Up to 80% of rare disease patients remain undiagnosed after genomic sequencing1, with many probably involving pathogenic variants in yet to be discovered disease-gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project2. A total of 141 new associations were identified, including five for which independent disease-gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence. The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator3,4 UNC13A, schizophrenia with GPR17, epilepsy with RBFOX3, Charcot-Marie-Tooth disease with ARPC3 and anterior segment ocular abnormalities with POMK. Further confirmation of these and other associations could lead to numerous diagnoses, highlighting the clinical impact of large-scale statistical approaches to rare disease-gene association discovery.

Aligning Science Across Parkinson's Collaborative Research Network Chevy Chase MD USA

Berlin Institute of Health Charité Universitätsmedizin Berlin Berlin Germany

Biosciences Institute Newcastle University Newcastle upon Tyne UK

Bristol Medical School University of Bristol Bristol UK

Cardiology Department St George's University Hospitals NHS Foundation Trust London UK

Cardiology Section Cardiovascular and Genomics Research Institute School of Health and Medical Sciences City St George's University of London London UK

Centre for Cell Biology and Cutaneous Research Blizard Institute QMUL London UK

Centre for Endocrinology William Harvey Research Institute Queen Mary University of London London UK

Centre for Human Genetics University of Oxford Oxford UK

Clinical Pharmacology and Precision Medicine William Harvey Research Institute Queen Mary University of London London UK

Department of Clinical and Biomedical Science University of Exeter Medical School Exeter UK

Department of Clinical Neurosciences School of Clinical Medicine University of Cambridge Cambridge UK

Department of Dermatology and NIHR Biomedical Research Centre Royal Victoria Infirmary Newcastle upon Tyne UK

Department of Genetics UMC Utrecht Utrecht Netherlands

Department of Medical Genetics NIHR Cambridge Biomedical Research Centre University of Cambridge Cambridge UK

Department of Medicine Royal College of Surgeons in Ireland and Department of Nephrology Beaumont Hospital Dublin Republic of Ireland

Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology University College London London UK

Department of Neuromuscular Diseases UCL Institute of Neurology London UK

Department of Oncology University of Oxford Oxford UK

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Renal Medicine University College London London UK

Division of Evolution Infection and Genomics University of Manchester Manchester UK

Division of Genetics and Epidemiology Institute of Cancer Research London UK

Division of Genetics and Epidemiology The Institute of Cancer Research London UK

Genetics and Genomic Medicine UCL Great Ormond Street Institute of Child Health University College London London UK

Great North Children's Hospital Newcastle upon Tyne UK

Institute of Cardiovascular Science University College London London UK

Institute of Translational and Clinical Research Newcastle University Newcastle upon Tyne UK

Kidney Genetics Group Division of Clinical Medicine School of Medicine and Population Health University of Sheffield Sheffield UK

Manchester Centre for Genomic Medicine Manchester University NHS Foundation Trust Manchester UK

Mc Gill University Montreal Quebec Canada

Medical Research Council Mitochondrial Biology Unit Cambridge Biomedical Campus University of Cambridge Cambridge UK

MRC Laboratory of Medical Sciences Imperial College London London UK

National Heart and Lung Institute Imperial College London London UK

National Hospital for Neurology and Neurosurgery London UK

National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital London UK

Newcastle University Translational and Clinical Research Institute Newcastle upon Tyne UK

NIHR Biomedical Research Centre Newcastle University Newcastle upon Tyne UK

NIHR GOSH Biomedical Research Centre Great Ormond Street Institute of Child Health London UK

Northern Genetics Centre The Newcastle upon Tyne NHS Foundation Trust Newcastle upon Tyne UK

Nuffield Department of Surgical Sciences University of Oxford Oxford UK

Oxford Centre for Genomic Medicine Oxford University Foundation Trust Oxford UK

Oxford NIHR Biomedical Research Centre Oxford UK

Paediatric Nephrology University Hospital and Catholic University Leuven Leuven Belgium

Pediatric Cardiology CHU Sainte Justine University of Montreal Montreal Quebec Canada

Renal Services The Newcastle upon Tyne NHS Foundation Trust Hospitals Newcastle upon Tyne UK

School of Cellular and Molecular Medicine University of Bristol Bristol UK

School of Pharmacy and Biomolecular Sciences Royal College of Surgeons in Ireland Dublin Republic of Ireland

Sheffield Kidney Institute Sheffield Teaching Hospitals NHS Foundation Trust Sheffield UK

The Jackson Laboratory for Genomic Medicine Farmington CT USA

UCL Ear Institute University College London London UK

UCL Genetics Institute University College London London UK

UCL Institute of Neurology London UK

UCL Institute of Ophthalmology University College London London UK

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medRxiv. 2023 Dec 21:2023.12.20.23300294. doi: 10.1101/2023.12.20.23300294. PubMed

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