LA-MARRVEL: A Knowledge-Grounded, Language-Aware LLM Framework for Clinically Robust Rare Disease Gene Prioritization

TL;DR

LA-MARRVEL is a knowledge-grounded, language-aware LLM framework that significantly improves rare disease gene prioritization accuracy by effectively encoding phenotypic context and providing interpretable, clinically relevant reasoning.

Contribution

It introduces a novel LLM-based approach with structured, phenotype-rich prompts that enhance gene ranking accuracy and clinical interpretability in rare disease diagnosis.

Findings

12-15 percentage-point improvement in Recall@1

Consistent performance across three real-world cohorts

Provides ACMG-aligned, interpretable reasoning for each candidate gene

Abstract

Rare disease diagnosis requires matching variant-bearing genes to complex patient phenotypes across large and heterogeneous evidence sources. This process remains time-intensive in current clinical interpretation pipelines. To overcome these limitations, We present LA-MARRVEL, a knowledge-grounded, language-aware LLM framework and designed for clinical robustness and practical deployment. LA-MARRVEL delivers a 12-15 percentage-point absolute improvement in Recall@1 over established gene prioritization approaches, showing that architectural design can drive substantial accuracy gains. We found that the central contributor is structured, phenotype-rich prompt construction that explicitly encodes patient and disease phenotypes, preserving clinically meaningful context more effectively than disease labels alone. Across three real-world cohorts, LA-MARRVEL consistently improves gene-ranking performance, including in challenging cases where the causal gene was initially ranked lower by first-stage prioritization. For each candidate gene, the system delivers clinically relevant, ACMG-aligned reasoning that integrates phenotype concordance, inheritance patterns, and variant-level evidence into auditable explanations, enabling streamlined clinical review. These findings suggest that knowledge-grounded LLM layer can enhance existing rare-disease gene prioritization workflows without altering established diagnostic pipelines.