Rare Disease Diagnosis

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Rare disease diagnosis connects a patient's symptoms and test results to conditions that may be unfamiliar or have overlapping features. Common approaches include standardizing symptoms with the Human Phenotype Ontology (HPO), ranking candidate diseases or genes with ontology and knowledge-graph methods, and using language models to extract and reason over clinical notes; some systems also combine genetic data with facial images. Researchers are testing active phenotype questions, multimodal agents, and synthetic images or records to address sparse data, while benchmarks assess diagnostic ranking, evidence quality, and performance on real clinical cases. A central challenge is making systems accurate across rare and underrepresented conditions while keeping their evidence verifiable, their outputs useful to clinicians, and patient data private.

Latest papers

32 papers3 papers in the last four weeks, down 25% on the four weeks before. 0.0% of all new papers.

ProtoGestalt: Interpretable Prototypes for Facial Phenotyping and Diagnosis of Rare Genetic Disorders
Nov 5, 2026Ranga Baminiwatte, Alexander Hustinx, Fabio Hellmann +1Rare Disease Diagnosis Explainable Medical Image Analysis
School of Computing, Clemson University, USA · Institute for Human Genetics, Clemson University, USA · Institute for Genomic Statistics and Bioinformatics, Rheinische Friedrich-Wilhelms Universität Bonn, Germany +1
Auditing evaluation artifacts and data leakage in large language model systems for rare disease diagnosis
Oct 24, 2026Jian Yang, Peilin Liu, Xiaohan Li +4Clinical Language Model Evaluation LLM Auditing
The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China. · The College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310027, China.
Unified Multiparadigm Fusion Intelligence for Rare Disease Diagnosis
Oct 16, 2026Jian Yang, Peiling Liu, Songda Li +10Rare Disease Diagnosis Clinical Decision Support
The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China. · The College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310027, China.
FaceKit: a Toolkit for Interpretable Facial Phenotyping, Synthetic Image Generation and Privacy Analysis in Rare Diseases
Oct 7, 2026Hongzhuo Chen, Zhanliang Wang, Florent Pollet +9Rare Disease Diagnosis Synthetic Data Evaluation
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA · Applied Mathematics and Computational Science Graduate Program, University of Pennsylvania, Philadelphia, PA, USA · Department of Biomedical Informatics, Columbia University, New York, NY, USA +6
Hindsight-Guided Rationale Distillation for Rare Disease Diagnosis
Oct 2, 2026Aarav Singh, Animesh Pathak, Navyansh SinghCoT Distillation Knowledge Distillation
Dr. Shyama Prasad Mukherjee International Institute of Information Technology, Naya Raipur
RareDx: Controlled Knowledge Integration and Graph-Grounded Policy Optimization for Rare-Disease Diagnosis
Sep 28, 2026Bo Zhang, Yuchen Wang, Dongbai Li +6Rare Disease Diagnosis LLM Reasoning with Graphs
Xi’an Jiaotong University · UIUC · Tsinghua University +4
Integrating knowledge from case reports: a medical ontology based multimodal information system with structured summary
Sep 17, 2026Shuyu Guo, Lan Huang, Yichen Liu +2Multimodal IR Rare Disease Diagnosis
College of Computer Science and Technology Jilin University Changchun · College of Software Jilin University Changchun · Department of Laboratory Medicine Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China Chengdu
HPOQuest: A Rare-Disease Diagnostic Agent Using Active Phenotype Acquisition
Sep 16, 2026Kamilia Zaripova, Nassir Navab, Azade Farshad +1Rare Disease Diagnosis Clinical Decision Support
Technical University of Munich, Munich, Germany · Computational Health Center, Helmholtz Center Munich, Oberschleißheim, Germany · Munich Center for Machine Learning (MCML), Munich, Germany +2
Learning to Fuse LLMs with Ontology Rankers for Rare-Disease Diagnosis
Sep 2, 2026Zhaoyang Jiang, Zhizhong Fu, Yunsoo Kim +5Rare Disease Diagnosis Rank Aggregation
School of Health & Wellbeing, University of Glasgow, Glasgow, UK · School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China · Department of Respiratory and Critical Care Medicine, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
NSIDDx: A Design Framework for Neuro-Symbolic, Practitioner-First Differential Diagnosis in Low-Resource Settings
Aug 31, 2026Aarav SinghRare Disease Diagnosis Healthcare
IIIT Naya Raipur
Multi-Level Evidence Aggregation for Robust Facial Phenotype Retrieval in Rare Genetic Disorder Prioritization
Aug 11, 2026Alexander Hustinx, Carolin Kaffiné, Behnam Javanmardi +2Rare Disease Diagnosis Image Matching
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany
GraphRareBench: An Auditable Graph-Evidence Benchmark for Phenotype-Driven Rare-Disease Diagnosis
Jul 27, 2026Guiling Guo, Jia Yang, Jiahao Xu +3Rare Disease Diagnosis Benchmark Design
National Institute for Data Science in Health and Medicine, Xiamen University · Institute of Artificial Intelligence, Xiamen University · School of Medicine, Xiamen University +1
RareLens: Towards End-to-End Rare Disease Care via Aligning Divergent Large Language Model Reasoning
Jul 25, 2026Xi Chen, Hongru Zhou, Shiyu Feng +24Rare Disease Diagnosis Healthcare
Sports Medicine Center, Department of Orthopedics and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China · Center for Cleft Lip and Palate Treatment, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China · School of Data Science, The Chinese University of Hong Kong, Shenzhen (CUHKSZ), Shenzhen, China +13
SYNRARE: Synthetic Rare Disease EHR Generation for ML Benchmarking
Jul 10, 2026Nicolai Dinh Khang Truong, Richard RöttgerRare Disease Diagnosis Synthetic Data Generation
Department of Mathematics and Computer Science, University of Southern Denmark, Campusvej 55, 5230, Odense, Denmark
RareDxR1: Autonomous Medical Reasoning for Rare Disease Diagnosis Beyond Human Annotation
Jun 30, 2026Deyang Jiang, Haoran Wu, Ziyi Wang +4Rare Disease Diagnosis RL for Language Model Reasoning
The Key Laboratory of Cognition and Decision Intelligence for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China · Peking Union Medical College Hospital, Beijing, China · School of Future Technology, University of Chinese Academy of Sciences, Beijing, China
DeepBD: A Grounded Agentic Workflow for Variant Prioritization and Diagnosis of Genetic Birth Defects
Jun 23, 2026Shiyu Li, Ziqi Yan, Zhihao Wu +7Rare Disease Diagnosis LLM Agents
College of Computer Science and Technology, Zhejiang University, Hangzhou, China
A specialized reasoning large language model for accelerating rare disease diagnosis: a randomized AI physician assistance trial
Jun 23, 2026Haichao Chen, Songchi Zhou, Zhengyun Zhao +28Rare Disease Diagnosis Clinical Decision Support
Tsinghua Medicine, Tsinghua University, Beijing, China. · Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. · Department of Statistics and Data Science, Tsinghua University, Beijing, China. +19
Evo-RAD: Navigating Rare Retinal Disease Diagnosis via Self-Evolving Agentic Retrieval
Jun 22, 2026Wangding Xia, Ye Du, Jiashi Lin +3Medical Image Retrieval Reinforcement Learning
Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China · School of Computer Science, Northwestern Polytechnical University, Xi’an, China · Centre for Innovation and Precision Eye Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore +3
Teaching agentic AI to generalize expert diagnostic reasoning in rare diseases
Jun 15, 2026Minh-Ha Nguyen, Erica Gray, Bryce A. Schuler +16RL for Language Models Rare Disease Diagnosis
Department of Epidemiology, Vanderbilt University, Nashville, TN, USA · Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA · Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA +4
LatentDx: Latent Multi-Agent Communication for Cross-Hospital Rare-Disease Diagnosis
Jun 11, 2026Ziqing Wang, Lili Zhao, Kaize DingMulti-Agent LLM Systems Rare Disease Diagnosis
Northwestern University
Synthetic Data Alone is Enough? Rethinking Data Scarcity in Pediatric Rare Disease Recognition
May 21, 2026Ganlin Feng, Yuxi Long, Erin Lou +4Rare Disease Diagnosis Synthetic Data Generation
1Western University · University of Toronto
A Multi-Dimensional Clustering Approach for Identifying Inborn Errors of Immunity
May 16, 2026Nishad Kulkarni, Alexandra K. Martinson, Nicholas L. Rider +2Rare Disease Diagnosis Training Data Curation
Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Hospital, Washington, DC 20010 · Childrens National Hospital, Washington, DC · School of Medicine and Health Sciences, George Washington University, Washington, DC 20052 +2
Shapley Regression for Rare Disease Diagnosis Support: a case study on APDS
May 9, 2026Safa Alsaidi, Tomás Brogueira, Nizar Mahlaoui +5Rare Disease Diagnosis Clinical Decision Support
Inria, Inserm, UPC, HeKA U1346, Paris, France. · Técnico, University of Lisbon, INESC-ID, Lisbon, Portugal · Necker Enfants Malades University Hospital, AP-HP, Paris, France +2
A Versatile AI Agent for Rare Disease Diagnosis and Risk Gene Prioritization
May 7, 2026Tianyu Liu, Wangjie Zheng, Rui Yang +12Rare Disease Diagnosis Medical AI Agents
Interdepartmental Program in Computational Biology and Bioinformatics, Yale University · Department of Biostatistics, Yale University · Broad Institute of MIT and Harvard +13
GAZE: Grounded Agentic Zero-shot Evaluation with Viewer-Level Tools and Literature Retrieval on Rare Brain MRI
Apr 25, 2026Duaa Alim, Mogtaba Alim, Liam ChalcroftVLM Evaluation Rare Disease Diagnosis
Imperial College London, UK · University of Toronto, Canada · University College London, UK
MMRareBench: A Rare-Disease Multimodal and Multi-Image Medical Benchmark
Apr 12, 2026Junzhi Ning, Jiashi Lin, Yingying Fang +9Medical Image Benchmarks Multimodal Model Evaluation
Shanghai AI Laboratory · Imperial College London · Shanghai Jiao Tong University +1
RDFace: A Benchmark Dataset for Rare Disease Facial Image Analysis under Extreme Data Scarcity and Phenotype-Aware Synthetic Generation
Apr 3, 2026Ganlin Feng, Yuxi Long, Hafsa Ali +5Rare Disease Diagnosis Synthetic Data Evaluation
Western University · Concordia University · University of Toronto +1
SkinGPT-X: A Self-Evolving Collaborative Multi-Agent System for Transparent and Trustworthy Dermatological Diagnosis
Mar 27, 2026Zhangtianyi Chen, Yuhao Shen, Florensia Widjaja +6Medical Diagnosis Dermatology
School of Data Science, The Chinese University of Hong Kong, Shenzhen · Department of Dermatology, Tianjin Institute of Integrative Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin 300120, China · Department of Dermatology, Beijing AnZhen Hospital, Capital Medical University, Beijing 100029, China..
Mind the Rarities: Can Rare Skin Diseases Be Reliably Diagnosed via Diagnostic Reasoning?
Mar 19, 2026Yang Liu, Jiyao Yang, Hongjin Zhao +10Rare Disease Diagnosis Medical VLMs
Carnegie Mellon University · University of Alabama at Birmingham · Australian National University +3
Evaluating Multi-Agent LLM Architectures for Rare Disease Diagnosis
Mar 6, 2026Ahmed AlmasoudMulti-Agent LLM Systems AI Agent Evaluation
Artificial Intelligence and Data Analytics (AIDA) Lab, College of Computing and Information Sciences, Prince Sultan University, Riyadh, Saudi Arabia.

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ProtoGestalt: Interpretable Prototypes for Facial Phenotyping and Diagnosis of Rare Genetic Disorders

Ranga Baminiwatte, Alexander Hustinx, Fabio Hellmann, Aaron J Masino

School of Computing, Clemson University, USA · Institute for Human Genetics, Clemson University, USA · Institute for Genomic Statistics and Bioinformatics, Rheinische Friedrich-Wilhelms Universität Bonn, Germany+1

Rare Disease Diagnosis Explainable Medical Image Analysis Prototype-Based Classification

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Rare genetic disorders are difficult to diagnose due to their diversity and overlapping clinical features. Facial morphology can provide diagnostic clues, yet most diagnostic models offer limited interpretability and are not designed to support broad screening for undiagnosed disease. We present ProtoGestalt, an interpretable prototype-based framework for facial phenotyping, rare-disease screening, and syndrome identification. The method extends prototype learning by constraining learned visual features to select facial regions, allowing predictions to be explained through localized and additive evidence. We assess ProtoGestalt's ability to distinguish syndromic from unaffected faces on multiple control datasets and class prevalence values. We further evaluate it's diagnostic performance on syndromes observed during training. The learned prototype-based representations provide significant separation between syndromic and case-matched control images and retain useful performance as the proportion of controls increases. The framework also demonstrates the ability to differentiate among syndromes. Although reasonably accurate specialized models for facial classification of rare disorders already exist, ProtoGestalt offers an interpretable alternative that links predictions to anatomically meaningful facial regions, potentially supporting clinical decision-making and the discovery of phenotype-gene associations.