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Phenotype Profiles

This ingest aggregates phenotype profile data from curated sources. Currently it includes data from the Human Phenotype Ontology Annotations (HPOA) and Orphanet gene-disease associations (Orphanet product 6).

HPOA

The Human Phenotype Ontology group curates and assembles over 115,000 annotations to hereditary diseases using the HPO ontology. This ingest transforms HPOA data into gene-phenotype, disease-phenotype, gene-disease, and disease-inheritance associations.

Data Sources

Gene to Phenotype

Gene-to-phenotype associations derived from HPOA, with disease context preserved. A preprocessing step joins the genes_to_phenotype file with disease mappings and Mondo SSSOM to normalize disease IDs to MONDO where possible (ORPHA: prefixes are also normalized to Orphanet: for SSSOM compatibility).

Only rows whose gene-to-disease association is MENDELIAN are kept, since HPOA's genes_to_phenotype.txt itself applies no type filter (it includes candidate genes, biomarkers and somatic associations). For OMIM diseases the association type comes from HPOA's genes_to_disease.txt; for Orphanet diseases, where HPOA reports every row as UNKNOWN, it comes from Orphanet product 6 (see Orphanet Gene to Disease): Disease-causing germline mutation(s) (plain, loss of function or gain of function) with status Assessed.

Frequency data is captured in multiple forms: as HPO frequency qualifier terms (HP:0040280-HP:0040285), as percentages, or as counts/totals from cohort data.

Biolink Captured:

  • biolink:GeneToPhenotypicFeatureAssociation
    • id (UUID)
    • subject (NCBIGene:{id})
    • predicate (biolink:has_phenotype)
    • object (HPO term ID)
    • disease_context_qualifier (MONDO or original disease ID)
    • frequency_qualifier (HPO frequency term, when available)
    • has_percentage (percentage, when available)
    • has_quotient (quotient, when available)
    • has_count (numerator from cohort ratio, when available)
    • has_total (denominator from cohort ratio, when available)
    • publications
    • primary_knowledge_source (infores:hpo-annotations)
    • aggregator_knowledge_source (["infores:monarchinitiative"])
    • knowledge_level (logical_entailment)
    • agent_type (automated_agent)

Disease to Phenotype

Disease-to-phenotype associations from the phenotype.hpoa file, filtered to only "P" (phenotypic anomaly) aspect records. Includes rich annotation data: evidence codes, sex qualifiers, onset, and frequency information.

The primary knowledge source is determined by the disease ID prefix: OMIM diseases use infores:omim, Orphanet diseases use infores:orphanet, and DECIPHER diseases use infores:decipher.

Biolink Captured:

  • biolink:DiseaseToPhenotypicFeatureAssociation
    • id (UUID)
    • subject (disease ID, with ORPHA: normalized to Orphanet:)
    • predicate (biolink:has_phenotype)
    • negated (true when qualifier is "NOT")
    • object (HPO term ID)
    • has_evidence (ECO term mapped from 3-letter evidence code)
    • sex_qualifier (PATO term: PATO:0000383 female, PATO:0000384 male)
    • onset_qualifier (HPO onset term, when available)
    • frequency_qualifier (HPO frequency term, when available)
    • has_percentage, has_quotient, has_count, has_total (frequency data)
    • publications
    • primary_knowledge_source (determined by disease prefix)
    • aggregator_knowledge_source (["infores:monarchinitiative", "infores:hpo-annotations"])
    • knowledge_level (knowledge_assertion)
    • agent_type (manual_agent)

Evidence Code Mapping

HPOA Code ECO Term Label
IEA ECO:0000501 inferred from electronic annotation
PCS ECO:0006017 published clinical study evidence
TAS ECO:0000304 traceable author statement
ICE ECO:0006019 individual clinical experience evidence

Orphanet Gene to Disease

Gene-to-disease associations read directly from Orphanet product 6 (en_product6.xml). HPOA's genes_to_disease.txt collapses every Orphanet row to association_type = UNKNOWN, so until this transform existed no Orphanet-curated gene-disease association could be causal in Monarch, and none could feed gene-to-phenotype inference (monarch-app#1488). OMIM gene-to-disease associations are produced by omim-ingest, not here.

A preprocessing step (scripts/orphanet_gene_to_disease_extras.py) flattens the XML to data/orphanet_gene_to_disease.tsv, resolving each gene to an NCBIGene id through the HGNC complete set (by HGNC id, falling back to symbol). Genes that cannot be resolved (withdrawn HGNC locus entries such as SPG34, snoRNA clusters such as SNORD116@) are counted and skipped.

The Orphanet DisorderGeneAssociationType and DisorderGeneAssociationStatus determine the Biolink class and predicate:

Orphanet association type Status Biolink Class Predicate Notes
Disease-causing germline mutation(s) in Assessed CausalGeneToDiseaseAssociation biolink:causes feeds g2p inference
Disease-causing germline mutation(s) (loss of function) in Assessed CausalGeneToDiseaseAssociation biolink:causes subject_form_or_variant_qualifier = loss_of_function_variant_form; feeds g2p inference
Disease-causing germline mutation(s) (gain of function) in Assessed CausalGeneToDiseaseAssociation biolink:causes subject_form_or_variant_qualifier = gain_of_function_variant_form; feeds g2p inference
Disease-causing somatic mutation(s) in Assessed CausalGeneToDiseaseAssociation biolink:causes not treated as Mendelian: does not feed g2p inference
Major susceptibility factor in Assessed CorrelatedGeneToDiseaseAssociation biolink:contributes_to
Modifying germline mutation in Assessed CorrelatedGeneToDiseaseAssociation biolink:contributes_to
Candidate gene tested in any CorrelatedGeneToDiseaseAssociation biolink:gene_associated_with_condition
Biomarker tested in any CorrelatedGeneToDiseaseAssociation biolink:gene_associated_with_condition
Part of a fusion gene in any CorrelatedGeneToDiseaseAssociation biolink:gene_associated_with_condition
Role in the phenotype of any CorrelatedGeneToDiseaseAssociation biolink:gene_associated_with_condition chromosomal-syndrome case (e.g. 22q11.2 deletion / TBX1); never causal
any type Not yet assessed CorrelatedGeneToDiseaseAssociation biolink:gene_associated_with_condition

The original Orphanet association type is kept verbatim in original_predicate, the status in qualifiers, and the HGNC id in original_subject. SourceOfValidation PMIDs become publications. Orphanet's product 9 inheritance is not used: inheritance is per disorder, not per gene, so multi-valued lists cannot be resolved to a gene.

Biolink Captured:

  • biolink:CausalGeneToDiseaseAssociation / biolink:CorrelatedGeneToDiseaseAssociation
    • id
    • subject (NCBIGene:{id}, resolved via HGNC)
    • predicate (mapped from association type and status, see above)
    • object (Orphanet:{OrphaCode})
    • original_subject (HGNC:{id})
    • original_predicate (Orphanet DisorderGeneAssociationType label)
    • qualifiers (Orphanet DisorderGeneAssociationStatus: Assessed or Not yet assessed)
    • subject_form_or_variant_qualifier (loss/gain of function, causal associations only)
    • publications (PMIDs from SourceOfValidation)
    • primary_knowledge_source (infores:orphanet)
    • aggregator_knowledge_source (["infores:monarchinitiative"])
    • knowledge_level (knowledge_assertion)
    • agent_type (manual_agent)

Disease Mode of Inheritance

Disease-to-inheritance associations from the phenotype.hpoa file, filtered to "I" (inheritance) aspect records. Only rows where the HPO term is a descendant of "Mode of inheritance" (HP:0000005) in the HP ontology are included.

Biolink Captured:

  • biolink:DiseaseOrPhenotypicFeatureToGeneticInheritanceAssociation
    • id (UUID)
    • subject (disease ID)
    • predicate (biolink:has_mode_of_inheritance)
    • object (HPO inheritance term ID)
    • has_evidence (ECO term mapped from evidence code)
    • publications
    • primary_knowledge_source (infores:hpo-annotations)
    • aggregator_knowledge_source (["infores:monarchinitiative"])
    • knowledge_level (knowledge_assertion)
    • agent_type (manual_agent)

Orphanet Citation

Orphanet: an online database of rare diseases and orphan drugs. Copyright, INSERM 1997. Available at https://www.orpha.net. Data: Orphadata, https://www.orphadata.com, licensed under CC BY 4.0.

HPOA Citation

Kohler S, Gargano M, Matentzoglu N, Carmody LC, Lewis-Smith D, Vasilevsky NA, Danis D, et al. The Human Phenotype Ontology in 2024: Phenotype-Based Knowledge for Rare Disease Discovery. Nucleic Acids Research. 2024;52(D1):D1333-D1346. doi: 10.1093/nar/gkad1005. PMID: 37953324

License

BSD-3-Clause