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Rare Disease Diagnosis Checklist

Pre-delivery verification checklist for rare disease diagnostic reports.

Report Quality Checklist

Structure & Format

  • Report file created: [PATIENT_ID]_rare_disease_report.md
  • All 8 main sections present
  • Executive summary completed (not [Researching...])
  • Data sources section populated

Phase 1: Phenotype Standardization

  • All clinical features converted to HPO terms
  • HPO IDs provided for each term
  • Core features distinguished from variable
  • Age of onset documented
  • Family history recorded (or "Unknown")
  • Inheritance pattern suspected (AD/AR/XL/Unknown)

Phase 2: Disease Matching

  • ≥5 candidate diseases identified (or all if fewer match)
  • Each disease has ORPHA ID
  • Each disease has OMIM ID (if available)
  • Phenotype match % calculated for each
  • Diseases ranked by match score
  • Inheritance pattern for each disease
  • Causative genes listed for each disease
  • Top 3 diseases have detailed feature comparison

Phase 3: Gene Panel

  • ≥5 genes in recommended panel (or all from top diseases)
  • Each gene has evidence level (ClinGen: Definitive/Strong/Moderate)
  • Constraint scores (pLI) provided
  • Expression validation for relevant tissue
  • Genes prioritized by tier (★★★/★★☆/★☆☆)
  • Testing strategy recommended (single gene vs panel vs WES)
  • Cost-effectiveness considered

Phase 4: Variant Interpretation (if variants provided)

  • ClinVar ID and classification retrieved
  • gnomAD allele frequency checked
  • Population-specific frequencies noted
  • CADD/REVEL scores obtained
  • ACMG criteria systematically applied
  • Each criterion has evidence documented
  • Preliminary classification stated
  • Confidence in classification noted

Phase 5: Structure Analysis (if VUS)

  • NVIDIA_API_KEY availability documented
  • Structure prediction method stated
  • pLDDT confidence at variant position reported
  • Domain location assessed
  • Conservation data included
  • Nearby pathogenic variants noted
  • Structural evidence summarized
  • Impact on ACMG classification stated

Phase 6: Recommendations

  • ≥3 specific next steps listed
  • Priority order for actions
  • Specialist referrals suggested (genetics, cardiology, etc.)
  • Family screening recommendations
  • Follow-up timeline suggested
  • Genetic counseling mentioned

Phase 7: Data Gaps

  • All gaps aggregated in one section
  • Reason for each gap documented
  • Alternative approaches suggested

Citation Requirements

Every Section Must Include

  • Source database name
  • Tool used (in backticks)
  • Specific identifiers (ORPHA, OMIM, HP, etc.)

Format Examples

*Source: Orphanet via `Orphanet_558` (ORPHA:558)*
*Source: OMIM via `OMIM_get_entry` (MIM:154700)*
*Source: HPO via `HPO_search_terms` (HP:0001166)*
*Source: ClinVar via `ClinVar_get_variant` (VCV000012345)*
*Source: gnomAD via `gnomAD_get_variant_frequencies` (AF: 0.00001)*
*Source: NVIDIA NIM via `NvidiaNIM_alphafold2` (pLDDT: 85.3)*

Evidence Grading

All Diagnoses Must Have

  • Evidence tier assigned (★★★ to ☆☆☆)
  • Phenotype match % documented
  • Genetic evidence level (if variant found)

Tier Definitions

Tier Symbol Criteria
T1 ★★★ Phenotype >80% + pathogenic variant OR clinical diagnosis met
T2 ★★☆ Phenotype 60-80% OR likely pathogenic variant
T3 ★☆☆ Phenotype 40-60% OR VUS in candidate gene
T4 ☆☆☆ Phenotype <40% OR no supporting genetic evidence

Quantified Minimums

Section Minimum Requirement
HPO terms ≥5 standardized terms
Candidate diseases ≥5 ranked diseases (or all matching)
Disease details Top 3 with full feature comparison
Gene panel ≥5 genes with evidence levels
ACMG criteria All applicable criteria evaluated
Recommendations ≥3 specific next steps

Phenotype-Specific Checks

Connective Tissue Phenotypes

  • Cardiac features assessed (aortic root, mitral valve)
  • Skeletal features documented (height, proportions)
  • Ocular features checked (lens, myopia)
  • Skin findings noted (striae, elasticity)
  • Ghent criteria referenced (if Marfan suspected)

Neurological Phenotypes

  • Developmental milestones documented
  • Seizure history (type, onset, frequency)
  • MRI findings (if available)
  • Cognitive assessment
  • Movement disorders noted

Metabolic Phenotypes

  • Biochemical markers (if available)
  • Dietary history relevant
  • Acute decompensation episodes
  • Treatment response history

Output Files

Required

  • [PATIENT_ID]_rare_disease_report.md - Main report

Optional (if applicable)

  • [PATIENT_ID]_gene_panel.csv - Prioritized genes
  • [PATIENT_ID]_variant_interpretation.csv - Variant details

CSV Column Requirements

gene_panel.csv:

Gene,Evidence_Level,Constraint_pLI,Associated_Diseases,Priority_Tier

variant_interpretation.csv:

Variant,Gene,ClinVar_Class,gnomAD_AF,ACMG_Criteria,Classification

Final Review

Before Delivery

  • No [Researching...] placeholders remaining
  • All tables properly formatted
  • No empty sections (use "Not applicable" if needed)
  • Executive summary synthesizes key findings
  • Most likely diagnosis clearly stated
  • Recommendations are actionable
  • Report is understandable to referring clinician

Common Issues to Avoid

  • HPO terms without IDs
  • Diseases without ORPHA/OMIM identifiers
  • Variants without population frequency
  • ACMG classification without documented criteria
  • Recommendations without priority order
  • Missing family history implications

Urgent Findings Protocol

If any of these found, flag prominently:

  • Pathogenic variant in actionable gene
  • High suspicion for condition requiring immediate intervention
  • Cardiac abnormality suggesting aortic pathology
  • Metabolic emergency risk
  • Cancer predisposition syndrome