{ "@context": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/context/doc", "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010", "id": "CG-AC:AC010", "type": "ClinicalActionabilityReport", "metadata": { "schemaLabel": "AC-Sepio.Beta-1 (Unofficial)", "contentVersionId": "26270", "producedAtUTC": "Thu, 10 Sep 2026 19:39:26 -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/AC010/co", "id": "CG-AC:AC010/co", "type": "GeneticCondition", "label": "Hypophosphatemic rickets, autosomal dominant" }, "outcome": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/ou/Morbidity%20of%20ADHR%20%28rickets%2C%20growth%2C%20bone%2Fjoint%20pain%29", "id": "CG-AC:AC010/ou/Morbidity of ADHR (rickets, growth, bone/joint pain)", "type": "Outcome", "label": "Morbidity of ADHR (rickets, growth, bone/joint pain)" } ], "intervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/intv/Oral%20phosphate%20plus%20vitamin%20D%20analog%20supplements", "id": "CG-AC:AC010/intv/Oral phosphate plus vitamin D analog supplements", "type": "Intervention", "label": "Oral phosphate plus vitamin D analog supplements" } ], "clinicalActionabilityProfile": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/cap", "id": "CG-AC:AC010/cap", "type": "Assertion", "assertionMethod": "The ClinGen AWG developed a standardized protocol to generate evidence-based profiles of clinical actionability of genes and associated disorders in the form of summary reports and semiquantitative metric (SQM) scores.", "releaseDate": "Wed, 09 Feb 2022 00:00:00 -0000", "releaseNum": "1.2.3", "media": "call" }, "evidenceStatements": { "evidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/en/ACMI2553", "id": "CG-AC:AC010/en/ACMI2553", "type": "EvidenceNarrative", "narrative": "Autosomal Dominant", "evidenceDomainTag": "Threat Materialization Chances.Modes of Inheritance", "publication": [ "CG-AC:RF002099", "CG-AC:RF002098" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/en/potgd", "id": "CG-AC:AC010/en/potgd", "type": "EvidenceNarrative", "narrative": "The population prevalence of autosomal dominant hypophosphatemic rickets (ADHR) is <1 in 1,000,000. Fewer than 100 cases have been described.", "evidenceDomainTag": "Nature of the Threat.Prevalence of the Genetic Disorder", "publication": [ "CG-AC:RF002099" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/en/cf", "id": "CG-AC:AC010/en/cf", "type": "EvidenceNarrative", "narrative": "ADHR is caused by mutations in the FGF23 gene which leads to inappropriately high intact FGF23 levels. ADHR is characterized by isolated renal phosphate wasting, hypophosphatemia, rickets and inappropriately low or normal calcitriol levels. During childhood ADHR presents with short stature and rickets affecting primarily lower extremity deformities. During adulthood clinical findings include bone pain, fatigue, muscle weakness, and repeated fractures.", "evidenceDomainTag": "Nature of the Threat.Clinical Features", "publication": [ "CG-AC:RF002099", "CG-AC:RF002098", "CG-AC:RF002100" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/en/nh", "id": "CG-AC:AC010/en/nh", "type": "EvidenceNarrative", "narrative": "Clinical manifestations depend on the age of onset (childhood, adolescence, adulthood) and on the severity of hypophosphatemia. In contrast to other inherited disorders of FGF23 excess (e.g., X-linked hypophosphatemia), ADHR shows incomplete penetrance and variable time of onset in the clinical phenotype. Two subgroups of patients appear to exist within ADHR. Patients may present in childhood with rickets and hypophosphatemia with some patients normalizing serum phosphate spontaneously as they age. A second group, primarily female, appears to grow normally and do not have hypophosphatemia but present in adolescence or adulthood with phosphatemic osteomalacia. These adults with delayed onset can also spontaneously normalize serum phosphate with a resolution of clinical symptoms. The timing and predisposing factors the waxing and waning of symptoms are largely unknown, recent evidence has indicated that changes in iron status may contribute to the changes in phenotype.", "evidenceDomainTag": "Nature of the Threat.Natural History", "publication": [ "CG-AC:RF002099", "CG-AC:RF002098", "CG-AC:RF002101", "CG-AC:RF002102", "CG-AC:RF002103" ] } ], "tieredEvidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/ten/CDEC2664", "id": "CG-AC:AC010/ten/CDEC2664", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Patients may have a delayed onset of phenotype and may display features that are not seen in other hereditary phosphaturic disorders, this may lead to difficulties in establishing the presence of the disorder.", "evidenceDomainTag": "Condition Escape Detection.Chances to Escape Clinical Detection", "publication": [ "CG-AC:RF002101" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/ten/NOI2680", "id": "CG-AC:AC010/ten/NOI2680", "type": "TieredEvidenceNarrative", "narrative": "In general, prescribing phosphate intake in disorders of phosphate wasting is a balance between excessive dosage tending to hyperparathyroidism and insufficient dosage slowing the healing of rickets. Toxicity from vitamin D analog supplementation may result in hypercalciuria, requiring monitoring of urinary calcium and creatinine. As for many chronic diseases, compliance to oral treatment in phosphate wasting is a major issue, even in expert hands. No specific harms of treatment in ADHR were identified.", "evidenceDomainTag": "Acceptability of Intervention.Natures of Intervention", "publication": [ "CG-AC:RF002100" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/ten/ACPE3629", "id": "CG-AC:AC010/ten/ACPE3629", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "ADHR exhibits incomplete penetrance. The onset of the features may be delayed and there is occasional resolution of the phosphate-wasting defect.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF002098" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/ten/PGM2622", "id": "CG-AC:AC010/ten/PGM2622", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "No information on prevalence of pathogenic variants causing ADHR was identified. Fewer than 100 cases have been described.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation", "publication": [ "CG-AC:RF002099" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/ten/EN2666", "id": "CG-AC:AC010/ten/EN2666", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Presentation is variable among families even within the same pedigree with patients’ presentations ranging from age 1 to 45 with variable clinical features.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF002098" ] } ], "tieredRecommendations": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/tr/REC2718", "id": "CG-AC:AC010/tr/REC2718", "type": "TieredRecommendation", "evidenceSourceTier": "5", "recommendation": "However, there is some evidence that current treatment strategies may actually increase the production of FGF23. Thus, some authors have suggested the normalization of FGF23 concentration that occurs in some patients is likely due to an intrinsic physiologic alternation in the patient’s metabolism of FGF23, leading to resolution of ADHR features and observed delayed penetrance.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF002104" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/tr/ACPM4848", "id": "CG-AC:AC010/tr/ACPM4848", "type": "TieredRecommendation", "evidenceSourceTier": "3", "recommendation": "There have been case reports of individuals with ADHR presenting during childhood and adolescence/adulthood responding to treatment with phosphate and high doses of vitamin D analogs.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF002098" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/tr/ACPM4849", "id": "CG-AC:AC010/tr/ACPM4849", "type": "TieredRecommendation", "evidenceSourceTier": "4", "recommendation": "Treatment aims at improving growth, bone or joint pain, enhancing mineralization of bones, and preventing skeletal deformities caused by rickets. It consists of daily oral administration of phosphate and calcitriol. Calcitriol is given to prevent secondary hyperparathyroidism that can be caused by phosphate administration.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF002099" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/tr/ACSU3364", "id": "CG-AC:AC010/tr/ACSU3364", "type": "TieredRecommendation", "evidenceSourceTier": "4", "recommendation": "Individuals should undergo frequent monitoring of height, calcium, alkaline phosphatase, parathyroid hormone, and phosphate serum concentrations, as well as urinary calcium and creatinine.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF002099" ] } ] }, "evidenceCategory": { "outcomeEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei", "id": "CG-AC:AC010/oei", "type": "EvidenceItem", "natureOfTheThreat": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei/nott", "id": "CG-AC:AC010/oei/nott", "type": "EvidenceLine", "prevalenceOfTheGeneticDisorder": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei/pgd", "id": "CG-AC:AC010/oei/pgd", "type": "EvidenceItem", "keyText": "< 1-2 in 100000", "sourceOfPopulation": "General population", "evidenceNarrative": { "@id": "CG-AC:AC010/en/potgd" } }, "clinicalFeatures": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei/cf", "id": "CG-AC:AC010/oei/cf", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC010/en/cf" } }, "naturalHistory": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei/nh", "id": "CG-AC:AC010/oei/nh", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC010/en/nh" } } }, "threatMaterializationChances": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei/tmc", "id": "CG-AC:AC010/oei/tmc", "type": "EvidenceLine", "modeOfInheritance": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei/moi", "id": "CG-AC:AC010/oei/moi", "type": "EvidenceItem", "keyText": "Autosomal Dominant", "evidenceNarrative": { "@id": "CG-AC:AC010/en/ACMI2553" } }, "prevalenceOfTheGeneticMutation": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei/pgm", "id": "CG-AC:AC010/oei/pgm", "type": "EvidenceItem", "keyText": "Unknown", "sourceOfPopulation": "General population", "tieredEvidenceNarrative": { "@id": "CG-AC:AC010/ten/PGM2622" } }, "penetrance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei/pe/ACPE3629", "id": "CG-AC:AC010/oei/pe/ACPE3629", "type": "EvidenceItem", "keyText": "Unknown", "tieredEvidenceNarrative": { "@id": "CG-AC:AC010/ten/ACPE3629" } } ], "expressivity": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/oei/ex/EN2666", "id": "CG-AC:AC010/oei/ex/EN2666", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC010/ten/EN2666" } } ] } }, "interventionEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei", "id": "CG-AC:AC010/iei", "type": "EvidenceItem", "acceptabilityOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei/aoi", "id": "CG-AC:AC010/iei/aoi", "type": "EvidenceLine", "natureOfIntervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei/noi/NOI2680", "id": "CG-AC:AC010/iei/noi/NOI2680", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC010/ten/NOI2680" } } ] }, "effectivenessOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei/eoi", "id": "CG-AC:AC010/iei/eoi", "type": "EvidenceLine", "patientManagement": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei/pm/ACPM4849", "id": "CG-AC:AC010/iei/pm/ACPM4849", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC010/tr/ACPM4849" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei/pm/ACPM4848", "id": "CG-AC:AC010/iei/pm/ACPM4848", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC010/tr/ACPM4848" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei/pm/REC2718", "id": "CG-AC:AC010/iei/pm/REC2718", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC010/tr/REC2718" } } ], "surveillance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei/su/ACSU3364", "id": "CG-AC:AC010/iei/su/ACSU3364", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC010/tr/ACSU3364" } } ] }, "conditionEscapeDetection": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei/ced", "id": "CG-AC:AC010/iei/ced", "type": "EvidenceLine", "chanceToEscapeDetection": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC010/iei/cted/CDEC2664", "id": "CG-AC:AC010/iei/cted/CDEC2664", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC010/ten/CDEC2664" } } ] } } }, "references": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/RF002098", "id": "CG-AC:RF002098", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Hypophosphatemic rickets, autosomal dominant; adhr. MIM: 1931002010 Oct 04. ", "webUrl": "https://www.omim.org/entry/193100", "xdbref": [ "OMIM:193100" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/RF002099", "id": "CG-AC:RF002099", "type": "Publication", "publicationType": "Orphanet", "citation": "Autosomal dominant hypophosphatemic rickets. Orphanet encyclopedia [Internet]", "xdbref": [ "Orphanet:89937" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/RF002100", "id": "CG-AC:RF002100", "type": "Publication", "publicationType": "PMID", "citation": "Linglart A, Biosse-Duplan M, Briot K, Chaussain C, Esterle L, Guillaume-Czitrom S, Kamenicky P, Nevoux J, Prie D, Rothenbuhler A, Wicart P, Harvengt P. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. (2014) 3(1):R13-30.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=24550322", "xdbref": [ "PMID:24550322" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/RF002101", "id": "CG-AC:RF002101", "type": "Publication", "publicationType": "PMID", "citation": "Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab. (1997) 82(2):674-81.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=9024275", "xdbref": [ "PMID:9024275" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/RF002102", "id": "CG-AC:RF002102", "type": "Publication", "publicationType": "PMID", "citation": "Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. (2011) 96(11):3541-9.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=21880793", "xdbref": [ "PMID:21880793" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/RF002103", "id": "CG-AC:RF002103", "type": "Publication", "publicationType": "PMID", "citation": "Kapelari K, Kohle J, Kotzot D, Hogler W. Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets. J Clin Endocrinol Metab. (2015) 100(9):3388-92.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=26186302", "xdbref": [ "PMID:26186302" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/RF002104", "id": "CG-AC:RF002104", "type": "Publication", "publicationType": "PMID", "citation": "Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. (2007) 22(4):520-6.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=17227222", "xdbref": [ "PMID:17227222" ] } ] }