials include other molecular RASopathies—especially RIT1-, RAF1-, PTPN11-, SOS1-, KRAS-, SHOC2- and PPP1CB-related disease—and nonsyndromic sarcomeric HCM. NS11 is distinguished by a pathogenic activating MRAS allele, not phenotype alone. LZTR1-related Noonan syndrome is explicitly a different disease mechanism and must not be labeled NS11.

No newborn population screen exists. Cascade testing is appropriate after a familial pathogenic variant is identified; testing apparently unaffected parents also informs recurrence counseling.

11. Outcome and prognosis

No MRAS-specific five- or ten-year survival, life expectancy, mortality rate or validated prognostic model exists. Prognosis is likely driven chiefly by HCM severity, ventricular obstruction, arrhythmia and heart failure, but this is reasoned from the observed phenotype and broader HCM/RASopathy practice, not an NS11 survival cohort.

Documented morbidity includes childhood myectomy, developmental disability, special-education need, hypotonia and short stature. (higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 2-4) No MRAS-specific tumor-risk estimate or evidence-based cancer-surveillance protocol has been established. Likewise, no disease-specific patient-reported outcome data exist.

12. Treatment

There is no approved MRAS-specific disease-modifying therapy. Management is multidisciplinary and phenotype-directed.

Cardiac treatment

General RASopathy/HCM practice uses non-vasodilating beta-blockers for symptoms/obstruction; disopyramide may be added for left-ventricular outflow-tract obstruction. Severe symptomatic obstruction refractory to medication may require septal myectomy; advanced heart failure or refractory arrhythmia may warrant transplantation. These are general recommendations, although childhood myectomy has been used in an MRAS case. (higgins2017elucidationofmrasmediated pages 2-4, faienza2024cardiacphenotypeand pages 7-8)

Suggested NCIt intervention mappings include echocardiography (C16525), electrocardiography, beta-adrenergic blocker therapy, antiarrhythmic therapy, septal myectomy/cardiac surgery and heart transplantation; exact current NCIt codes should be verified during database ingestion.

Developmental and supportive care

Early developmental evaluation, physical/occupational/speech therapy, individualized education, nutritional/feeding support and hearing/vision assessment should follow general Noonan care. Orthopedic, endocrine/growth, renal and hemostatic evaluations should be driven by examination and standard Noonan guidance. Evidence for these measures is not MRAS-specific.

Targeted/experimental therapy

MEK inhibition is biologically rational because the causal pathway culminates in RAF–MEK–ERK hyperactivation, but efficacy and long-term safety in MRAS-NS11 are unproven. NCT06555237 (MEKinRAS) is a recruiting phase 2 randomized trial begun August 1, 2024, targeting 40 patients aged 0–18 years with genetically confirmed RASopathy and echocardiographic HCM. It compares trametinib 0.025 mg/kg orally once daily plus beta-blocker/disopyramide against standard therapy, measuring echocardiographic hypertrophy, NT-proBNP and high-sensitivity troponin I through 12 months. The Warsaw registry does not explicitly document an MRAS subgroup or MRAS-positive enrollment. (NCT06555237 chunk 1)

There is no established MRAS-directed gene therapy, CRISPR therapy, ASO, siRNA, cell therapy or immunotherapy. Structural studies identify the SHOC2–MRAS–PP1C interface as a potential drug target, but this remains preclinical and is largely being developed in oncology. (bonsor2024rasandshoc2 pages 6-8)

13. Prevention

Primary prevention by diet, vaccination or environmental modification is impossible because NS11 is germline genetic. Reproductive options after identification of a familial pathogenic variant include genetic counseling, prenatal diagnosis and preimplantation genetic testing. For a proven heterozygous affected parent, the theoretical recurrence probability is 50% per conception; after an apparently de novo case, recurrence is low but not zero because of possible parental germline mosaicism.

Secondary prevention consists of early molecular diagnosis and cardiac/developmental surveillance. Tertiary prevention includes prompt management of HCM/outflow obstruction, arrhythmias, developmental needs and other detected complications. There is no NS11-specific prophylactic medication or public-health screening program.

14. Other species and natural disease

MRAS signaling is evolutionarily conserved, and orthologs exist in standard vertebrate model species. However, no well-established naturally occurring veterinary disorder equivalent to human MRAS-NS11, breed association, zoonotic potential or cross-species transmission was identified. NS11 is not transmissible.

15. Model organisms and experimental systems

The strongest models are in vitro biochemical and cellular systems, not a validated whole-animal NS11 model. HEK293T/17 and related transfected-cell assays demonstrated enhanced GTP loading, ERK phosphorylation and transcriptional signaling by mutant MRAS. (higgins2017elucidationofmrasmediated pages 8-9, higgins2017elucidationofmrasmediated pages 9-11)

Purified-protein, crystallographic and cryo-EM studies define the SHOC2–MRAS–PP1C complex and effects of G23V, T68I and Q71R. These models provide high mechanistic resolution but cannot reproduce organism-level cardiomyopathy, development, penetrance or treatment toxicity. (bonsor2024rasandshoc2 pages 6-8, young2018shoc2–mras–pp1complexpositively pages 5-6)

No retrieved evidence established a knock-in mouse, rat, zebrafish, Drosophila, organoid or patient-derived iPSC model that comprehensively recapitulates MRAS-NS11. Such models—especially heterozygous variant-specific cardiomyocyte/iPSC and mouse or zebrafish knock-ins—remain important priorities for natural-history and therapeutic studies.

Key evidence limitations and interpretation

  1. Very small patient numbers: apparent phenotype frequencies are unstable and should remain qualitative.
  2. Ascertainment bias: discovery focused on genotype-negative patients with cardiac hypertrophy, enriching the apparent HCM association.
  3. Mechanistic strength exceeds clinical depth: biochemical causality is strong, but longitudinal prognosis, penetrance and treatment response remain poorly defined.
  4. No 2023–2024 MRAS-specific clinical cohort was retrieved: recent work chiefly refines protein structure and therapeutic hypotheses rather than expanding natural history.
  5. General Noonan recommendations are not genotype-specific evidence: cardiac and multidisciplinary care should be individualized, especially because severe HCM appears prominent in NS11.

Principal publications and URLs

  • Higgins EM et al. “Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy.” JCI Insight. Published March 2017. PMID 28289718. DOI/URL: https://doi.org/10.1172/jci.insight.91225. The report identified de novo MRAS variants and concluded that mutant MRAS enhanced RAS/MAPK signaling. (higgins2017elucidationofmrasmediated pages 1-2, higgins2017elucidationofmrasmediated pages 2-4)
  • Young LC et al. “SHOC2–MRAS–PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.” PNAS. Published October 2018. PMID 30348783. DOI/URL: https://doi.org/10.1073/pnas.1720352115. Abstract-level conclusion: the variants enhance a ternary complex that dephosphorylates inhibitory RAF and activates downstream signaling. (young2018shoc2–mras–pp1complexpositively pages 5-6)
  • Motta M et al. “Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy.” Human Molecular Genetics. Published online 2019; volume publication July 2020. DOI/URL: https://doi.org/10.1093/hmg/ddz108; literature databases associated with the MRAS–NS11 record include PMID 31108500. This is the key expanded human-genetic study, although complete patient-level tables were not retrievable in the present evidence set. (OpenTargets Search: Noonan syndrome 11-MRAS)
  • Bonsor DA, Simanshu DK. “RAS and SHOC2 Roles in RAF Activation and Therapeutic Considerations.” Annual Review of Cancer Biology. Published June 2024. DOI/URL: https://doi.org/10.1146/annurev-cancerbio-062822-030450. This recent authoritative structural review identifies G23V, T68I and Q71R as constitutively active MRAS alleles. (bonsor2024rasandshoc2 pages 6-8)
  • Faienza MF et al. “Cardiac Phenotype and Gene Mutations in RASopathies.” Genes. Published August 2024. DOI/URL: https://doi.org/10.3390/genes15081015. Its treatment discussion is RASopathy-wide rather than MRAS-specific. (faienza2024cardiacphenotypeand pages 7-8)
  • ClinicalTrials.gov. MEKinRAS, NCT06555237. Registered/started 2024: https://clinicaltrials.gov/study/NCT06555237. It is potentially relevant to NS11-associated HCM but is not an MRAS-specific trial. (NCT06555237 chunk 1)

References

  1. (OpenTargets Search: Noonan syndrome 11-MRAS): Open Targets Query (Noonan syndrome 11-MRAS, 3 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (higgins2017elucidationofmrasmediated pages 1-2): Erin M. Higgins, J. Martijn Bos, Heather Mason-Suares, David J. Tester, Jaeger P. Ackerman, Calum A. MacRae, Katia Sol-Church, Karen W. Gripp, Raul Urrutia, and Michael J. Ackerman. Elucidation of mras-mediated noonan syndrome with cardiac hypertrophy. JCI Insight, Mar 2017. URL: https://doi.org/10.1172/jci.insight.91225, doi:10.1172/jci.insight.91225. This article has 111 citations and is from a domain leading peer-reviewed journal.

  3. (bonsor2024rasandshoc2 pages 6-8): Daniel A. Bonsor and Dhirendra K. Simanshu. Ras and shoc2 roles in raf activation and therapeutic considerations. Jun 2024. URL: https://doi.org/10.1146/annurev-cancerbio-062822-030450, doi:10.1146/annurev-cancerbio-062822-030450. This article has 16 citations and is from a peer-reviewed journal.

  4. (young2018shoc2–mras–pp1complexpositively pages 5-6): Lucy C. Young, Nicole Hartig, Isabel Boned del Río, Sibel Sari, Benjamin Ringham-Terry, Joshua R. Wainwright, Greg G. Jones, Frank McCormick, and Pablo Rodriguez-Viciana. Shoc2–mras–pp1 complex positively regulates raf activity and contributes to noonan syndrome pathogenesis. Proceedings of the National Academy of Sciences, 115:E10576-E10585, Oct 2018. URL: https://doi.org/10.1073/pnas.1720352115, doi:10.1073/pnas.1720352115. This article has 106 citations and is from a highest quality peer-reviewed journal.

  5. (higgins2017elucidationofmrasmediated pages 8-9): Erin M. Higgins, J. Martijn Bos, Heather Mason-Suares, David J. Tester, Jaeger P. Ackerman, Calum A. MacRae, Katia Sol-Church, Karen W. Gripp, Raul Urrutia, and Michael J. Ackerman. Elucidation of mras-mediated noonan syndrome with cardiac hypertrophy. JCI Insight, Mar 2017. URL: https://doi.org/10.1172/jci.insight.91225, doi:10.1172/jci.insight.91225. This article has 111 citations and is from a domain leading peer-reviewed journal.

  6. (higgins2017elucidationofmrasmediated pages 9-11): Erin M. Higgins, J. Martijn Bos, Heather Mason-Suares, David J. Tester, Jaeger P. Ackerman, Calum A. MacRae, Katia Sol-Church, Karen W. Gripp, Raul Urrutia, and Michael J. Ackerman. Elucidation of mras-mediated noonan syndrome with cardiac hypertrophy. JCI Insight, Mar 2017. URL: https://doi.org/10.1172/jci.insight.91225, doi:10.1172/jci.insight.91225. This article has 111 citations and is from a domain leading peer-reviewed journal.

  7. (higgins2017elucidationofmrasmediated pages 2-4): Erin M. Higgins, J. Martijn Bos, Heather Mason-Suares, David J. Tester, Jaeger P. Ackerman, Calum A. MacRae, Katia Sol-Church, Karen W. Gripp, Raul Urrutia, and Michael J. Ackerman. Elucidation of mras-mediated noonan syndrome with cardiac hypertrophy. JCI Insight, Mar 2017. URL: https://doi.org/10.1172/jci.insight.91225, doi:10.1172/jci.insight.91225. This article has 111 citations and is from a domain leading peer-reviewed journal.

  8. (higgins2017elucidationofmrasmediated pages 11-12): Erin M. Higgins, J. Martijn Bos, Heather Mason-Suares, David J. Tester, Jaeger P. Ackerman, Calum A. MacRae, Katia Sol-Church, Karen W. Gripp, Raul Urrutia, and Michael J. Ackerman. Elucidation of mras-mediated noonan syndrome with cardiac hypertrophy. JCI Insight, Mar 2017. URL: https://doi.org/10.1172/jci.insight.91225, doi:10.1172/jci.insight.91225. This article has 111 citations and is from a domain leading peer-reviewed journal.

  9. (higgins2017elucidationofmrasmediated pages 6-8): Erin M. Higgins, J. Martijn Bos, Heather Mason-Suares, David J. Tester, Jaeger P. Ackerman, Calum A. MacRae, Katia Sol-Church, Karen W. Gripp, Raul Urrutia, and Michael J. Ackerman. Elucidation of mras-mediated noonan syndrome with cardiac hypertrophy. JCI Insight, Mar 2017. URL: https://doi.org/10.1172/jci.insight.91225, doi:10.1172/jci.insight.91225. This article has 111 citations and is from a domain leading peer-reviewed journal.

  10. (faienza2024cardiacphenotypeand pages 7-8): Maria Felicia Faienza, Giovanni Meliota, Donatella Mentino, Romina Ficarella, Mattia Gentile, Ugo Vairo, and Gabriele D’amato. Cardiac phenotype and gene mutations in rasopathies. Genes, 15:1015, Aug 2024. URL: https://doi.org/10.3390/genes15081015, doi:10.3390/genes15081015. This article has 16 citations.

  11. (NCT06555237 chunk 1): MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies. Medical University of Warsaw. 2024. ClinicalTrials.gov Identifier: NCT06555237

  12. (bonsor2024rasandshoc2 pages 19-20): Daniel A. Bonsor and Dhirendra K. Simanshu. Ras and shoc2 roles in raf activation and therapeutic considerations. Jun 2024. URL: https://doi.org/10.1146/annurev-cancerbio-062822-030450, doi:10.1146/annurev-cancerbio-062822-030450. This article has 16 citations and is from a peer-reviewed journal.

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References checked 6
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References weighed for topical relevance 6
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