Rare disease gene association discovery in the 100,000 Genomes Project

Valentina Cipriani^#^{1

2

3}, Letizia Vestito^#⁴, Emma F Magavern⁴, Julius O B Jacobsen⁴, Gavin Arno^{5

6}, Elijah R Behr^{7

8}, Katherine A Benson⁹, Marta Bertoli¹⁰, Detlef Bockenhauer^{11

12}, Michael R Bowl¹³, Kate Burley¹⁴, Li F Chan¹⁵, Patrick Chinnery¹⁶, Peter J Conlon¹⁷, Marcos A Costa⁵, Alice E Davidson⁵, Sally J Dawson¹³, Elhussein A E Elhassan¹⁷, Sarah E Flanagan¹⁸, Marta Futema^{7

19}, Daniel P Gale¹², Sonia García-Ruiz^{20

21

22}, Cecilia Gonzalez Corcia^{23

24}, Helen R Griffin²⁵, Sophie Hambleton^{25

26}, Amy R Hicks^{20

21

22}, Henry Houlden^{27

28}, Richard S Houlston²⁹, Sarah A Howles³⁰, Robert Kleta¹², Iris Lekkerkerker³¹, Siying Lin^{5

6}, Petra Liskova^{32

33}, Hannah H Mitchison²¹, Heba Morsy³⁴, Andrew D Mumford¹⁴, William G Newman^{35

36}, Ruxandra Neatu³⁷, Edel A O'Toole³⁸, Albert C M Ong^{39

40}, Alistair T Pagnamenta^{41

42}, Shamima Rahman²¹, Neil Rajan^{25

43}, Peter N Robinson^{44

45}, Mina Ryten^{21

22

46

47

48}, Omid Sadeghi-Alavijeh¹², John A Sayer^{49

50

51}, Claire L Shovlin⁵², Jenny C Taylor^{41

42}, Omri Teltsh⁹, Ian Tomlinson⁵³, Arianna Tucci^{4

20}, Clare Turnbull⁵⁴, Albertien M van Eerde³¹, James S Ware^{52

55}, Laura M Watts^{41

56}, Andrew R Webster^{5

6}, Sarah K Westbury⁵⁷, Sean L Zheng^{52

55}, Mark Caulfield⁴, Damian Smedley⁵⁸

Affiliations

¹ Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK. v.cipriani@qmul.ac.uk.
² UCL Institute of Ophthalmology, University College London, London, UK. v.cipriani@qmul.ac.uk.
³ UCL Genetics Institute, University College London, London, UK. v.cipriani@qmul.ac.uk.
⁴ Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK.
⁵ UCL Institute of Ophthalmology, University College London, London, UK.
⁶ National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital, London, UK.
⁷ Cardiology Section, Cardiovascular and Genomics Research Institute, School of Health & Medical Sciences, City St George's, University of London, London, UK.
⁸ Cardiology Department, St George's University Hospitals NHS Foundation Trust, London, UK.
⁹ School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Republic of Ireland.
¹⁰ Northern Genetics Centre, The Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK.
¹¹ Paediatric Nephrology, University Hospital and Catholic University Leuven, Leuven, Belgium.
¹² Department of Renal Medicine, University College London, London, UK.
¹³ UCL Ear Institute, University College London, London, UK.
¹⁴ School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
¹⁵ Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK.
¹⁶ Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
¹⁷ Department of Medicine, Royal College of Surgeons in Ireland and Department of Nephrology, Beaumont Hospital, Dublin, Republic of Ireland.
¹⁸ Department of Clinical and Biomedical Science, University of Exeter Medical School, Exeter, UK.
¹⁹ Institute of Cardiovascular Science, University College London, London, UK.
²⁰ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
²¹ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
²² Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
²³ Pediatric Cardiology, CHU Sainte Justine, University of Montreal, Montreal, Quebec, Canada.
²⁴ Mc Gill University, Montreal, Quebec, Canada.
²⁵ Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK.
²⁶ Great North Children's Hospital, Newcastle upon Tyne, UK.
²⁷ UCL Institute of Neurology, London, UK.
²⁸ National Hospital for Neurology and Neurosurgery, London, UK.
²⁹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
³⁰ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
³¹ Department of Genetics, UMC Utrecht, Utrecht, Netherlands.
³² Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
³³ Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
³⁴ Department of Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
³⁵ Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK.
³⁶ Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
³⁷ Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK.
³⁸ Centre for Cell Biology and Cutaneous Research, Blizard Institute, QMUL, London, UK.
³⁹ Kidney Genetics Group, Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK.
⁴⁰ Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
⁴¹ Centre for Human Genetics, University of Oxford, Oxford, UK.
⁴² Oxford NIHR Biomedical Research Centre, Oxford, UK.
⁴³ Department of Dermatology and NIHR Biomedical Research Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
⁴⁴ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
⁴⁵ Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴⁶ NIHR GOSH Biomedical Research Centre, Great Ormond Street Institute of Child Health, London, UK.
⁴⁷ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
⁴⁸ Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
⁴⁹ Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
⁵⁰ Renal Services, The Newcastle upon Tyne NHS Foundation Trust Hospitals, Newcastle upon Tyne, UK.
⁵¹ NIHR Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
⁵² National Heart and Lung Institute, Imperial College London, London, UK.
⁵³ Department of Oncology, University of Oxford, Oxford, UK.
⁵⁴ Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
⁵⁵ MRC Laboratory of Medical Sciences, Imperial College London, London, UK.
⁵⁶ Oxford Centre for Genomic Medicine, Oxford University Foundation Trust, Oxford, UK.
⁵⁷ Bristol Medical School, University of Bristol, Bristol, UK.
⁵⁸ Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK. d.smedley@qmul.ac.uk.

^# Contributed equally.

PMID: 40011789
DOI: 10.1038/s41586-025-08623-w

Rare disease gene association discovery in the 100,000 Genomes Project

Valentina Cipriani et al. Nature. 2025.

. 2025 Feb 26.

doi: 10.1038/s41586-025-08623-w. Online ahead of print.

Authors

Affiliations

¹ Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK. v.cipriani@qmul.ac.uk.
² UCL Institute of Ophthalmology, University College London, London, UK. v.cipriani@qmul.ac.uk.
³ UCL Genetics Institute, University College London, London, UK. v.cipriani@qmul.ac.uk.
⁴ Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK.
⁵ UCL Institute of Ophthalmology, University College London, London, UK.
⁶ National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital, London, UK.
⁷ Cardiology Section, Cardiovascular and Genomics Research Institute, School of Health & Medical Sciences, City St George's, University of London, London, UK.
⁸ Cardiology Department, St George's University Hospitals NHS Foundation Trust, London, UK.
⁹ School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Republic of Ireland.
¹⁰ Northern Genetics Centre, The Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK.
¹¹ Paediatric Nephrology, University Hospital and Catholic University Leuven, Leuven, Belgium.
¹² Department of Renal Medicine, University College London, London, UK.
¹³ UCL Ear Institute, University College London, London, UK.
¹⁴ School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
¹⁵ Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK.
¹⁶ Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
¹⁷ Department of Medicine, Royal College of Surgeons in Ireland and Department of Nephrology, Beaumont Hospital, Dublin, Republic of Ireland.
¹⁸ Department of Clinical and Biomedical Science, University of Exeter Medical School, Exeter, UK.
¹⁹ Institute of Cardiovascular Science, University College London, London, UK.
²⁰ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
²¹ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
²² Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
²³ Pediatric Cardiology, CHU Sainte Justine, University of Montreal, Montreal, Quebec, Canada.
²⁴ Mc Gill University, Montreal, Quebec, Canada.
²⁵ Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK.
²⁶ Great North Children's Hospital, Newcastle upon Tyne, UK.
²⁷ UCL Institute of Neurology, London, UK.
²⁸ National Hospital for Neurology and Neurosurgery, London, UK.
²⁹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
³⁰ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
³¹ Department of Genetics, UMC Utrecht, Utrecht, Netherlands.
³² Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
³³ Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
³⁴ Department of Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
³⁵ Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK.
³⁶ Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
³⁷ Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK.
³⁸ Centre for Cell Biology and Cutaneous Research, Blizard Institute, QMUL, London, UK.
³⁹ Kidney Genetics Group, Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK.
⁴⁰ Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
⁴¹ Centre for Human Genetics, University of Oxford, Oxford, UK.
⁴² Oxford NIHR Biomedical Research Centre, Oxford, UK.
⁴³ Department of Dermatology and NIHR Biomedical Research Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
⁴⁴ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
⁴⁵ Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴⁶ NIHR GOSH Biomedical Research Centre, Great Ormond Street Institute of Child Health, London, UK.
⁴⁷ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
⁴⁸ Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
⁴⁹ Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
⁵⁰ Renal Services, The Newcastle upon Tyne NHS Foundation Trust Hospitals, Newcastle upon Tyne, UK.
⁵¹ NIHR Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
⁵² National Heart and Lung Institute, Imperial College London, London, UK.
⁵³ Department of Oncology, University of Oxford, Oxford, UK.
⁵⁴ Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
⁵⁵ MRC Laboratory of Medical Sciences, Imperial College London, London, UK.
⁵⁶ Oxford Centre for Genomic Medicine, Oxford University Foundation Trust, Oxford, UK.
⁵⁷ Bristol Medical School, University of Bristol, Bristol, UK.
⁵⁸ Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK. d.smedley@qmul.ac.uk.

^# Contributed equally.

PMID: 40011789
DOI: 10.1038/s41586-025-08623-w

Abstract

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 regulator^3,4 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.

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Conflict of interest statement

Competing interests: The authors declare the following competing interests: D.S. and M.C. were seconded to, and received salary from, Genomics England, a wholly owned Department of Health and Social Care company, from 2016 to 2018 and 2013 to 2021, respectively. E.A.O. has research funding from Kamari Pharma, Pavella Therapeutics, Unilever and the Leo Foundation unrelated to this work. She is CI for a trial for Kamari Pharma and performs consultancy for Kamari Pharma, Azitra and Palvella Therapeutics (all money goes to the university). S.L.Z. has provided consultancy services to Health Lumen. All other authors declare no competing interests.

Update of

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.
Cipriani V, Vestito L, Magavern EF, Jacobsen JO, Arno G, Behr ER, Benson KA, Bertoli M, Bockenhauer D, Bowl MR, Burley K, Chan LF, Chinnery P, Conlon P, Costa M, Davidson AE, Dawson SJ, Elhassan E, Flanagan SE, Futema M, Gale DP, García-Ruiz S, Corcia CG, Griffin HR, Hambleton S, Hicks AR, Houlden H, Houlston RS, Howles SA, Kleta R, Lekkerkerker I, Lin S, Liskova P, Mitchison H, Morsy H, Mumford AD, Newman WG, Neatu R, O'Toole EA, Ong AC, Pagnamenta AT, Rahman S, Rajan N, Robinson PN, Ryten M, Sadeghi-Alavijeh O, Sayer JA, Shovlin CL, Taylor JC, Teltsh O, Tomlinson I, Tucci A, Turnbull C, van Eerde AM, Ware JS, Watts LM, Webster AR, Westbury SK, Zheng SL, Caulfield M, Smedley D. Cipriani V, et al. medRxiv [Preprint]. 2023 Dec 21:2023.12.20.23300294. doi: 10.1101/2023.12.20.23300294. medRxiv. 2023. Update in: Nature. 2025 Feb 26. doi: 10.1038/s41586-025-08623-w. PMID: 38196618 Free PMC article. Updated. Preprint.

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Rare disease gene association discovery in the 100,000 Genomes Project

Affiliations

Rare disease gene association discovery in the 100,000 Genomes Project

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

LinkOut - more resources

Full Text Sources