Module 7 · Part 2 · Data Architecture

HPO, GA4GH & Phenopackets

Understand the Human Phenotype Ontology (HPO), the GA4GH data sharing framework, and Phenopackets, the emerging standard for exchanging participant phenotype and genomic data.

Patient Registries 101 · Dr. Danielle Boyce · EpilepsyLive

What is HPO?

The Human Phenotype Ontology is a standardized vocabulary of over 18,000 terms describing human phenotypic abnormalities, symptoms, clinical findings, and disease features.
HPO was developed by the Monarch Initiative and is now the international standard for phenotype description in rare disease research.
hpo.jax.org

Why your registry needs HPO

Without HPO, "seizure" in your registry and "convulsion" in a collaborator's registry may or may not mean the same thing.
This is very important for
Genotype phenotype analysis , Linking specific genetic variants to specific clinical features
Cross-registry comparison , Comparing phenotype frequencies across institutions
Diagnosis support , Tools like Phenomizer and LIRICAL use HPO terms to suggest diagnoses
GA4GH / Phenopackets , HPO is the phenotype backbone of the Phenopackets standard (see below)

Implementing HPO in your registry

Map each clinical feature you collect to the most specific applicable HPO term
For each feature, record: HPO term ID, observation status (present/absent/unknown), age at onset, severity modifier
Use HPO's own browser to identify appropriate terms: hpo.jax.org
Avoid creating custom phenotype terms, if the concept exists in HPO, use it

Related ontologies

OMIM (Online Mendelian Inheritance in Man): Gene-disease relationships, omim.org
HGNC (HUGO Gene Nomenclature Committee): Standardized gene symbols, genenames.org
ClinVar: Variant-disease assertions, ncbi.nlm.nih.gov/clinvar

What is GA4GH?

GA4GH is an international standards-setting body that develops frameworks and technical standards for responsible genomic and health data sharing.
ga4gh.org

The GA4GH Framework for Responsible Sharing

The GA4GH framework, adopted by hundreds of institutions globally, establishes principles for
Data access: Who can access genomic data and under what conditions
Data security: Technical standards for protecting genomic data in transit and at rest
Ethics: Consent standards, benefit sharing, vulnerable populations
Identity management: How individuals are identified across systems
Even if your registry doesn't immediately involve genomics, aligning with the GA4GH framework builds credibility with academic and industry partners who operate within it.

What is a Phenopacket?

A Phenopacket is a structured, computable representation of a participant's phenotype, medical history, and genomic data.
The Phenopacket schema (v2) includes
Subject: Individual ID, date of birth, sex, taxonomy
Phenotypic features: HPO coded observations with onset, severity, and status (present/absent)
Diseases: OMIM/ORDO-coded diagnoses with onset
Measurements: LOINC-coded lab values and clinical measurements

What is a Phenopacket? (cont.)

Genomic interpretations: Variant data with ACMG classifications
Medical actions: Treatments, procedures, doses
Family history: Pedigree information
github.com/phenopackets/phenopacket-schema

Why Phenopackets matter for your registry

Phenopackets are becoming the submission standard for
NCBI ClinVar , Variant submissions increasingly require Phenopacket format
Matchmaker Exchange , Connecting undiagnosed participants globally
ERDERA , European rare disease data sharing networks
Monarch Initiative , Cross-species phenotype analysis
GA4GH Beacon , Federated data discovery

Why Phenopackets matter for your registry (cont.)

Designing your registry to export Phenopackets from the start means your data is immediately accessible to this entire ecosystem.

Getting started with Phenopackets

Review the Phenopackets v2 schema documentation: phenopackets.readthedocs.io
Use the Python or Java SDK for programmatic creation
Validate Phenopackets with the official validator before submission
Map your existing data elements to Phenopacket fields

Checklist

[ ] HPO terms mapped to all phenotypic features in registry
[ ] HPO term IDs stored alongside display labels (not just text)
[ ] OMIM and/or ORDO codes assigned to diagnoses
[ ] HGNC gene symbols used for all genetic data
[ ] Reviewed GA4GH Framework for data sharing alignment
[ ] Evaluated whether Phenopacket export is feasible with chosen platform

Checklist (cont.)

[ ] Consent language covers genomic data sharing via GA4GH-compliant networks

Key resources

Human Phenotype Ontology
GA4GH
Phenopackets Schema v2
Monarch Initiative
Matchmaker Exchange
ClinVar

Key resources (cont.)

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