{ "@context": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/context/doc", "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107", "id": "CG-AC:AC107", "type": "ClinicalActionabilityReport", "metadata": { "schemaLabel": "AC-Sepio.Beta-1 (Unofficial)", "contentVersionId": "30102", "producedAtUTC": "Thu, 10 Sep 2026 19:39:55 -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/Pediatric/api/sepio/doc/AC107/co", "id": "CG-AC:AC107/co", "type": "GeneticCondition", "label": "Hereditary Hemorrhagic Telangiectasia", "description": "Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. Epistaxis and gastrointestinal bleeding are frequent complications of mucosal involvement. Visceral involvement includes that of the lung, liver, and brain." }, "outcome": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ou/Morbidity%20and%20mortality%20from%20pulmonary%20AVMs", "id": "CG-AC:AC107/ou/Morbidity and mortality from pulmonary AVMs", "type": "Outcome", "label": "Morbidity and mortality from pulmonary AVMs" }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ou/Morbidity%20and%20mortality%20from%20cerebral%20AVMs", "id": "CG-AC:AC107/ou/Morbidity and mortality from cerebral AVMs", "type": "Outcome", "label": "Morbidity and mortality from cerebral AVMs" } ], "intervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/intv/Transthoracic%20contrast%20echocardiography%20%28TTCE%29%20to%20detect%20pulmonary%20AVM%20and%20assess%20pulmonary%20arterial%20hypertension%20%28ACVRL1%20or%20ENG%20only%29", "id": "CG-AC:AC107/intv/Transthoracic contrast echocardiography (TTCE) to detect pulmonary AVM and assess pulmonary arterial hypertension (ACVRL1 or ENG only)", "type": "Intervention", "label": "Transthoracic contrast echocardiography (TTCE) to detect pulmonary AVM and assess pulmonary arterial hypertension (ACVRL1 or ENG only)" }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/intv/Evaluation%20and%20surveillance%20by%20specialist%20to%20guide%20treatment%20with%20discussion%20about%20screening%20for%20cerebral%20AVM", "id": "CG-AC:AC107/intv/Evaluation and surveillance by specialist to guide treatment with discussion about screening for cerebral AVM", "type": "Intervention", "label": "Evaluation and surveillance by specialist to guide treatment with discussion about screening for cerebral AVM" } ], "clinicalActionabilityProfile": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/cap", "id": "CG-AC:AC107/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": "Sun, 24 Mar 2024 00:00:00 -0000", "releaseNum": "1.0.2", "media": "call" }, "evidenceStatements": { "evidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/en/ACMI2827", "id": "CG-AC:AC107/en/ACMI2827", "type": "EvidenceNarrative", "narrative": "Autosomal Dominant", "evidenceDomainTag": "Threat Materialization Chances.Modes of Inheritance", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF000302", "CG-AC:RF003452", "CG-AC:RF003453", "CG-AC:RF003454", "CG-AC:RF003455", "CG-AC:RF003456", "CG-AC:RF003457", "CG-AC:RF003458", "CG-AC:RF003445", "CG-AC:RF003459" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/en/potgd", "id": "CG-AC:AC107/en/potgd", "type": "EvidenceNarrative", "narrative": "The estimated prevalence of hereditary hemorrhagic telangiectasia (HHT) ranges from 1/10,000 to 1/5000.", "evidenceDomainTag": "Nature of the Threat.Prevalence of the Genetic Disorder", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF000302", "CG-AC:RF003452", "CG-AC:RF003453", "CG-AC:RF003454", "CG-AC:RF003455", "CG-AC:RF003456", "CG-AC:RF003457" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/en/cf", "id": "CG-AC:AC107/en/cf", "type": "EvidenceNarrative", "narrative": "HHT is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. AVMs occur most commonly in the brain, lung, and liver, but can also occur in the spine and pancreas. Telangiectasias (small AVMs) close to the surface of the skin and mucous membranes often rupture and bleed after slight trauma and are most evident on the lips, tongue, buccal, nasal and gastrointestinal (GI) mucosa, face, and fingers. Telangiectasias typically appear as pinpoint to pinhead-size lesions and it is typical for patients to have only ten to 20 on careful examination. They are common in adulthood throughout the GI mucosa. Recurrent and spontaneous epistaxis (nosebleed) is the most common symptom of HHT and is the most common feature to bring individuals with HHT to medical attention. It is caused by minor insults from drying air and repeated minor abrasions to the fragile nasal mucosa. Epistasis and/or GI bleeding can cause mild to severe anemia, often requiring iron replacement therapy or blood transfusion. Visceral AVMs are usually asymptomatic but can lead to complications that produce highly variable manifestations. Cerebrovascular symptoms can include headache, focal neurologic deficit, or seizures. \n\nPulmonary arterial hypertension (PAH) that is clinically and histologically indistinguishable from primary PAH has been reported in a subset of patients with HHT due to pathogenic variants in ACVRL1 and ENG. [This phenotype is addressed in this actionability report]\n\nPatients with pathogenic variants in the SMAD4 gene are usually affected by a rare syndrome that combines HHT and juvenile polyposis syndrome (JPS). Myhre syndrome is not addressed in this actionability report. [JPS is addressed in a separate actionability report]\n\nPAWG JPS report link: https://actionability.clinicalgenome.org/ac/Pediatric/ui/stg2SummaryRpt?doc=AC066\nAAWG JPS report link: https://actionability.clinicalgenome.org/ac/Adult/ui/stg2SummaryRpt?doc=AC066", "evidenceDomainTag": "Nature of the Threat.Clinical Features", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF000302", "CG-AC:RF003452", "CG-AC:RF003453", "CG-AC:RF003454", "CG-AC:RF003455", "CG-AC:RF003456", "CG-AC:RF003457", "CG-AC:RF003458", "CG-AC:RF003445", "CG-AC:RF003459", "CG-AC:RF003460" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/en/nh", "id": "CG-AC:AC107/en/nh", "type": "EvidenceNarrative", "narrative": "Although HHT is a progressive multisystemic vascular dysplasia and infants are occasionally severely affected, in most people the features are age-dependent. AVMs of the brain are typically present at birth, whereas those in the lung and liver typically develop over time. Complications related to large AVMs are bleeding or shunting which may be sudden and catastrophic. Hemorrhage is often the presenting symptom of cerebral AVMs (CAVMs). Cerebrovascular abnormalities span multiple different lesions that differ in hemorrhagic risk and preponderance. Cerebrovascular malformations at higher risk of bleeding (AV fistulas or giant aneurysms) are those found almost exclusively in newborns, probably because of the low survival rate. Most patients report the appearance of telangiectasia of the mouth, face, or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade, though their appearance can be apparent during childhood. The average age at diagnosis of anemia is 38 years. GI bleeding, when present, usually presents in the 5th or 6th decades of life. Patients rarely develop significant GI bleeding before 50 years of age. GI bleeding occurs more frequently for females compared to men, in a ratio of 2-3:1. Hepatic AVMs typically appear around age 30, occurring predominantly in females, and can present as high-output heart failure, portal hypertension, or biliary ischemia. Pulmonary AVMs (PAVMs) present with a wide variety of clinical manifestations including dyspnea or hypoxemia; but even in asymptomatic individuals they pose a significant risk of serious complications including stroke, transient ischemic attacks, and brain abscess. Life expectancy is reduced in unscreened patients. Pregnancy-related death has been reported and is a particular risk for individuals with PAVMs.", "evidenceDomainTag": "Nature of the Threat.Natural History", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF000302", "CG-AC:RF003453", "CG-AC:RF003456", "CG-AC:RF003457" ] } ], "tieredEvidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/CDEC3051", "id": "CG-AC:AC107/ten/CDEC3051", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Although HHT is a development disorder and infants are occasionally severely affected, in most people the features are age-dependent, and the diagnosis is not suspected until adolescence or later. Many individuals do not have nosebleeds that are frequent or severe enough to cause anemia or result in medical treatment or consultation. In addition, HHT is often underdiagnosed, and a long diagnostic delay is common. As such, entire families remain unaware of available screening and treatment, and children and adults unnecessarily develop stroke or life-threatening hemorrhage. Hepatic VMs can present with nodular liver, varices, ascites, and splenomegaly, leading to an erroneous diagnosis of cirrhosis.", "evidenceDomainTag": "Condition Escape Detection.Chances to Escape Clinical Detection", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF000302", "CG-AC:RF003453" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/NOI3018", "id": "CG-AC:AC107/ten/NOI3018", "type": "TieredEvidenceNarrative", "narrative": "Identified interventions include various forms of imaging and management of bleeding risks. Embolization for large PAVMs has been found to be safe and effective. Brain MRI typically requires sedation or anesthesia in young children. There are no medical (conservative) treatments available for cerebral vascular malformations. Any treatment consists of either neurosurgical resection and/or endovascular embolization, and/or radiosurgery, which are not trivial and carry a non-negligible risk of complication; decision to treat versus observe is based on risk of treatment versus risk for hemorrhage.", "evidenceDomainTag": "Acceptability of Intervention.Natures of Intervention", "publication": [ "CG-AC:RF003451", "CG-AC:RF003456" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/ACPE4533", "id": "CG-AC:AC107/ten/ACPE4533", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "The frequency of PAH in individuals with HHT has been estimated to be 1-5%.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000302" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/ACPE4532", "id": "CG-AC:AC107/ten/ACPE4532", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Epistaxis has an average age of onset of approximately 12 years; 33% have onset by age ten years, approximately 80% by age 20 years, and 90% before age 30 years.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000302" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/ACPE4534", "id": "CG-AC:AC107/ten/ACPE4534", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "The prevalence of cerebral hemorrhage among individuals with HHT has been reported as 1.6-3.5% and 0.4-1.1% in individuals with pathogenic variants in ENG and ACVRL1, respectively.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF003456" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/ACPE4531", "id": "CG-AC:AC107/ten/ACPE4531", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "5", "narrative": "A retrospective, single center, 14-year longitudinal study in a pediatric population found that the prevalence of PAVMs was 40 in 62 (65%) in those with ENG pathogenic variants, 2 in 11 (18%) in those with ACVRL1 pathogenic variants, and 1 in 4 (25%) in those with SMAD4 pathogenic variants.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF003461" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/ACPE4536", "id": "CG-AC:AC107/ten/ACPE4536", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "5", "narrative": "A retrospective review from 5 clinical centers identified 34 individuals with SMAD4 pathogenic variants from 20 families with a mean age of 35.1 years. Features associated with HHT were documented in 76% of individuals. Five of eight (63%) of individuals under the age of 21 had HHT features.\\n•Epistaxis: 61%\\n•Telangiectasias: 48%\\n•Pulmonary AVM: 53%\\n•Cerebral AVM: 4%\\n•Hepatic AVM: 38% \\n•Colon polyps: 97%", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000307" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/ACPE4537", "id": "CG-AC:AC107/ten/ACPE4537", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "5", "narrative": "A French-Italian HHT network examined the frequency of manifestations among 343 patients including 135 probands and 208 relatives with ENG or ACVRL1 pathogenic variants (mean age of 50). \\nAmong those with an ENG pathogenic variant the frequency of manifestations were:\\n•Epistaxis: 97%\\n•Telangiectasias: 98%\\n•Pulmonary AVM: 54%\\n•Hepatic AVM: 44%\\n•GI bleeding: 7% \\nAmong those with an ACVRL1 pathogenic variant the frequency of manifestations were:\\n•Epistaxis: 89%\\n•Telangiectasias: 93%\\n•Pulmonary AVM: 13%\\n•Hepatic AVM: 57%\\n•GI bleeding: 16%", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000306" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/ACPE4530", "id": "CG-AC:AC107/ten/ACPE4530", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "1", "narrative": "A meta-analysis of 39 studies of CAVM prevalence rates in various HHT patient populations (excluding JPS/HHT syndrome) found an overall prevalence rate of CAVMs of 10.4% (95% CI 7.9-13.0%). Patients with ENG-related HHT had significantly higher prevalence (13.4%, 95% CI 9.5%-17.4%) compared with those with ACVRL1-related HHT (2.4%; 95% CI 1.0%-3.8%) (p<0.0001). In 55.2% (95% CI 38.3-72.1%) of patients, the AVMs were symptomatic. There was no significant difference in the prevalence of CAVMs in pediatric (12.2%; 95% CI 6.0-18.3%) and adult patients (9.0%; 95% CI 7.2-10.8%) (p=0.08).", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF003458" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/ACPE4535", "id": "CG-AC:AC107/ten/ACPE4535", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Overall penetrance is approximately 95% by late adulthood.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000302" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/PGM2994", "id": "CG-AC:AC107/ten/PGM2994", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Information on the prevalence of HHT-related pathogenic variants was unavailable. In 97% of patients with a definite clinical diagnosis of HHT, a causative pathogenic variant is identified in one of these genes: ENG, ACVRL1, SMAD4. Pathogenic variants in SMAD4 account for 1% of patients with HHT.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation", "publication": [ "CG-AC:RF003451", "CG-AC:RF000302" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/RR2752", "id": "CG-AC:AC107/ten/RR2752", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "Not provided", "narrative": "No information on relative risk was identified.", "evidenceDomainTag": "Threat Materialization Chances.Relative Risks" }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/EN3082", "id": "CG-AC:AC107/ten/EN3082", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "PAH has occurred most in individuals with pathogenic variants in ACVRL1 (some of whom have no feature of HHT) but has also been reported in individuals with pathogenic variants in ENG.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF000302", "CG-AC:RF003460" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/EN3083", "id": "CG-AC:AC107/ten/EN3083", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "The proportion of persons with a pathogenic variant in SMAD4 who manifest HHT only is unknown, but all pathogenic variants in SMAD4 most likely put individuals at risk for manifestations of both JPS & HHT.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF000302" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/EN3081", "id": "CG-AC:AC107/ten/EN3081", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Epistaxis has an age-related expression, as does the appearance of the typical telangiectasia.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF003451" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/ten/EN3080", "id": "CG-AC:AC107/ten/EN3080", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "There may be marked intrafamilial clinical variations or among individuals who carry the same pathogenic variant.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF003455" ] } ], "tieredRecommendations": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACSU4010", "id": "CG-AC:AC107/tr/ACSU4010", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Guidelines for the screening for hepatic VMs varies. One guideline states that asymptomatic hepatic VMs do not warrant therapy or imaging surveillance. Another recommends screening for hepatic VMs be offered to adults, ideally with Doppler ultrasonography, or alternatively multiphase contrast CT or MRI. Several cross-sectional diagnostic studies demonstrated high yield and accuracy of Doppler ultrasonography, multiphase contrast computed tomography (CT), and magnetic resonance imaging (MRI) for detection of hepatic VMs. Determining severity of hepatic VM can be useful to tailor management and follow-up. In a prospective cohort study of 154 patients (mean age 48 years, range 7-82) with HHT and hepatic VMs undergoing surveillance 8 (5.2%) died of hepatic VM-related complications. There were 2 deaths in the 13 patients (15%) who were symptomatic at the baseline evaluation, and there were 6 deaths in the 141 patients (4%) who were asymptomatic at baseline; this difference was not statistically significant (p=0.28).", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF003451", "CG-AC:RF003455", "CG-AC:RF003457" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACSU4012", "id": "CG-AC:AC107/tr/ACSU4012", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Patients with HHT should be screened PAVMs using transthoracic contrast echocardiography (TTCE). Screening should be performed at the time of initial clinical evaluation to identify patients appropriate for treatment. In asymptomatic children, repeat screening should be performed at 5-year intervals. In adults with negative initial screening, repeat screening should be considered every 5-10 years, within 5 years preceding a planned pregnancy, or after pregnancy. Embolization has been shown in several non-controlled series to be efficacious and have shown high rates of immediate technical success. Longer term, reperfusion did occur in up to 15% of patients and growth of small PAVMs in up to 18%.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACSU4011", "id": "CG-AC:AC107/tr/ACSU4011", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Guidelines differ regarding CAVM screening in HHT. One guideline states that the current evidence base does not favor the treatment of unruptured CAVMs. An international guideline recommends that patients with HHT be screened for cerebral vascular malformations (CVMs) and that screening is recommended in the first 6 months of life (or at time of diagnosis) with unenhanced MRI in asymptomatic children, and in an adult patient at age 18 using MRI with and without contrast. Another guideline states that all patients with HHT should have the opportunity to discuss screening issues with their healthcare provider, and that screening discussions in asymptomatic individuals should be preceded by informed pre-test review of the latest evidence regarding preventative and therapeutic efficacies of any interventions. The possibility of harm due to detection or intervention on a vascular malformation that would not have necessarily caused any consequence in later life should be stated explicitly. Those screening positive for CAVM should be referred to a center with neurovascular expertise to be considered for invasive testing and individualized management. There is no evidence for any role of repeat MRI screening in adults after an initial negative study. No published studies of the specific efficacy or safety of any form of treatment of CAVMs in HHT patients were identified. Results of a randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) trial indicated that individuals who were randomized to medical management alone (pharmacologic therapy for neurologic symptoms as needed) compared to medical management with interventional therapy (surgery, embolization, radiotherapy, alone or in combination) had a significantly decreased risk of death or stroke (hazard ratio 0.27, 95% CI 0.14–0.54). This trial included 223 randomized adult patients (not known to have HHT) with a mean follow-up of 33.3 months. Interventional therapy led to a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy. However, the main goal of treatment should be to achieve full AVM occlusion (since partial occlusion does not reduce but increases risk of hemorrhage) and a complete occlusion was achieved in a small minority of patients in the ARUBA trial. There is no evidence that natural history or treatment risks are higher in CAVMs associated with HHT than the general population. The risk of hemorrhagic complication across all cerebrovascular malformations in HHT is estimated to be < 1% per year. Although the prevalence of CAVMs is higher than in the general population, in HHT patients unruptured AVMs may present a lower risk of rupture.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF003456" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACPM6596", "id": "CG-AC:AC107/tr/ACPM6596", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Individuals with pathogenic variants in ACVRL1 or ENG (including children) should receive education on the symptoms of PAH and the recommendation to seek clinical evaluation if they develop symptoms.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003460" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACPM6593", "id": "CG-AC:AC107/tr/ACPM6593", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Additional care recommendations for pregnant people include: \n•unenhanced MRI in those with symptoms suggestive of CAVMs\n•those with asymptomatic CAVM during pregnancy should have definitive treatment of their CAVM deferred until after delivery of their fetus \n•management at a tertiary care center by a multidisciplinary team if they have untreated PAVMs and/or CAVMs or have not been recently screened for PAVMs.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACPM6590", "id": "CG-AC:AC107/tr/ACPM6590", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "It is recommended that pregnant people not recently screened and/or treated for PAVM be approached as follows:\n•In asymptomatic patients, perform initial PAVM screening using either agitated saline transthoracic contrast echocardiography (TTCE) or low-dose non-contrast chest CT, depending on local expertise. Chest CT, when performed, should be done early in the second trimester.\n•In patients with symptoms suggestive of PAVM, perform diagnostic testing using low-dose non-contrast chest CT. This testing can be performed at any gestational age.\n•PAVMs should be treated starting in the second trimester unless otherwise clinically indicated.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003451" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACPM6594", "id": "CG-AC:AC107/tr/ACPM6594", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Individuals with documented PAVMs, treated or untreated, should be advised to have antibiotic prophylaxis for procedures with risk of bacteremia and, when IV access is in place, to take extra care to avoid IV air.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF003454" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACPM6592", "id": "CG-AC:AC107/tr/ACPM6592", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Diagnostic testing for hepatic VMs is recommended in patients with symptoms and/or signs suggestive of complicated hepatic VMs (including heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension, or encephalopathy), using Doppler ultrasound, multiphase contrast CT scan, or contrast abdominal MRI. Symptomatic patients should be managed at a specialized center with a multidisciplinary team.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF003455", "CG-AC:RF003457" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACPM6591", "id": "CG-AC:AC107/tr/ACPM6591", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Esophagogastroduodenoscopy (EGD) is recommended as the first-line diagnostic test for suspected HHT-related GI bleeding. Several cross-sectional studies of diagnostic yield demonstrated a high yield from EGD for upper GI telangiectasias in adult patients with HHT and suspected GI bleeding.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003451" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACPM6595", "id": "CG-AC:AC107/tr/ACPM6595", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "It is recommended that adults with HHT presenting with acute hemorrhage secondary to CAVM be considered for definitive treatment in a center with neurovascular expertise. Management approaches for CAVMs should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion (neurosurgery, embolization, stereotactic radiosurgery).", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF003456" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACPM6598", "id": "CG-AC:AC107/tr/ACPM6598", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "HHT-related epistaxis recommendations include: \n•Using moisturizing topical therapies that humidify the nasal mucosa to reduce epistaxis. Topical saline has been shown to reduce epistaxis severity score compared with baseline in an RCT of topical therapies.\n•Packing with material or products that have a low likelihood of causing rebleeding with removal (e.g., lubricated low-pressure pneumatic packing) for acute epistaxis requiring intervention\n•All adults and children with HHT and recurrent bleeding and/or symptoms of anemia should be tested for iron deficiency anemia. Testing typically includes complete blood count and ferritin measurement. Iron supplementation is recommended for treatment of iron deficiency. \n•Referring patients with epistaxis and who desire treatment to otorhinolaryngologists with HHT expertise for evaluation. \n•Additional treatments that can be considered (such as tranexamic acid and antiangiogenic therapies) if less intensive treatment is not successful in managing epistaxis.\n•When considering nasal surgery for reasons other than epistaxis, consultation should be obtained from an otorhinolaryngologists with expertise in HHT-related epistaxis.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACPM6597", "id": "CG-AC:AC107/tr/ACPM6597", "type": "TieredRecommendation", "evidenceSourceTier": "Not provided", "recommendation": "Individuals with SMAD4 pathogenic variants should also be evaluated for JPS. [JPS is addressed in a separate actionability report]", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003451" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACCA3723", "id": "CG-AC:AC107/tr/ACCA3723", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Patients with documented PAVMs (treated or untreated) should be advised to avoid scuba diving.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACCA3721", "id": "CG-AC:AC107/tr/ACCA3721", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Liver biopsy should be avoided in any patient with HHT; its indication should be discussed with a multidisciplinary panel.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003451", "CG-AC:RF000301", "CG-AC:RF003455", "CG-AC:RF003457" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACCA3720", "id": "CG-AC:AC107/tr/ACCA3720", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Chemical or electric cauterization is contraindicated for epistaxis in HHT. One guideline states that dermoplasty is not recommended.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003451", "CG-AC:RF003454" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACCA3722", "id": "CG-AC:AC107/tr/ACCA3722", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "It is recommended that dual antiplatelet therapy and/or combination of antiplatelet therapy and anticoagulation be avoided where possible. However, patients can receive anticoagulation (prophylactic or therapeutic) or antiplatelet therapy when there is an indication, with consideration of their individualized bleeding risks; bleeding in HHT is not an absolute contraindication for these therapies.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003451" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACSU4008", "id": "CG-AC:AC107/tr/ACSU4008", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Individuals with pathogenic variants in ACVRL1 or ENG (including children) should receive screening for PAH via serial echocardiograms and possibly other non-invasive studies.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF003460" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACSU4009", "id": "CG-AC:AC107/tr/ACSU4009", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Patients should be referred to a reference center for annual follow-up.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF003454" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/ACCA3719", "id": "CG-AC:AC107/tr/ACCA3719", "type": "TieredRecommendation", "evidenceSourceTier": "4", "recommendation": "Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF000302" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/tr/REC2206", "id": "CG-AC:AC107/tr/REC2206", "type": "TieredRecommendation", "evidenceSourceTier": "5", "recommendation": "A retrospective, single center, 14-year longitudinal study assessed prevalence, clinical impact, and progression of PAVMs in 129 children diagnosed with HHT using Curacao criteria and/or confirmed by genetic testing (77 had a pathogenic variant in ENG, ACVRL1 or SMAD4 out of 80 children tested). Mean age of PAVM detection was approximately nine years. Of the 129 children, 76 (59%) were found to have PAVMs (88% of those were found on initial screening). Of the 63 children w/out PAVMs on initial screening, 31 were followed for >1 year. Nine of the 31 (29%) developed new PAVMs after initial negative study (mean time to detection = 5.6 years). Thirty-eight (50%) of the total 76 children with PAVMs had or developed lesions large enough to be treated w/embolization. The majority, 60% (20/38) of children w/large PAVMs had no related clinical symptoms. After embolization, 21% (8/38) of patients underwent repeat interventions. Primary reason for repeat intervention was reperfusion to the previously embolized PAVMs. No children suffered complications from having a PAVM embolized.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF003461" ] } ] }, "evidenceCategory": { "outcomeEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei", "id": "CG-AC:AC107/oei", "type": "EvidenceItem", "natureOfTheThreat": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/nott", "id": "CG-AC:AC107/oei/nott", "type": "EvidenceLine", "prevalenceOfTheGeneticDisorder": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pgd", "id": "CG-AC:AC107/oei/pgd", "type": "EvidenceItem", "keyText": "1-2 in 10000", "sourceOfPopulation": "General population", "evidenceNarrative": { "@id": "CG-AC:AC107/en/potgd" } }, "clinicalFeatures": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/cf", "id": "CG-AC:AC107/oei/cf", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC107/en/cf" } }, "naturalHistory": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/nh", "id": "CG-AC:AC107/oei/nh", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC107/en/nh" } } }, "threatMaterializationChances": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/tmc", "id": "CG-AC:AC107/oei/tmc", "type": "EvidenceLine", "modeOfInheritance": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/moi", "id": "CG-AC:AC107/oei/moi", "type": "EvidenceItem", "keyText": "Autosomal Dominant", "evidenceNarrative": { "@id": "CG-AC:AC107/en/ACMI2827" } }, "prevalenceOfTheGeneticMutation": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pgm", "id": "CG-AC:AC107/oei/pgm", "type": "EvidenceItem", "keyText": "Unknown", "sourceOfPopulation": "Other", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/PGM2994" } }, "penetrance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pe/ACPE4535", "id": "CG-AC:AC107/oei/pe/ACPE4535", "type": "EvidenceItem", "keyText": ">= 40 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/ACPE4535" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pe/ACPE4530", "id": "CG-AC:AC107/oei/pe/ACPE4530", "type": "EvidenceItem", "keyText": "5-39 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/ACPE4530" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pe/ACPE4537", "id": "CG-AC:AC107/oei/pe/ACPE4537", "type": "EvidenceItem", "keyText": ">= 40 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/ACPE4537" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pe/ACPE4536", "id": "CG-AC:AC107/oei/pe/ACPE4536", "type": "EvidenceItem", "keyText": ">= 40 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/ACPE4536" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pe/ACPE4531", "id": "CG-AC:AC107/oei/pe/ACPE4531", "type": "EvidenceItem", "keyText": ">= 40 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/ACPE4531" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pe/ACPE4534", "id": "CG-AC:AC107/oei/pe/ACPE4534", "type": "EvidenceItem", "keyText": "1-4 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/ACPE4534" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pe/ACPE4532", "id": "CG-AC:AC107/oei/pe/ACPE4532", "type": "EvidenceItem", "keyText": ">= 40 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/ACPE4532" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/pe/ACPE4533", "id": "CG-AC:AC107/oei/pe/ACPE4533", "type": "EvidenceItem", "keyText": "5-39 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/ACPE4533" } } ], "relativeRisk": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/rr/RR2752", "id": "CG-AC:AC107/oei/rr/RR2752", "type": "EvidenceItem", "keyText": "Unknown", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/RR2752" } } ], "expressivity": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/ex/EN3080", "id": "CG-AC:AC107/oei/ex/EN3080", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/EN3080" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/ex/EN3081", "id": "CG-AC:AC107/oei/ex/EN3081", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/EN3081" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/ex/EN3083", "id": "CG-AC:AC107/oei/ex/EN3083", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/EN3083" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/oei/ex/EN3082", "id": "CG-AC:AC107/oei/ex/EN3082", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/EN3082" } } ] } }, "interventionEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei", "id": "CG-AC:AC107/iei", "type": "EvidenceItem", "acceptabilityOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/aoi", "id": "CG-AC:AC107/iei/aoi", "type": "EvidenceLine", "natureOfIntervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/noi/NOI3018", "id": "CG-AC:AC107/iei/noi/NOI3018", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/NOI3018" } } ] }, "effectivenessOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/eoi", "id": "CG-AC:AC107/iei/eoi", "type": "EvidenceLine", "patientManagement": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/pm/ACPM6597", "id": "CG-AC:AC107/iei/pm/ACPM6597", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACPM6597" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/pm/ACPM6598", "id": "CG-AC:AC107/iei/pm/ACPM6598", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACPM6598" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/pm/ACPM6595", "id": "CG-AC:AC107/iei/pm/ACPM6595", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACPM6595" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/pm/ACPM6591", "id": "CG-AC:AC107/iei/pm/ACPM6591", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACPM6591" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/pm/ACPM6592", "id": "CG-AC:AC107/iei/pm/ACPM6592", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACPM6592" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/pm/ACPM6594", "id": "CG-AC:AC107/iei/pm/ACPM6594", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACPM6594" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/pm/ACPM6590", "id": "CG-AC:AC107/iei/pm/ACPM6590", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACPM6590" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/pm/ACPM6593", "id": "CG-AC:AC107/iei/pm/ACPM6593", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACPM6593" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/pm/ACPM6596", "id": "CG-AC:AC107/iei/pm/ACPM6596", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACPM6596" } } ], "circumstanceToAvoid": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/cta/ACCA3722", "id": "CG-AC:AC107/iei/cta/ACCA3722", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACCA3722" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/cta/ACCA3720", "id": "CG-AC:AC107/iei/cta/ACCA3720", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACCA3720" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/cta/ACCA3721", "id": "CG-AC:AC107/iei/cta/ACCA3721", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACCA3721" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/cta/ACCA3723", "id": "CG-AC:AC107/iei/cta/ACCA3723", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACCA3723" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/cta/ACCA3719", "id": "CG-AC:AC107/iei/cta/ACCA3719", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACCA3719" } } ], "surveillance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/su/ACSU4009", "id": "CG-AC:AC107/iei/su/ACSU4009", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACSU4009" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/su/ACSU4011", "id": "CG-AC:AC107/iei/su/ACSU4011", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACSU4011" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/su/ACSU4012", "id": "CG-AC:AC107/iei/su/ACSU4012", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACSU4012" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/su/REC2206", "id": "CG-AC:AC107/iei/su/REC2206", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/REC2206" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/su/ACSU4010", "id": "CG-AC:AC107/iei/su/ACSU4010", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACSU4010" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/su/ACSU4008", "id": "CG-AC:AC107/iei/su/ACSU4008", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC107/tr/ACSU4008" } } ] }, "conditionEscapeDetection": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/ced", "id": "CG-AC:AC107/iei/ced", "type": "EvidenceLine", "chanceToEscapeDetection": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC107/iei/cted/CDEC3051", "id": "CG-AC:AC107/iei/cted/CDEC3051", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC107/ten/CDEC3051" } } ] } } }, "references": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/RF000301", "id": "CG-AC:RF000301", "type": "Publication", "publicationType": "PMID", "citation": "Faughnan ME, Palda VA, Garcia-Tsao G, Geisthoff UW, McDonald J, Proctor DD, Spears J, Brown DH, Buscarini E, Chesnutt MS, Cottin V, Ganguly A, Gossage JR, Guttmacher AE, Hyland RH, Kennedy SJ, Korzenik J, Mager JJ, Ozanne AP, Piccirillo JF, Picus D, Plauchu H, Porteous ME, Pyeritz RE, Ross DA, Sabba C, Swanson K, Terry P, Wallace MC, Westermann CJ, White RI, Young LH, Zarrabeitia R. 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