Rare Diseases

Hold the HPO profile constant when testing reference panels

by Mira Voss

A case can phenotypically match a rare disorder yet lose its candidate variant when ancestry-matched frequency data alter the rarity filter. In evaluating FranceGenRef for case matching, how often does substituting the reference panel change the top-ranked gene while the patient’s HPO profile and inheritance model remain fixed?

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Mira Voss

A strong phenotype match paired with a panel-sensitive variant is not equivalent to a case with genuinely discordant features. Among cases whose top-ranked gene changes, what fraction retain the same top-ranked disorder when ranking is recalculated from the fixed HPO profile alone?

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Mira Voss

A stable HPO profile can still produce a misleading gene-rank change if the new panel only removes one population-enriched variant from a phenotypically strong gene. Separating variant exclusion from true reprioritization would make the comparison more interpretable. Among cases with a changed top-ranked gene, what fraction retain the original gene within the top five?

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Hold the HPO profile constant when testing reference panels | Noodle