{ "@context": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/context/doc", "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003", "id": "CG-AC:AC1003", "type": "ClinicalActionabilityReport", "metadata": { "schemaLabel": "AC-Sepio.Beta-1 (Unofficial)", "contentVersionId": "27162", "producedAtUTC": "Thu, 10 Sep 2026 19:39:07 -0000", "note": "DISCLAIMER: The SEPIO-inspired schema presented here is an initial prototype for Clinical Actionability curation summaries and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema." }, "description": "JSON-LD representation of ClinGen Actionability Stage 2 report modeled with SEPIO. The hierarchically structured document will include:\n1. Contextual & topic information, such as the **conditions/diseases** and the **genes**.\n2. Categorized **evidence narratives**, with references.\n\t* This content corresponds to the texts within the *Actionability Summary Report*\n4. **Outcome & Intervention** pairs, with **consensus scoring** in 5 dimensions:\n\t1. Outcome Severity\n\t2. Outcome Likelihood\n\t3. Intervention Effectiveness\n\t4. Nature of the Intervention\n\t5. Total (Overall) Score\n\n*( Note: The summary report does not include the **Screening Survey** which led to preparation of the actionability report. )", "condition": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/co", "id": "CG-AC:AC1003/co", "type": "GeneticCondition", "label": "Noonan syndrome" }, "outcome": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ou/Cardiac%20manifestations", "id": "CG-AC:AC1003/ou/Cardiac manifestations", "type": "Outcome", "label": "Cardiac manifestations" } ], "intervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/intv/Cardiac%20surveillance", "id": "CG-AC:AC1003/intv/Cardiac surveillance", "type": "Intervention", "label": "Cardiac surveillance" } ], "clinicalActionabilityProfile": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/cap", "id": "CG-AC:AC1003/cap", "type": "Assertion", "assertionMethod": "The ClinGen AWG developed a standardized protocol to generate evidence-based profiles of clinical actionability of genes and associated disorders in the form of summary reports and semiquantitative metric (SQM) scores.", "releaseDate": "Wed, 22 Apr 2020 00:00:00 -0000", "releaseNum": "1.0.1" }, "evidenceStatements": { "evidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/en/ACMI2613", "id": "CG-AC:AC1003/en/ACMI2613", "type": "EvidenceNarrative", "narrative": "Autosomal Dominant", "evidenceDomainTag": "Threat Materialization Chances.Modes of Inheritance" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/en/nh", "id": "CG-AC:AC1003/en/nh", "type": "EvidenceNarrative", "narrative": "HCM usually presents early in life: the median age at diagnosis is five months and more than 50% of individuals with NS and HCM are diagnosed by age six months. HCM is variable in severity and natural history. The condition resolves in some, but rapidly progresses and may be fatal in others. The severity of NS is the same in males and females. \\n\\nThere are no phenotypic features exclusive to a specific genotype; however, there are significant differences in the risk of various NS manifestations based on the causative gene. PTPN11 is associated with a predisposition to JMML, which runs a more benign course in NS compared to the general population. Patients with PTPN11 variants are more likely to have PVS, but less likely to have atrial septal defects and HCM. PTPN11 has also been associated more with short stature, pectus deformity, easy bruising, characteristic facial appearance, and cryptorchidism compared to other causes of NS. SOS1 is associated with more frequent ectodermal abnormalities and PVS and a greater likelihood of normal development and stature compared to other causes of NS and more cardiac septal defects than PTPN11. RAF1 and RIT1 are associated with increased rates of HCM. RIT1 is associated with a high prevalence of perinatal abnormalities, cardiovascular disease, and lymphatic abnormalities but lower prevalence of short stature and intellectual disability. KRAS is associated with greater likelihood and severity of intellectual disability and developmental delays. BRAF is associated with florid ectodermal manifestations.", "evidenceDomainTag": "Nature of the Threat.Natural History", "publication": [ "CG-AC:RF002578", "CG-AC:RF002579", "CG-AC:RF002580", "CG-AC:RF002581", "CG-AC:RF002582", "CG-AC:RF002572" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/en/potgd", "id": "CG-AC:AC1003/en/potgd", "type": "EvidenceNarrative", "narrative": "Noonan syndrome (NS) is reported to occur in 1:1000 and 1:2500 live births.", "evidenceDomainTag": "Nature of the Threat.Prevalence of the Genetic Disorder", "publication": [ "CG-AC:RF002578", "CG-AC:RF002579", "CG-AC:RF002580", "CG-AC:RF002581", "CG-AC:RF002582" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/en/cf", "id": "CG-AC:AC1003/en/cf", "type": "EvidenceNarrative", "narrative": "NS is characterized by facial dysmorphism, short stature, congenital heart defects, and developmental delay. Cardiac issues include pulmonary valve stenosis (PVS; the most common), hypertrophic cardiomyopathy (HCM), atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. There is a spectrum of other clinical outcomes associated with NS. Coagulation defects may manifest as severe surgical hemorrhage, clinically mild bruising, or laboratory abnormalities with no clinical consequences. Lymphatic abnormalities may be localized or widespread; dorsal limb lymphedema is the most common. Ocular abnormalities include strabismus, refractive errors, amblyopia, and nystagmus. Hearing loss can be present. Renal abnormalities are generally mild; dilation of the renal pelvis as the most common. Mild intellectual disability and language impairments can be present. Male pubertal development and subsequent fertility may be delayed or inadequate; puberty may be delayed in females, but normal fertility is the rule. Physical findings include broad or webbed neck, chest deformity, cryptorchidism, and bone and joint anomalies. Skin differences include follicular keratosis over extensor surfaces and face, café-au-lait spots, and lentigines. Giant-cell granulomas can occur. There is an increased risk of myeloproliferative disorder (MPD), juvenile myelomonocytic leukemia (JMML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and solid tumors, such as rhabdomyosarcoma and neuroblastoma. Hepatosplenomegaly is frequent; the cause is likely related to subclinical myelodysplasia.", "evidenceDomainTag": "Nature of the Threat.Clinical Features", "publication": [ "CG-AC:RF002578", "CG-AC:RF002579", "CG-AC:RF002580", "CG-AC:RF002581", "CG-AC:RF002582", "CG-AC:RF002583", "CG-AC:RF002584", "CG-AC:RF002570", "CG-AC:RF002571", "CG-AC:RF002575", "CG-AC:RF002576", "CG-AC:RF002577" ] } ], "tieredEvidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/CDEC2742", "id": "CG-AC:AC1003/ten/CDEC2742", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "For many years before the understanding of their underlying genetic causes, cardiofaciocutaneous syndrome and Costello syndrome were often confused for NS. Mild expression is likely to be overlooked; many with milder forms escape early detected and are identified later in life. Because of differences in prognosis, recurrence concerns, and treatment, accurate diagnosis is essential.", "evidenceDomainTag": "Condition Escape Detection.Chances to Escape Clinical Detection", "publication": [ "CG-AC:RF002578", "CG-AC:RF002579", "CG-AC:RF000648" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/CDEC2743", "id": "CG-AC:AC1003/ten/CDEC2743", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "There are several disorders with significant phenotypic overlap with NS, such as Turner syndrome. Many adults with NS are only ascertained after the birth of their more seriously affected child.", "evidenceDomainTag": "Condition Escape Detection.Chances to Escape Clinical Detection", "publication": [ "CG-AC:RF002579", "CG-AC:RF002582" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/NOI2755", "id": "CG-AC:AC1003/ten/NOI2755", "type": "TieredEvidenceNarrative", "narrative": "NS is a multisystem disorder that requires various tests, screening, assessments, referrals, and multidisciplinary interventions at different stages of life. Cardiac surveillance is lifelong. Potential treatment includes GH, which has been used without significant adverse events. Among combined 889 patients from 6 articles that reported adult-height outcomes in patients with NS on GH there were only 5 reported cardiac events (2 mild progressions of PVS, 1 HCM, 1 increased biventricular hypertrophy, and 1 cardiac decompensation). No effects on other comorbidities associated with NS have been noted.", "evidenceDomainTag": "Acceptability of Intervention.Natures of Intervention", "publication": [ "CG-AC:RF002579", "CG-AC:RF002580", "CG-AC:RF002581" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/EN2747", "id": "CG-AC:AC1003/ten/EN2747", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Some adults with NS are only ascertained after the birth of their more seriously affected child.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF002582" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/EN2748", "id": "CG-AC:AC1003/ten/EN2748", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "NS has variable expressivity.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF002579" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3842", "id": "CG-AC:AC1003/ten/ACPE3842", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Hypothyroidism is described in 5% of individuals with NS, although antimicrosomal thyroid antibodies are more frequently found (38%).", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002582" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3841", "id": "CG-AC:AC1003/ten/ACPE3841", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Lymphatic manifestations are seen in 20% of individuals with NS.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002579", "CG-AC:RF002582" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3843", "id": "CG-AC:AC1003/ten/ACPE3843", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Disordered bleeding has been reported for 30% to 65% of individuals with NS. A variety of small studies have shown that while 50%-89% of those with NS have either a history of bleeding and/or abnormal hemostatic lab results, only 10%-42% have both.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002578", "CG-AC:RF002579", "CG-AC:RF002582" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3840", "id": "CG-AC:AC1003/ten/ACPE3840", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Renal abnormalities are present in 10-11% of individuals with NS.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002579" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3844", "id": "CG-AC:AC1003/ten/ACPE3844", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "However, significant bias in the frequency of congenital heart disease may exist because many clinicians have in the past required the presence of cardiac anomalies for diagnosis of NS.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002578" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/RR2579", "id": "CG-AC:AC1003/ten/RR2579", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "One study of 571 molecularly confirmed cases of NS reported four cases of JMML, two of brain tumor, one ALL, and one neuroblastoma, and calculated a childhood cancer standardized incidence ratio of 7.9 (95% CI: 3.2-16.2) compared to population-based incidence rates, indicating that individuals with NS are at an almost eightfold greater risk of developing a childhood cancer than those in the general population.", "evidenceDomainTag": "Threat Materialization Chances.Relative Risks", "publication": [ "CG-AC:RF002578", "CG-AC:RF002583" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3833", "id": "CG-AC:AC1003/ten/ACPE3833", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "One study found that of 641 patients with a confirmed germline PTPN11 variant, 16 (2.5%) developed an MPD and 20 (3.1%) developed JMML.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002570" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3835", "id": "CG-AC:AC1003/ten/ACPE3835", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Oral findings in patients with NS include a high arched palate (55-100%), dental malocclusion (50–67%), articulation difficulties (72%), and micrognathia (33%–43%).", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002579" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3838", "id": "CG-AC:AC1003/ten/ACPE3838", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "In a study of 151 subjects with NS, 76% had feeding difficulties, 94% had ocular problems, 50% had hypermobility of joints/hypotonia, 13% had recurrent seizures, 3% had hearing loss, and 3% had peripheral neuropathy.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002579" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3839", "id": "CG-AC:AC1003/ten/ACPE3839", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Cryptorchidism is noted in 60-80% of males with NS.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002578", "CG-AC:RF002579" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3836", "id": "CG-AC:AC1003/ten/ACPE3836", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Approximately 50% to 70% of individuals with NS have short stature.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002579", "CG-AC:RF002581", "CG-AC:RF002570" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/ACPE3834", "id": "CG-AC:AC1003/ten/ACPE3834", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "More than 80% of patients with NS have an abnormality of the cardiovascular system. HCM is present in about 20-30% and approximately 50% have an unusual electrocardiographic pattern characterized by left-axis deviation, an abnormal R/S ratio over the left precordial leads, and an abnormal Q wave. The prevalence of these outcomes may vary by gene:\\n• PTPN11: HCM in 6%, pulmonic stenosis in 71%, and septal defects in 12%\\n• SOS1: HCM in 12%, pulmonic stenosis in 62%, septal defects in 25%\\n• RAF1: HCM in 80-95%\\n• RIT1: HCM in 45-75%.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002579", "CG-AC:RF002582", "CG-AC:RF002570", "CG-AC:RF002576" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/PGM2692", "id": "CG-AC:AC1003/ten/PGM2692", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Variant testing will provide a diagnosis of NS in 70% of cases; in 30% the responsible gene remains unknown.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation", "publication": [ "CG-AC:RF002574" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/ten/PGM2693", "id": "CG-AC:AC1003/ten/PGM2693", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "The prevalence of pathogenic variants associated with NS was not available. However, molecular genetic testing identifies a pathogenic variant in PTPN11 in 40-50% of affected individuals; SOS1 in 10-13%; RAF1 and RIT1 each in 5%; KRAS in <5%; and NRAS, BRAF, and SOS2 in <1%.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation", "publication": [ "CG-AC:RF002578", "CG-AC:RF002579", "CG-AC:RF002582", "CG-AC:RF002583", "CG-AC:RF002586", "CG-AC:RF002587" ] } ], "tieredRecommendations": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACPM5170", "id": "CG-AC:AC1003/tr/ACPM5170", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "A low threshold for investigation of neurological symptoms is recommended (e.g. consider Arnold-Chiari malformation and hydrocephalus if patient presents with headache or other neurological symptoms).", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF002580" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACPM5172", "id": "CG-AC:AC1003/tr/ACPM5172", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Potential pregnancy difficulties, for example those arising from coagulation defects during childbirth, should be considered and planned for as appropriate.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF002579" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACPM5173", "id": "CG-AC:AC1003/tr/ACPM5173", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Treatment of complications of NS is generally standard and does not differ from treatment from the general population, including cardiovascular anomalies, developmental delay, cryptorchidism, hearing problems, lymphedema, thyroid abnormalities, and epilepsy.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF002580" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACPM5174", "id": "CG-AC:AC1003/tr/ACPM5174", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "At diagnosis, individuals with NS should undergo:\\n• Cardiac evaluation by a cardiologist, including electrocardiogram and echocardiogram\\n• Kidney ultrasound\\n• Coagulation screening with CBC with differential and prothrombin time/activated partial thromboplastin time; repeat after 6-12 months of age if initial screen performed in infancy\\n• Detailed eye examination\\n• Hearing test\\n• Evaluate failure to thrive, growth, and feeding problems\\n• Developmental, neuropsychological, and behavioral assessment.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF002579", "CG-AC:RF002580" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACPM5169", "id": "CG-AC:AC1003/tr/ACPM5169", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Preoperative evaluation with CBC with differential count, prothrombin time/activated partial thromboplastin time, specific factor activity (factor XI, factor XII, factor IX, factor VIII, von Willebrand factor), and platelet function (bleeding time or platelet aggregation) for bleeding risk should be performed, with hematology consultation as needed for management of bleeding risk.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF002579", "CG-AC:RF002580" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACPM5168", "id": "CG-AC:AC1003/tr/ACPM5168", "type": "TieredRecommendation", "evidenceSourceTier": "4", "recommendation": "At diagnosis of NS, individuals with NS should also undergo:\\n• Complete physical and neurologic examination\\n• Clinical and radiographic assessment of spine and rib cage.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF002582" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACCA3197", "id": "CG-AC:AC1003/tr/ACCA3197", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Due to risk of skin problems, skin dryness, which can be worsened by long hot baths, perfumed soaps and dry atmospheres, should be avoided.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF002580" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACCA3198", "id": "CG-AC:AC1003/tr/ACCA3198", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Aspirin and aspirin-containing medications should be avoided due to a tendency for bleeding.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF002579" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACSU3508", "id": "CG-AC:AC1003/tr/ACSU3508", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "To assess for MPD/JMML in patients with NS with certain variants in PTPN11 and KRAS, a physical exam (with assessment of the spleen) and CBC with differential should be performed every 3-6 months from ages 0-5 years. There are no data indicating that this strategy leads to a survival advantage, but the sometimes more aggressive course of MPD and JMML may justify this recommendation in selected patients.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF002583" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/tr/ACSU3509", "id": "CG-AC:AC1003/tr/ACSU3509", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Recommended surveillance in adulthood includes:\\n• Cardiovascular: Individuals without heart disease should have cardiac reevaluation every 5 years. Adults should not discontinue periodic cardiac evaluations even if their evaluations in childhood or adolescence were normal; unexpected cardiac findings can occur at any point. \\n• Thyroid: Screen for thyroid abnormalities every 3-5 years\\n• Fertility: Care providers should be made aware of the increased risk of infertility in males\\n• Vision: Patients should be referred to an ophthalmologist for assessment\\n• Dental: Routine follow-up is essential.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF002579", "CG-AC:RF002580" ] } ] }, "evidenceCategory": { "outcomeEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/oei", "id": "CG-AC:AC1003/oei", "type": "EvidenceItem", "natureOfTheThreat": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1003/oei/nott", "id": "CG-AC:AC1003/oei/nott", "type": "EvidenceLine", "prevalenceOfTheGeneticDisorder": { "@id": 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"id": "CG-AC:RF000648", "type": "Publication", "publicationType": "PMID", "citation": "Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. (2014) 35(39):2733-79.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=25173338", "xdbref": [ "PMID:25173338" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002570", "id": "CG-AC:RF002570", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Noonan syndrome 1; ns1. MIM: 1639502019 Mar 29. ", "webUrl": "https://www.omim.org/entry/163950", "xdbref": [ "OMIM:163950" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002571", "id": "CG-AC:RF002571", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Noonan syndrome 3; ns3. MIM: 6099422011 May 18. ", "webUrl": "https://www.omim.org/entry/609942", "xdbref": [ "OMIM:609942" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002572", "id": "CG-AC:RF002572", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Noonan syndrome 4; ns4. MIM: 6107332014 Dec 01. ", "webUrl": "https://www.omim.org/entry/610733", "xdbref": [ "OMIM:610733" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002574", "id": "CG-AC:RF002574", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Noonan syndrome 6; ns6. MIM: 6132242017 Sep 26. ", "webUrl": "https://www.omim.org/entry/613224", "xdbref": [ "OMIM:613224" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002575", "id": "CG-AC:RF002575", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Noonan syndrome 7; ns7. MIM: 6137062011 Mar 03. ", "webUrl": "https://www.omim.org/entry/613706", "xdbref": [ "OMIM:613706" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002576", "id": "CG-AC:RF002576", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Noonan syndrome 8; ns8. MIM: 6153552017 Mar 03. ", "webUrl": "https://www.omim.org/entry/615355", "xdbref": [ "OMIM:615355" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002577", "id": "CG-AC:RF002577", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Noonan syndrome 9; ns9. MIM: 6165592016 Oct 25. ", "webUrl": "https://www.omim.org/entry/616559", "xdbref": [ "OMIM:616559" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002578", "id": "CG-AC:RF002578", "type": "Publication", "publicationType": "GeneReview", "citation": "JE Allanson, AE Roberts. Noonan syndrome. 2001 Nov 15[Updated 2019 Aug 08]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washingtom, Seattle; 1993-2026. ", "webUrl": "https://www.ncbi.nlm.nih.gov/books/NBK1124/", "xdbref": [ "PMID:20301303", "GeneReview:NBK1124" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002579", "id": "CG-AC:RF002579", "type": "Publication", "publicationType": "PMID", "citation": "Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. (2010) 126(4):746-59.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=20876176", "xdbref": [ "PMID:20876176" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002580", "id": "CG-AC:RF002580", "type": "Publication", "publicationType": "Other", "citation": "true. Management of noonan syndrome: a clinical guideline. Publisher: University of manchester. (2010) ", "webUrl": "https://rasopathiesnet.org/wp-content/uploads/2014/01/265_Noonan_Guidelines.pdf" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002581", "id": "CG-AC:RF002581", "type": "Publication", "publicationType": "PMID", "citation": "Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S. The impact of growth hormone therapy on adult height in noonan syndrome: a systematic review. Horm Res Paediatr. (2015) 83(3):167-76.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=25721697", "xdbref": [ "PMID:25721697" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002582", "id": "CG-AC:RF002582", "type": "Publication", "publicationType": "PMID", "citation": "Allanson JE. Noonan syndrome. Am J Med Genet C Semin Med Genet. (2007) 145C(3):274-9.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=17639592", "xdbref": [ "PMID:17639592" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002583", "id": "CG-AC:RF002583", "type": "Publication", "publicationType": "PMID", "citation": "Villani A, Greer MC, Kalish JM, Nakagawara A, Nathanson KL, Pajtler KW, Pfister SM, Walsh MF, Wasserman JD, Zelley K, Kratz CP. Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk. Clin Cancer Res. (2017) 23(12):e83-e90.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=28620009", "xdbref": [ "PMID:28620009" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002584", "id": "CG-AC:RF002584", "type": "Publication", "publicationType": "Orphanet", "citation": "Noonan syndrome. Orphanet encyclopedia [Internet]", "xdbref": [ "Orphanet:648" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002586", "id": "CG-AC:RF002586", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Protein-tyrosine phosphatase, nonreceptor-type, 11; ptpn11. MIM: 1768762019 Sep 06. ", "webUrl": "https://www.omim.org/entry/176876", "xdbref": [ "OMIM:176876" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF002587", "id": "CG-AC:RF002587", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. V-raf murine sarcoma viral oncogene homolog b1; braf. MIM: 1647572019 Jun 13. ", "webUrl": "https://www.omim.org/entry/164757", "xdbref": [ "OMIM:164757" ] } ] }