Rare Disease Diagnosis Advisor

Systematic diagnosis support for rare diseases using phenotype matching, gene panel prioritization, and variant interpretation across Orphanet, OMIM, HPO, ClinVar, and structure-based analysis.

KEY PRINCIPLES

:

Report-first approach

- Create report file FIRST, update progressively

Phenotype-driven

- Convert symptoms to HPO terms before searching

Multi-database triangulation

- Cross-reference Orphanet, OMIM, OpenTargets

Evidence grading

- Grade diagnoses by supporting evidence strength

Actionable output

- Prioritized differential diagnosis with next steps

Genetic counseling aware

- Consider inheritance patterns and family history

English-first queries

- Always use English terms in tool calls (phenotype descriptions, gene names, disease names), even if the user writes in another language. Only try original-language terms as a fallback. Respond in the user's language

When to Use

Apply when user asks:

"Patient has [symptoms], what rare disease could this be?"

"Unexplained developmental delay with [features]"

"WES found VUS in [gene], is this pathogenic?"

"What genes should we test for [phenotype]?"

"Differential diagnosis for [rare symptom combination]"

Report-First Approach (MANDATORY)

Create the report file FIRST

:

[PATIENT_ID]_rare_disease_report.md

with all section headers and

[Researching...]

placeholders

Progressively update

as you gather data

Output separate data files

:

[PATIENT_ID]_gene_panel.csv

- Prioritized genes for testing

[PATIENT_ID]_variant_interpretation.csv

- If variants provided

Every finding MUST include source citation (ORPHA code, OMIM number, tool name).

See

REPORT_TEMPLATE.md

for the full template and example outputs for each phase.

Tool Parameter Corrections

Tool

WRONG Parameter

CORRECT Parameter

OpenTargets_get_associated_diseases_by_target_ensemblId

ensemblID

ensemblId

ClinVar_get_variant_by_id

variant_id

id

MyGene_query_genes

gene

q

gnomAD_get_variant_frequencies

variant

variant_id

Workflow Overview

Phase 1: Phenotype Standardization

Convert symptoms to HPO terms, identify core vs. variable features, note onset/inheritance

|

Phase 2: Disease Matching

Search Orphanet, cross-reference OMIM, query DisGeNET -> Ranked differential diagnosis

|

Phase 3: Gene Panel Identification

Extract genes from top diseases, validate with ClinGen, check expression (GTEx)

|

Phase 3.5: Expression & Tissue Context

CELLxGENE cell-type expression, ChIPAtlas regulatory context

|

Phase 3.6: Pathway Analysis

KEGG pathways, Reactome processes, IntAct protein interactions

|

Phase 4: Variant Interpretation (if provided)

ClinVar lookup, gnomAD frequency, computational predictions (CADD, AlphaMissense, EVE, SpliceAI)

|

Phase 5: Structure Analysis (for VUS)

AlphaFold2 prediction, domain impact assessment (InterPro)

|

Phase 6: Literature Evidence

PubMed studies, BioRxiv/MedRxiv preprints, OpenAlex citation analysis

|

Phase 7: Report Synthesis

Prioritized differential, recommended testing, next steps

For detailed code examples and algorithms for each phase, see

DIAGNOSTIC_WORKFLOW.md

.

Phase Summaries

Phase 1: Phenotype Standardization

Use

HPO_search_terms(query=symptom)

to convert each clinical description to HPO terms

Classify features as Core (always present), Variable (>50%), Occasional (<50%), or Age-specific

Record age of onset and family history for inheritance pattern hints

Phase 2: Disease Matching

Orphanet

:

Orphanet_search_diseases(operation="search_diseases", query=keyword)

then

Orphanet_get_genes(operation="get_genes", orpha_code=code)

for each hit

OMIM

:

OMIM_search(operation="search", query=gene)

then

OMIM_get_entry

and

OMIM_get_clinical_synopsis

for details

DisGeNET

:

DisGeNET_search_gene(operation="search_gene", gene=symbol)

for gene-disease association scores

Score phenotype overlap: Excellent (>80%), Good (60-80%), Possible (40-60%), Unlikely (<40%)

Phase 3: Gene Panel Identification

Extract genes from top candidate diseases

ClinGen validation

(critical):

ClinGen_search_gene_validity

,

ClinGen_search_dosage_sensitivity

,

ClinGen_search_actionability

ClinGen classification determines panel inclusion:

Definitive/Strong/Moderate: Include in panel

Limited: Include but flag

Disputed/Refuted: Exclude

Expression

Use

MyGene_query_genes

for Ensembl ID, then

GTEx_get_median_gene_expression

to confirm tissue expression

Prioritization scoring: Tier 1 (top disease gene +5), Tier 2 (multi-disease +3), Tier 3 (ClinGen Definitive +3), Tier 4 (tissue expression +2), Tier 5 (pLI >0.9 +1)

Phase 3.5: Expression & Tissue Context

CELLxGENE

:

CELLxGENE_get_expression_data

and

CELLxGENE_get_cell_metadata

for cell-type specific expression

ChIPAtlas

:

ChIPAtlas_enrichment_analysis

and

ChIPAtlas_get_peak_data

for regulatory context (TF binding)

Confirms candidate genes are expressed in disease-relevant tissues/cells

Phase 3.6: Pathway Analysis

KEGG

:

kegg_find_genes(query="hsa:{gene}")

then

kegg_get_gene_info

for pathway membership

IntAct

:

intact_search_interactions(query=gene, species="human")

for protein-protein interactions

Identify convergent pathways across candidate genes (strengthens candidacy)

Phase 4: Variant Interpretation (if provided)

ClinVar

:

ClinVar_search_variants(query=hgvs)

for existing classifications

gnomAD

:

gnomAD_get_variant_frequencies(variant_id=id)

for population frequency

Ultra-rare (<0.00001), Rare (<0.0001), Low frequency (<0.01), Common (likely benign)

Computational predictions

(for VUS):

CADD:

CADD_get_variant_score

- PHRED >=20 supports PP3

AlphaMissense:

AlphaMissense_get_variant_score

- pathogenic classification = strong PP3

EVE:

EVE_get_variant_score

- score >0.5 supports PP3

SpliceAI:

SpliceAI_predict_splice

- delta score >=0.5 indicates splice impact

ACMG criteria

PVS1 (null variant), PS1 (same AA change), PM2 (absent from pop), PP3 (computational), BA1 (>5% AF)

Consensus from 2+ concordant predictors strengthens PP3 evidence

Phase 5: Structure Analysis (for VUS)

Perform when: VUS, missense in critical domain, novel variant, or additional evidence needed

AlphaFold2

:

NvidiaNIM_alphafold2(sequence=seq, algorithm="mmseqs2")

for structure prediction

Domain impact

:

InterPro_get_protein_domains(accession=uniprot_id)

to check functional domains

Assess pLDDT confidence at variant position, domain location, structural role

Phase 6: Literature Evidence

PubMed

:

PubMed_search_articles(query="disease AND genetics")

for published studies

Preprints

:

BioRxiv_search_preprints

,

ArXiv_search_papers(category="q-bio")

for latest findings

Citations

:

openalex_search_works

for citation analysis of key papers

Note: preprints are not peer-reviewed; flag accordingly

Phase 7: Report Synthesis

Compile all phases into final report with evidence grading

Provide prioritized differential diagnosis with next steps

Include specialist referral suggestions and family screening recommendations

Evidence Grading

Tier

Criteria

Example

T1

(High)

Phenotype match >80% + gene match

Marfan with FBN1 mutation

T2

(Medium-High)

Phenotype match 60-80% OR likely pathogenic variant

Good phenotype fit

T3

(Medium)

Phenotype match 40-60% OR VUS in candidate gene

Possible diagnosis

T4

(Low)

Phenotype <40% OR uncertain gene

Low probability

Completeness Checklist

Phase 1 (Phenotype)

All symptoms as HPO terms, core vs. variable distinguished, onset documented, family history noted

Phase 2 (Disease Matching)

>=5 candidates (or all matching), overlap % calculated, inheritance patterns, ORPHA + OMIM IDs

Phase 3 (Gene Panel)

>=5 genes prioritized, ClinGen evidence level per gene, expression validated, testing strategy recommended

Phase 4 (Variants)

ClinVar classification, gnomAD frequency, ACMG criteria applied, classification justified

Phase 5 (Structure)

Structure predicted (if VUS), pLDDT reported, domain impact assessed, structural evidence summarized
Phase 6 (Recommendations): =3 next steps, specialist referrals, family screening addressed See CHECKLIST.md for the full interactive checklist. Fallback Chains Primary Tool Fallback 1 Fallback 2 Orphanet_search_by_hpo OMIM_search PubMed phenotype search ClinVar_get_variant gnomAD_get_variant VEP annotation NvidiaNIM_alphafold2 alphafold_get_prediction UniProt features GTEx_expression HPA_expression Tissue-specific literature gnomAD_get_variant ExAC_frequencies 1000 Genomes Reference Files DIAGNOSTIC_WORKFLOW.md - Detailed code examples and algorithms for each phase REPORT_TEMPLATE.md - Report template, phase output examples, CSV formats TOOLS_REFERENCE.md - Complete tool documentation CHECKLIST.md - Interactive completeness checklist EXAMPLES.md - Worked diagnosis examples

tooluniverse-rare-disease-diagnosis

安装