This page is part of the MII Implementation Guide Seltene Erkrankungen (v2027.0.0-ballot: 2027 Ballot 1) based on FHIR (HL7® FHIR® Standard) R4. This is the current published version in its permanent home (it will always be available at this URL). For a full list of available versions, see the Directory of published versions

Clinical vs. Genetic Diagnosis

Overview

In the modeling of rare diseases we distinguish between two kinds of diagnosis:

1. Clinical diagnosis (MII_PR_Seltene_ClinicalDiagnosis) — based on phenotypic features
2. Genetic diagnosis (MII_PR_Seltene_GeneticDiagnosis) — molecularly confirmed

This distinction is important because many rare diseases are first suspected clinically and later confirmed genetically.

Clinical diagnosis

Usage

The clinical diagnosis is used when:

• The diagnosis is based on clinical findings and symptoms
• Genetic testing is still pending or not available
• The diagnosis is made phenotypically (e.g. for characteristic syndromes)

Specifics

• HPO codes: additional slice code.coding[hpo] (0..*), required-bound to the HPO phenotype code value set
• Phenotypic evidence: evidence.detail references HPO-coded symptom observations
• Verification status: not constrained by the profile (0..1, inherited required binding to condition-ver-status); "provisional" or "differential" are recommended while genetic confirmation is pending
• Category: category is mandatory (1..) but its value is not fixed — typically problem-list-item or encounter-diagnosis. Why the genetic diagnosis handles this differently is explained below under *Why the category differs.

Structural comparison

The spelled-out instances live with the profiles themselves; what matters here is the difference, not the syntax.

Genetic diagnosis

Usage

The genetic diagnosis is used when:

• The diagnosis has been confirmed by molecular genetic examination
• Pathogenic variants have been identified
• A definite genetic cause has been demonstrated

Specifics

• OMIM codes: additional slice for Online Mendelian Inheritance in Man codes
• Genetic evidence: evidence is mandatory (1..), evidence.detail (1..) references an Observation or DiagnosticReport. The profile does not constrain the target profiles; the MolGen resources are recommended:
  • MII_PR_MolGen_Variante for individual variants
  • MII_PR_MolGen_DiagnostischeImplikation for comprehensive genetic reports
• Genetic evidence marker: evidence.code.coding[geneticEvidence] carries 106221001 | Genetic finding |
• Verification status: not constrained by the profile; "confirmed" is recommended
• Additional genetic information: penetrance extension
• Category: MANDATORY: 782964007 | Genetic disease | for unambiguous labeling

Why the category differs

The two profiles treat category differently, and that deserves an explanation:

	category
Clinical diagnosis	mandatory, value free
Genetic diagnosis	mandatory, fixed value 782964007 \| Genetic disease \|

In FHIR, Condition.category answers the question of the condition's role in the record — the element's short text reads literally problem-list-item | encounter-diagnosis. The kind of disease belongs in Condition.code.

The clinical diagnosis follows that: it requires a category but prescribes no value. The genetic diagnosis additionally fixes a code — deliberately, for two reasons.

It is permitted. Condition.category is 0..* and bound extensibly to condition-category. An extensible binding explicitly allows codes outside the value set where none of them fits; FHIR itself notes on the element that the categorization is "often highly contextual".

It is needed. Whether a disease is genetically confirmed is not stated in Condition.code — that carries the disease itself — and cannot be derived from it, because the same disease may be confirmed clinically or genetically. The module carries that distinction in two separate profiles; category makes it searchable across registries.

To be distinguished from the retired value set mii-vs-seltene-clinical-diagnosis-category: that bound category module-wide to kinds of disease instead of the record role, and so answered the wrong question. This is a single, reasoned additional marker.

Open point for the ballot. patternCodeableConcept on a repeating element requires every repetition to match the pattern. A second category — encounter-diagnosis for the record role, say — is therefore not currently allowed, and all examples accordingly carry only this one value. An open slice requiring 782964007 while admitting further categories would be cleaner. That changes the published constraint shape and is therefore put up for comment.

Parallel diagnosis model

In rare diseases, clinical and genetic diagnoses exist in parallel:

The diagram shows all three stages: the suspected diagnosis from screening or first contact, the clinical diagnosis after phenotypic work-up, and the genetic diagnosis after molecular confirmation.

Important: The genetic diagnosis does NOT replace the clinical diagnosis. Both exist in parallel and complement each other.

Decision tree

The ClinicalImpression links the stages: problem → suspected diagnosis, finding → clinical diagnosis, finding → genetic diagnosis, investigation → examinations.

Practical notes

When to use which profile?

Situation	Profile	Verification status
Newborn screening positive	ClinicalDiagnosis	unconfirmed
Clinically unambiguous syndrome	ClinicalDiagnosis	provisional
Genetically confirmed	GeneticDiagnosis	confirmed
Clinically + genetically confirmed	Both profiles in parallel	confirmed
Excluded diagnosis	Corresponding profile	refuted
Differential diagnosis	ClinicalDiagnosis	differential

Linking diagnoses via ClinicalImpression

The ClinicalImpression links the different diagnostic stages:

1. problem: reference to the suspected diagnosis (reason for the examination)
2. finding: references to the confirmed diagnoses (clinical AND genetic)
3. investigation: references to the examinations performed

Both diagnoses remain as independent resources and document different aspects of the same disease.

Evidence linking

Clinical diagnosis:

• Evidence → Observation with HPO-coded symptoms
• Evidence → DiagnosticReport with clinical findings
• Evidence → ClinicalImpression with clinical assessment

Genetic diagnosis:

• Evidence → MolGen variant (Observation)
• Evidence → MolGen diagnostic implication (DiagnosticReport)
• Evidence → MolGen examined region (Observation)

Validation

Checklist, clinical diagnosis

• category set — mandatory (1..*)
• HPO code in code.coding[hpo] where the phenotype is known (the profile does not enforce it, but for rare diseases it carries the actual content)
• evidence.detail referencing phenotypic observations
• Appropriate verificationStatus

Checklist, genetic diagnosis

• category = 782964007 | Genetic disease | — mandatory, fixed value
• At least one evidence with evidence.detail — mandatory (1..*)
• OMIM code if available
• evidence.code.coding[geneticEvidence] = 106221001 | Genetic finding |
• verificationStatus = confirmed for a confirmed diagnosis

Excluded diagnoses

Important note

Excluded diagnoses (refuted) MUST also be documented!

For rare diseases, the documentation of excluded diagnoses is essential for:

• Avoiding redundant diagnostics
• Documenting the diagnostic process
• Supporting differential diagnoses
• Research and registry data

Modeling excluded diagnoses

Excluded diagnoses use the same profile as confirmed ones; only the status differs:

Field	Clinically excluded	Genetically excluded
Profile	MII_PR_Seltene_ClinicalDiagnosis	MII_PR_Seltene_GeneticDiagnosis
verificationStatus	refuted	refuted
clinicalStatus	inactive	inactive
Justification	note.text	note.text
Evidence	negative phenotypic finding	negative molecular finding

Best practices for excluded diagnoses

1. Always document when:
   • A suspected diagnosis has been refuted
   • Genetic tests are negative
   • Differential diagnoses are excluded
2. Mandatory information:
   • verificationStatus = refuted
   • clinicalStatus = inactive
   • Justification in note.text
   • Evidence if available
3. Temporal documentation:
   • recordedDate: when it was excluded
   • abatementDateTime: time of exclusion

Examples

Complete examples can be found in:

• SMA case example — diagnostic course from screening to genetic confirmation
• Marfan case example — clinical diagnosis with phenotypic features