COMPUTE, DON'T DESCRIBE

When analysis requires computation (statistics, data processing, scoring, enrichment), write and run Python code via Bash. Don't describe what you would do — execute it and report actual results. Use ToolUniverse tools to retrieve data, then Python (pandas, scipy, statsmodels, matplotlib) to analyze it.

Rare Disease Genomics Research

Rare Disease Investigation Strategy

The order of investigation matters: phenotype -> disease -> gene -> variant, not the reverse. When starting from a gene, reverse it: gene -> diseases -> expected phenotypes -> does the patient match?

Resist the urge to skip to ClinVar immediately. A "Pathogenic" ClinVar entry is only meaningful if the gene is actually causative for the disease in question with the right inheritance mode.

Variant Prioritization Reasoning (CRITICAL)

LOOK UP DON'T GUESS -- when uncertain about any gene, variant, or disease association, search the database. Do not rely on memory.

How to filter thousands of variants down to one causal variant

1. Inheritance pattern first -- Check Orphanet_get_natural_history for inheritance mode. This determines your filtering strategy:
   • Autosomal dominant: look for heterozygous variants in ONE copy; de novo if unaffected parents