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arXiv · 2606.24779

DeepBD: A Grounded Agentic Workflow for Variant Prioritization and Diagnosis of Genetic Birth Defects

Shiyu Li·Ziqi Yan·Zhihao Wu·Jielong Lu·Weiran Liao·Jiajun Yu·Genjie Li·Zeyu Chu·Jiajun Bu·Haishuai Wang
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Abstract

Birth defects are a major cause of fetal loss, neonatal morbidity and long-term disability. In the subset with suspected genetic etiologies, exome and genome sequencing have moved many cases from variant detection to post-sequencing interpretation: clinicians must rank patient-specific candidate variants under incomplete fetal or infant phenotypes and heterogeneous evidence from population genetics, variant-effect prediction, gene-disease validity, phenotype ontologies, cellular and pathway context, protein structure and clinical literature. We present DeepBD, a grounded agentic workflow for variant prioritization and diagnostic interpretation of genetic birth defects. DeepBD organizes the workflow into LLM-assisted case structuring, a pretrained evidence engine, specialist evidence modules and a grounded diagnostic review layer. The evidence engine learns patient-specific variant scores from structured rule evidence, sequence and variant-effect representations and phenotype-conditioned biological context, whereas specialist modules and the agentic layer provide tool-based refinement, candidate-pool review and diagnosis-oriented synthesis from ranked candidates. Developed using an in-house fetal and infant cohort comprising 18,622 cases, DeepBD achieved Recall@1/3/5/10 of 0.658/0.882/0.912/0.929 on an internal held-out solved-case benchmark, outperforming standalone Exomiser, DeepRare and prompted LLM reranking baselines evaluated on Exomiser-derived top-20 candidate variants. Ablation and overlap analyses show that rule evidence, mechanistic context, and specialist refinement provide complementary signals. These findings support a grounded agentic workflow that separates evidence integration, tool-based refinement, and LLM-assisted diagnostic review for retrospective variant prioritization in genetic birth defects.

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Shiyu Li, Ziqi Yan, Zhihao Wu, Jielong Lu, Weiran Liao, Jiajun Yu, Genjie Li, Zeyu Chu, Jiajun Bu, Haishuai Wang. 2026-06-23. DeepBD: A Grounded Agentic Workflow for Variant Prioritization and Diagnosis of Genetic Birth Defects. https://arxiv.org/abs/2606.24779

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