{ "@context": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/context/doc", "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045", "id": "CG-AC:AC1045", "type": "ClinicalActionabilityReport", "metadata": { "schemaLabel": "AC-Sepio.Beta-1 (Unofficial)", "contentVersionId": "28680", "producedAtUTC": "Thu, 10 Sep 2026 20:44:03 -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/AC1045/co", "id": "CG-AC:AC1045/co", "type": "GeneticCondition", "label": "Diamond-Blackfan anemia" }, "outcome": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ou/Morbidity%20and%20mortality%20due%20to%20hematopoietic%20manifestations", "id": "CG-AC:AC1045/ou/Morbidity and mortality due to hematopoietic manifestations", "type": "Outcome", "label": "Morbidity and mortality due to hematopoietic manifestations" } ], "intervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/intv/Referral%20to%20specialist%3B%20initial%20treatment%20with%20corticosteroids%20and%20consideration%20of%20more%20intensive%20therapies%20%28transfusion%20therapy%2C%20hematopoietic%20stem%20cell%20transplantation%29%20in%20those%20without%20sustained%20response%20or%20who%20have%20unacceptable%20side%20effects", "id": "CG-AC:AC1045/intv/Referral to specialist; initial treatment with corticosteroids and consideration of more intensive therapies (transfusion therapy, hematopoietic stem cell transplantation) in those without sustained response or who have unacceptable side effects", "type": "Intervention", "label": "Referral to specialist; initial treatment with corticosteroids and consideration of more intensive therapies (transfusion therapy, hematopoietic stem cell transplantation) in those without sustained response or who have unacceptable side effects" } ], "clinicalActionabilityProfile": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/cap", "id": "CG-AC:AC1045/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": "Thu, 21 Jul 2022 00:00:00 -0000", "releaseNum": "1.0.0", "media": "call" }, "evidenceStatements": { "evidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/en/ACMI2736", "id": "CG-AC:AC1045/en/ACMI2736", "type": "EvidenceNarrative", "narrative": "Autosomal Dominant", "evidenceDomainTag": "Threat Materialization Chances.Modes of Inheritance", "publication": [ "CG-AC:RF003370", "CG-AC:RF003371", "CG-AC:RF003361", "CG-AC:RF003372", "CG-AC:RF003373", "CG-AC:RF003369", "CG-AC:RF003367", "CG-AC:RF003377" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/en/potgd", "id": "CG-AC:AC1045/en/potgd", "type": "EvidenceNarrative", "narrative": "The incidence of Diamond-Blackfan anemia (DBA) is estimated at between 5-10/1,000,000 live births, remaining consistent across populations. The estimated incidence of classic DBA (i.e., typical onset within the first year of life) is 7/1,000,000 live births.", "evidenceDomainTag": "Nature of the Threat.Prevalence of the Genetic Disorder", "publication": [ "CG-AC:RF003370", "CG-AC:RF003371", "CG-AC:RF003361", "CG-AC:RF003372" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/en/cf", "id": "CG-AC:AC1045/en/cf", "type": "EvidenceNarrative", "narrative": "DBA is a rare congenital pure red-cell aplasia caused by a disorder in ribosome synthesis. DBA is characterized by early onset severe anemia, congenital anomalies, and growth deficiency. Hematopoietic findings include macrocytic anemia, reticulocytopenia, and a paucity of erythroid precursors. Craniofacial features include microcephaly; hypertelorism, epicanthus, ptosis; microtia, low-set ears; broad, depressed nasal bridge; cleft lip/palate, high arched palate; micrognathia; and low anterior hairline. Eye findings include congenital glaucoma and cataract, and strabismus. Individuals can have neck webbing, a short neck, Klippel-Feil anomaly, and Sprengel shoulder. Upper limb and hand (including thumb) findings include absent radial artery; flat thenar eminence; and triphalangeal, duplex, bifid, hypoplastic, or absent thumb. Genitourinary findings include absent kidney, horseshoe kidney, and hypospadias. Cardiac findings include ventricular septal defect, atrial septal defect, coarctation of the aorta, and other anomalies. DBA is considered a cancer predisposition syndrome and is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcomas, and carcinomas of the lung, colon, cervix, and others. Other features include pallor, dyspnea during feeding or while sucking, weakness, failure to thrive, and in rare cases, developmental delay.", "evidenceDomainTag": "Nature of the Threat.Clinical Features", "publication": [ "CG-AC:RF003370", "CG-AC:RF003371", "CG-AC:RF003361", "CG-AC:RF003373", "CG-AC:RF003374", "CG-AC:RF003375", "CG-AC:RF003369", "CG-AC:RF003367", "CG-AC:RF003376", "CG-AC:RF003377" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/en/nh", "id": "CG-AC:AC1045/en/nh", "type": "EvidenceNarrative", "narrative": "The phenotypic spectrum of DBA is broad and ranges from mild (atypical) forms to classic DBA, to a rare but severe form. Onset of mild DBA can be later than age one year and may present only as congenital anomalies, without anemia, or with a mild hematological phenotype (macrocytosis only). In classic DBA, hematologic features (e.g., macrocytic anemia) typically occur in affected individuals during the first year of life, with a median age at presentation of 2 months. Rarely, a severe form may present as fetal anemia and nonimmune hydrops fetalis. \\n\\nOver half of all individuals with DBA present with growth deficiency and congenital anomalies, the most frequent being craniofacial, thumb, and urogenital anomalies. Individuals with DBA have an overall cumulative cancer incidence of 13.7% by age 45 years, excluding MDS. Recent data from the North American (N.A.) DBA registry reported the median age of osteogenic sarcoma diagnosis as 11 years (range 4-34), MDS as 25 years, breast cancer as 34 years (range 22-43), colorectal cancer as 41 years (range 20-51), AML as 44 years (range 15-46), and squamous cell carcinoma as 50 years (range 44-69). Severe evolution of the disease, transfusion dependence, or death is associated with a younger age at presentation. There are known individuals with DBA who survive late into adulthood. Individuals with DBA can also be newly diagnosed as adults, but there is little known about natural disease progression and what factors lead to long-term survival in these individuals. It is unclear whether DBA worsens over time. Complications of pregnancy are numerous and can affect the mother, fetus, and newborn. However, the direct cause of pregnancy-specific complications may be multifactorial. DBA affects males and females equally.", "evidenceDomainTag": "Nature of the Threat.Natural History", "publication": [ "CG-AC:RF003370", "CG-AC:RF003371", "CG-AC:RF003361", "CG-AC:RF003372", "CG-AC:RF003369", "CG-AC:RF003367", "CG-AC:RF003376" ] } ], "tieredEvidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/CDEC2905", "id": "CG-AC:AC1045/ten/CDEC2905", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Macrocytosis may be masked by iron deficiency or thalassemia minor and, in the newborn, can be obscured by residual fetal erythrocytes. Heterogeneity of presentation and atypical clinical features may be confounding factors in the diagnosis of DBA. In some instances, the diagnosis of DBA may only be established after other disorders in the have been ruled out.", "evidenceDomainTag": "Condition Escape Detection.Chances to Escape Clinical Detection", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/NOI2902", "id": "CG-AC:AC1045/ten/NOI2902", "type": "TieredEvidenceNarrative", "narrative": "The mainstays of treatment for DBA are corticosteroid therapy and chronic transfusions, either alone or in combination. An N.A. DBA registry study found that 70% of the deaths reported to the registry were treatment related: infections, complications of iron overload, vascular access device complication, and HSCT complications. Transfusions often lead to iron overload and resulting extensive iron-induced injury in the heart, liver, pancreas, thyroid, and other organs. Cardiac disease and cardiac-related mortality may ensue. In data from the French DBA registry, complications due to corticosteroid therapy, including hypertension, diabetes mellitus, and growth deficiency, were noted in 20% of individuals on long-term therapy. The N.A. DBA registry reported 22% of individuals on corticosteroids with pathological fractures and 12% with cataracts. Some corticosteroid side effects are of particular concern in growing children and therefore must be closely monitored, often requiring discontinuation of corticosteroids. HCST is associated with transplant-related morbidity and mortality and unknown long-term side effects. Conditioning regimens may be associated with increased risk of acute toxicities, GVHD, veno-occlusive disease, pulmonary toxicity, and may contribute to the risk of developing secondary malignancies.", "evidenceDomainTag": "Acceptability of Intervention.Natures of Intervention", "publication": [ "CG-AC:RF003370", "CG-AC:RF003371", "CG-AC:RF003378" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/RR2654", "id": "CG-AC:AC1045/ten/RR2654", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Based on case reports only, the survival of individuals with DBA with cancer appears to be less than that of individuals with similar cancers in the general population.", "evidenceDomainTag": "Threat Materialization Chances.Relative Risks", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/RR2655", "id": "CG-AC:AC1045/ten/RR2655", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "2", "narrative": "Individuals with DBA have a 4.8-fold higher relative risk of developing cancer with an overall cumulative incidence of 13.7% by age 45 years. There is a steep hazard curve for solid tumors in DBA, rising from <1% to >5% per year between the ages of 35 and 60 years, with poor outcomes for those individuals who develop cancer. There is an observed to expected case ratio of 45 for colon cancer in DBA compared to the general population and a crude incidence of 2.5% (9 of 366 individuals 20–50 years of age).", "evidenceDomainTag": "Threat Materialization Chances.Relative Risks", "publication": [ "CG-AC:RF003376" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/PGM2852", "id": "CG-AC:AC1045/ten/PGM2852", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Approximately 55%-75% of individuals diagnosed with DBA have the disorder as the result of a de novo pathogenic variant, including but not limited to those found in the RPS10, RPS19 and RPS24 genes.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation", "publication": [ "CG-AC:RF003373" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/PGM2851", "id": "CG-AC:AC1045/ten/PGM2851", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Approximately 25-30% of cases are attributed to RPS19, 1-6% to RPS10, and 2-3% to RPS24.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation", "publication": [ "CG-AC:RF003370", "CG-AC:RF003361", "CG-AC:RF003369", "CG-AC:RF003367" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/ACPE4222", "id": "CG-AC:AC1045/ten/ACPE4222", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "In a review of 25 pregnant individuals with a clinical diagnosis of DBA (29 pregnancies total), 40% of the pregnancies required multiple transfusions and 30% required corticosteroid treatment. The study reported an increased risk of cesarean section (25%), low birth weight (21%), and premature delivery of offspring both with and without DBA. A large prospective study of 64 pregnancies in 26 individuals with DBA (genetic status not reported) reported adverse outcomes in 66% of pregnancies. Congenital malformations were noted in 12.5% of all pregnancies and were independent of the DBA status of the child. The direct causes of these complications were not clear but were likely multifactorial. A summary of pregnancy outcomes in a large case series (75 women, 145 pregnancies) reported a spontaneous abortion rate of 30%.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF003373" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/ACPE4220", "id": "CG-AC:AC1045/ten/ACPE4220", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Between 7-50% of individuals with DBA have craniofacial, upper limb, heart, and/or urinary system congenital malformations. In a study of 80 individuals with a clinical diagnosis of DBA from a 20-year birth cohort in the U.K., 35% of individuals with classic DBA were found to have one or more unequivocal congenital anomalies. A similar proportion has been described in the French, Italian, and N.A. registries (40%, 46%, and 47%, respectively).", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF003370", "CG-AC:RF003371", "CG-AC:RF003361", "CG-AC:RF003373", "CG-AC:RF003375", "CG-AC:RF003367" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/ACPE4221", "id": "CG-AC:AC1045/ten/ACPE4221", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "A recent analysis of the data from the N.A. DBA registry, including 813 individuals with molecular diagnoses of DBA (not limited to the genes listed in this report), with a median age of 24 years, reported the most common cancer diagnoses as:\\n•MDS: 10/41 (24%)\\n•Colorectal cancer: 9/41 (22%)\\n•Osteogenic sarcoma: 4/41 (10%) \\n•Breast cancer: 4/41 (10%)\\n•Squamous cell carcinoma (3 different organs): 3/41 (7%)\\n•AML: 3/41 (7%).", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF003376" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/EN2910", "id": "CG-AC:AC1045/ten/EN2910", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Non-classic cases of DBA with less distinct phenotypes have been described in adults as well as children.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/EN2911", "id": "CG-AC:AC1045/ten/EN2911", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "There are examples of reduced penetrance and co-existence of both mild and severe forms within a pedigree. Approximately 10–15% of affected individuals are from multiplex families, with classic DBA in more than one family member.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/ACPE4218", "id": "CG-AC:AC1045/ten/ACPE4218", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Based on combined data from multiple registries, the following features have also been reported: \\n•Anemia: 100% (90% in 1st year of life)\\n•Growth deficiency: 30%", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF003370", "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/ACPE4219", "id": "CG-AC:AC1045/ten/ACPE4219", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Penetrance is almost complete with loss-of-function variants in the three most common DBA-associated genes, RPL5, RPS19, and RPS26. Penetrance is high with loss-of-function variants in other genes (including RPS10, RPS24, and others). Missense variants (58% of which are found in RPS19) appear to be less penetrant.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF003370" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/ten/EN2909", "id": "CG-AC:AC1045/ten/EN2909", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "DBA is a clinically heterogenous condition, and symptoms as well as severity of congenital anomalies, can vary between affected family members possessing the same pathogenic variant.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF003361", "CG-AC:RF003369", "CG-AC:RF003367" ] } ], "tieredRecommendations": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACCA3489", "id": "CG-AC:AC1045/tr/ACCA3489", "type": "TieredRecommendation", "evidenceSourceTier": "4", "recommendation": "Chemotherapy for treatment of malignancies must be given cautiously as it may lead to prolonged cytopenia and subsequent toxicities.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003370" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACCA3487", "id": "CG-AC:AC1045/tr/ACCA3487", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Given the risk of sarcoma, radiation exposure from diagnostic tests for cancers should be minimized.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACCA3488", "id": "CG-AC:AC1045/tr/ACCA3488", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Oral contraceptives and other estrogen mimetic agents should be avoided in corticosteroid-dependent individuals with DBA, as estrogens may induce corticosteroid refractoriness.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5847", "id": "CG-AC:AC1045/tr/ACPM5847", "type": "TieredRecommendation", "evidenceSourceTier": "3", "recommendation": "In a review of 25 pregnant individuals with a clinical diagnosis of DBA (29 pregnancies total), 40% of the pregnancies required multiple transfusions and 30% required corticosteroid treatment to maintain maternal hemoglobin levels. All corticosteroid-treated individuals were also transfused.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003373" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5849", "id": "CG-AC:AC1045/tr/ACPM5849", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Close monitoring and care throughout pregnancy should be administered by an experienced multidisciplinary team in a high-risk obstetrical practice and include hematologists and other appropriate subspecialists. There are no clear guidelines on the use of iron chelators in patients with DBA and management of iron chelation therapy during pregnancy remains controversial. The recommendations for DBA throughout pregnancy are as follows:\\n•Monitor cardiac, hepatic, and thyroid function\\n•Evaluate iron overload status and ensure adequate management of iron overload\\n•Monitor hemoglobin level and transfuse if symptomatic or fetal growth distress. If hemoglobin level drops below 10 g/dL consider transfusion therapy. \\n•Monthly utero-placental doppler ultrasound starting week 20 of gestational age to monitor for growth restriction, fetal distress, and hydrops fetalis in the fetus; and to assess for a potential placental vascular disorder\\n•Acetyl salicylic acid 80-100 mg once daily during pregnancy, since many of the observed complications have similar presentations to placental vasculopathy\\n•Regular folic acid supplementation of 800–1000mg daily to prevent superimposed megaloblastic anemia.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003371", "CG-AC:RF003373" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5846", "id": "CG-AC:AC1045/tr/ACPM5846", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Preconception consultations with maternal-fetal medicine, medical genetics, and hematology specialists are recommended for individuals with DBA who are planning to become pregnant. These individuals should undergo a thorough evaluation of any feature that may interfere with pregnancy outcome, including the presence of blood-borne infections, iron overload and related diabetes mellitus, hypothyroidism, or cardiomyopathy. When indicated, an intensification of iron chelation should be performed before pregnancy.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003371", "CG-AC:RF003373" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5848", "id": "CG-AC:AC1045/tr/ACPM5848", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "In children and adolescents with DBA, the judicious use of corticosteroids, maintenance of hemoglobin levels at 80 g/l or more, and appropriate iron chelation (if indicated due to transfusion-related iron overload) are essential in optimizing growth. When corticosteroids are started in infants less than 1 year of age, growth and neuromotor development should be closely monitored. Growth curves should be also closely monitored especially during periods of high growth velocity, such as puberty. In children and adolescents, a growth plateau and/or puberty-induced corticosteroid resistance warrants the use of short-term transfusion program. If growth is severely impaired in children while being treated, corticosteroids should be stopped and replaced by a short-term red blood cell transfusion regimen.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5845", "id": "CG-AC:AC1045/tr/ACPM5845", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Corticosteroids are the mainstay of treatment in DBA, although their mode of action remains unknown. Some experts recommend a corticosteroid trial beginning at one year of age, but there is no consensus. Prior to one year of age, chronic transfusion therapy with packed red blood cells is necessary to avoid steroid toxicity. An earlier trial of corticosteroids may be considered if there is poor venous access, or where the safety of the blood supply is questionable. Corticosteroid therapy is not generally recommended in individuals under 6 months of age. In infants with DBA, the need for relatively high doses and prolonged duration of corticosteroid therapy should be balanced against the possible detrimental effects. The recommended starting dose is 2 mg/kg, given as a single daily dose. Once corticosteroid therapy is started, an increase in hemoglobin is usually seen within 2-4 weeks. This starting dose should be given for a maximum of 4 weeks. If transfusion independence is not achieved after this time, corticosteroids should be discontinued. Based on consensus, after the initial response, corticosteroids should be tapered over 8–12 weeks and then be further tapered to find the minimal maintenance dose necessary to sustain growth and activity. The maintenance dose in responders is highly variable with some individuals requiring extremely small doses for continued response. If an acceptable hemoglobin cannot be sustained at the recommended dose, corticosteroids should be tapered and discontinued. Some individuals become refractory to corticosteroids despite an initial response, while a proportion of corticosteroid responders become increasingly resistant, requiring progressively higher doses to maintain their hemoglobin in the target range. Others may need to discontinue treatment due to unacceptable side effects. An analysis of the N.A. DBA registry data found that the overall actuarial survival at greater than 40 years of age was 86.7% for corticosteroid-maintainable individuals with DBA. There is limited long-term follow-up data on the use of corticosteroids in infancy. Although there is limited data on adults with DBA, individuals who are first recognized in adulthood have been reported to respond to corticosteroid therapy.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5844", "id": "CG-AC:AC1045/tr/ACPM5844", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "The lifetime management of individuals with DBA should be by a multidisciplinary team involving pediatric and adult hematologists, internists, and subspecialists, as needed. Physicians should be aware of the possibility of developing aplastic anemia, AML, MDS, or solid tumors. In general, asymptomatic adults with known pathogenic variants in genes associated with DBA should be followed like pediatric individuals in remission. Management pathways for individuals with DBA are primarily derived from the analysis of data from worldwide DBA registries.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACSU3792", "id": "CG-AC:AC1045/tr/ACSU3792", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Annual monitoring of cardiac function by echocardiography or MRI, and Holter monitoring has some utility and is recommended, even though the onset of cardiac failure is often sudden and may occur even after reassuring normal parameters on routine echocardiography and electrocardiography. Detailed endocrine evaluation, including bone densitometry, is recommended at intervals based on age, compliance with chelation therapy (if using), and iron status.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACSU3790", "id": "CG-AC:AC1045/tr/ACSU3790", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Preliminary recommendations from a DBA registry state that screening colonoscopy of young adults with DBA should begin at age 20 years, with follow-up every 5 years for those with normal colonoscopies. For those with positive findings, gastrointestinal and oncologic society guidelines for surveillance colonoscopy should be followed. These recommendations are based on the effectiveness of screening and surveillance colonoscopy in significantly reducing colorectal cancer (CRC)-related morbidity and mortality in the general population as well as in those with CRC risk syndromes, particularly Li-Fraumeni syndrome. Current DBA N.A. registry data includes 9 de novo diagnoses of CRC ranging in age of diagnosis from 20-50 years (median age 41 years, with three diagnosed between 20–39 years).", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF003376" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACSU3791", "id": "CG-AC:AC1045/tr/ACSU3791", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "For cancer screening, a periodic history and physical examination with blood count monitoring is done at 4 to 6-month intervals in individuals who are stable. Individuals with pathogenic variants associated with DBA should undergo surveillance for myeloid malignancies, regardless of clinical presentation. If abnormalities appear in the blood, bone marrow aspirate, biopsy, and cytogenetic studies (karyotype, as well as FISH analysis for abnormalities in chromosomes 5, 7, and 8) should be performed. There should be a low threshold for investigation of bone or joint pain in individuals with DBA", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF003371", "CG-AC:RF003374" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/REC2997", "id": "CG-AC:AC1045/tr/REC2997", "type": "TieredRecommendation", "evidenceSourceTier": "5", "recommendation": "In a recent report of the German and French DBA registries, 70 children with clinically diagnosed DBA (64% of which were genetically confirmed) underwent HSCT. Median age at HSCT was 5.5 years (range, 0.9-17.3 years) and 64% were transplanted from a matched sibling donor. With a median follow-up of 4.5 years (range, 0.2-22.2 years), the overall survival was 91% with no difference by donor type. All individuals engrafted, but one individual had secondary graft failure. All individuals remained transfusion-independent at the time of follow-up. The cumulative incidence of chronic graft-versus-host-disease (GVHD) was 11%, but the difference between children transplanted before age 10 years compared with older children was not significant.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003378" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/REC2996", "id": "CG-AC:AC1045/tr/REC2996", "type": "TieredRecommendation", "evidenceSourceTier": "3", "recommendation": "In another study of 61 persons with DBA (genetic status not reported) who underwent bone marrow transplantation, 67% received their bone marrow grafts from an HLA-matched related donor. The 3-year probability of overall survival was 64% (range 50%-74%). Transplantation from an HLA-identical sibling donor was associated with better survival.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003370" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/REC2995", "id": "CG-AC:AC1045/tr/REC2995", "type": "TieredRecommendation", "evidenceSourceTier": "3", "recommendation": "In a United Kingdom (U.K.) registry study of 222 individuals with DBA available for long-term follow-up analysis, 62.6% initially responded to corticosteroid therapy. Initial corticosteroid responsiveness was significantly and independently associated with older age at presentation, family history of DBA, and normal platelet count at the time of diagnosis.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003361" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACCA3492", "id": "CG-AC:AC1045/tr/ACCA3492", "type": "TieredRecommendation", "evidenceSourceTier": "3", "recommendation": "Individuals with DBA, especially those on corticosteroid therapy, should take reasonable precautions to avoid infections, as corticosteroid-dependent individuals are more prone to complications resulting from immune system dysfunction.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003370" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACCA3490", "id": "CG-AC:AC1045/tr/ACCA3490", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Chelation to alleviate iron burden is contraindicated during pregnancy. Deferoxamine is teratogenic, based on animal studies.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACCA3491", "id": "CG-AC:AC1045/tr/ACCA3491", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Deferiprone should be avoided as a chelation treatment for iron overload, as it can cause neutropenia.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5850", "id": "CG-AC:AC1045/tr/ACPM5850", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "In cases where the father of the child has a diagnosis of DBA, the pregnancy should also be considered high risk and closely monitored for signs of fetal distress, hydrops fetalis, and other complications of the fetus.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5853", "id": "CG-AC:AC1045/tr/ACPM5853", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Hematopoietic stem cell transplantation (HSCT) is curative of the hematological phenotype in DBA. However, its role is controversial and strict criteria must be applied to ensure that the potential donor does not have a silent DBA phenotype. The development of malignancies in individuals with DBA must be considered when planning conditioning regimens for HSCT. A recent guideline states that indications for HSCT include non-response to corticosteroids after two trials of corticosteroid therapy, clonal evolution, and aplastic anemia in children with an available HLA-matched family donor. Only matched sibling donors are recommended. An N.A. DBA registry study described 36 individuals (genetic status not reported) who underwent HSCT: 21 HLA-matched sib HSCTs and 15 alternative donor HSCTs. Although the major indication for HSCT was transfusion dependence, two individuals were transplanted due to severe aplastic anemia and one due to significant thrombocytopenia. Survival greater than 5 years from HSCT with allogeneic sib transplants was 72.7% ±10.7% versus 17.1% ±11.9% with alternative donor transplants. Survival was the highest (92.3%) for children younger than 10 years transplanted using an HLA-matched siblings.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003377" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5852", "id": "CG-AC:AC1045/tr/ACPM5852", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Chronic transfusion therapy is recommended during the first year of life to avoid steroid-induced toxicity, and in those not responsive to a trial of corticosteroids at age 12 months. Transfusion therapy should be initiated if an individual has become unresponsive to corticosteroids. Occasional transfusions may be given to offset transient falls in hemoglobin, as seen with non-specific viral infections and hormonal stress. An analysis of DBA registry data found that the overall actuarial survival at greater than 40 years of age is 57.2% for transfusion-dependent individuals with DBA.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5854", "id": "CG-AC:AC1045/tr/ACPM5854", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Renal imaging and echocardiogram are recommended to identify congenital anomalies, with nephrology, urology, and cardiology referrals as appropriate.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003371" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/tr/ACPM5851", "id": "CG-AC:AC1045/tr/ACPM5851", "type": "TieredRecommendation", "evidenceSourceTier": "4", "recommendation": "To establish the extent of disease and needs in an individual diagnosed with DBA, the following should be performed:\\n•Evaluation by hematologist for anemia\\n•Evaluation by clinical geneticist for congenital anomalies\\n•Ophthalmology evaluation for glaucoma and cataracts\\n•Orthopedic evaluation for persons with neck, upper-limb and/or thumb anomalies\\n•Growth assessment\\n•Developmental assessment\\n•Assessment of family support needs.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF003370" ] } ] }, "evidenceCategory": { "outcomeEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei", "id": "CG-AC:AC1045/oei", "type": "EvidenceItem", "natureOfTheThreat": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/nott", "id": "CG-AC:AC1045/oei/nott", "type": "EvidenceLine", "prevalenceOfTheGeneticDisorder": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/pgd", "id": "CG-AC:AC1045/oei/pgd", "type": "EvidenceItem", "keyText": "< 1-2 in 100000", "sourceOfPopulation": "General population", "evidenceNarrative": { "@id": "CG-AC:AC1045/en/potgd" } }, "clinicalFeatures": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/cf", "id": "CG-AC:AC1045/oei/cf", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC1045/en/cf" } }, "naturalHistory": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/nh", "id": "CG-AC:AC1045/oei/nh", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC1045/en/nh" } } }, "threatMaterializationChances": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/tmc", "id": "CG-AC:AC1045/oei/tmc", "type": "EvidenceLine", "modeOfInheritance": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/moi", "id": "CG-AC:AC1045/oei/moi", "type": "EvidenceItem", "keyText": "Autosomal Dominant", "evidenceNarrative": { "@id": "CG-AC:AC1045/en/ACMI2736" } }, "prevalenceOfTheGeneticMutation": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/pgm", "id": "CG-AC:AC1045/oei/pgm", "type": "EvidenceItem", "keyText": ">1-2 in 100", "sourceOfPopulation": "General population", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/PGM2852" } }, "penetrance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/pe/ACPE4219", "id": "CG-AC:AC1045/oei/pe/ACPE4219", "type": "EvidenceItem", "keyText": ">= 40 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/ACPE4219" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/pe/ACPE4221", "id": "CG-AC:AC1045/oei/pe/ACPE4221", "type": "EvidenceItem", "keyText": "5-39 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/ACPE4221" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/pe/ACPE4220", "id": "CG-AC:AC1045/oei/pe/ACPE4220", "type": "EvidenceItem", "keyText": ">= 40 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/ACPE4220" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/pe/ACPE4218", "id": "CG-AC:AC1045/oei/pe/ACPE4218", "type": "EvidenceItem", "keyText": ">= 40 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/ACPE4218" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/pe/ACPE4222", "id": "CG-AC:AC1045/oei/pe/ACPE4222", "type": "EvidenceItem", "keyText": "5-39 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/ACPE4222" } } ], "relativeRisk": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/rr/RR2655", "id": "CG-AC:AC1045/oei/rr/RR2655", "type": "EvidenceItem", "keyText": ">3", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/RR2655" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/rr/RR2654", "id": "CG-AC:AC1045/oei/rr/RR2654", "type": "EvidenceItem", "keyText": "Unknown", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/RR2654" } } ], "expressivity": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/ex/EN2909", "id": "CG-AC:AC1045/oei/ex/EN2909", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/EN2909" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/ex/EN2911", "id": "CG-AC:AC1045/oei/ex/EN2911", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/EN2911" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/oei/ex/EN2910", "id": "CG-AC:AC1045/oei/ex/EN2910", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/EN2910" } } ] } }, "interventionEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei", "id": "CG-AC:AC1045/iei", "type": "EvidenceItem", "acceptabilityOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/aoi", "id": "CG-AC:AC1045/iei/aoi", "type": "EvidenceLine", "natureOfIntervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/noi/NOI2902", "id": "CG-AC:AC1045/iei/noi/NOI2902", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/NOI2902" } } ] }, "effectivenessOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/eoi", "id": "CG-AC:AC1045/iei/eoi", "type": "EvidenceLine", "patientManagement": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5851", "id": "CG-AC:AC1045/iei/pm/ACPM5851", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5851" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5854", "id": "CG-AC:AC1045/iei/pm/ACPM5854", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5854" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5844", "id": "CG-AC:AC1045/iei/pm/ACPM5844", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5844" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5845", "id": "CG-AC:AC1045/iei/pm/ACPM5845", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5845" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/REC2995", "id": "CG-AC:AC1045/iei/pm/REC2995", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/REC2995" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5848", "id": "CG-AC:AC1045/iei/pm/ACPM5848", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5848" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5852", "id": "CG-AC:AC1045/iei/pm/ACPM5852", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5852" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5853", "id": "CG-AC:AC1045/iei/pm/ACPM5853", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5853" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/REC2996", "id": "CG-AC:AC1045/iei/pm/REC2996", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/REC2996" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/REC2997", "id": "CG-AC:AC1045/iei/pm/REC2997", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/REC2997" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5846", "id": "CG-AC:AC1045/iei/pm/ACPM5846", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5846" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5849", "id": "CG-AC:AC1045/iei/pm/ACPM5849", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5849" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5847", "id": "CG-AC:AC1045/iei/pm/ACPM5847", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5847" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/pm/ACPM5850", "id": "CG-AC:AC1045/iei/pm/ACPM5850", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACPM5850" } } ], "circumstanceToAvoid": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/cta/ACCA3488", "id": "CG-AC:AC1045/iei/cta/ACCA3488", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACCA3488" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/cta/ACCA3491", "id": "CG-AC:AC1045/iei/cta/ACCA3491", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACCA3491" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/cta/ACCA3490", "id": "CG-AC:AC1045/iei/cta/ACCA3490", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACCA3490" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/cta/ACCA3487", "id": "CG-AC:AC1045/iei/cta/ACCA3487", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACCA3487" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/cta/ACCA3492", "id": "CG-AC:AC1045/iei/cta/ACCA3492", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACCA3492" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/cta/ACCA3489", "id": "CG-AC:AC1045/iei/cta/ACCA3489", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACCA3489" } } ], "surveillance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/su/ACSU3791", "id": "CG-AC:AC1045/iei/su/ACSU3791", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACSU3791" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/su/ACSU3790", "id": "CG-AC:AC1045/iei/su/ACSU3790", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACSU3790" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/su/ACSU3792", "id": "CG-AC:AC1045/iei/su/ACSU3792", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC1045/tr/ACSU3792" } } ] }, "conditionEscapeDetection": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/ced", "id": "CG-AC:AC1045/iei/ced", "type": "EvidenceLine", "chanceToEscapeDetection": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1045/iei/cted/CDEC2905", "id": "CG-AC:AC1045/iei/cted/CDEC2905", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC1045/ten/CDEC2905" } } ] } } }, "references": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/RF003361", "id": "CG-AC:RF003361", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. 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