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

被引：1

作者：

Cipriani, Valentina ^{[1
,2
,3
]}

Vestito, Letizia ^{[1
]}

Magavern, Emma F. ^{[1
]}

Jacobsen, Julius O. B. ^{[1
]}

Arno, Gavin ^{[2
,4
]}

Behr, Elijah R. ^{[5
,6
]}

Benson, Katherine A. ^{[7
]}

Bertoli, Marta ^{[8
]}

Bockenhauer, Detlef ^{[9
,10
,11
]}

Bowl, Michael R. ^{[12
]}

Burley, Kate ^{[13
]}

Chan, Li F. ^{[14
]}

Chinnery, Patrick ^{[15
]}

Conlon, Peter J. ^{[16
,17
]}

Costa, Marcos A. ^{[2
]}

Davidson, Alice E. ^{[2
]}

Dawson, Sally J. ^{[12
]}

Elhassan, Elhussein A. E. ^{[16
,17
]}

Flanagan, Sarah E. ^{[18
]}

Futema, Marta ^{[5
,19
]}

Gale, Daniel P. ^{[11
]}

Garcia-Ruiz, Sonia ^{[20
,21
,22
]}

Corcia, Cecilia Gonzalez ^{[23
,24
]}

Griffin, Helen R. ^{[25
]}

Hambleton, Sophie ^{[25
,26
]}

Hicks, Amy R. ^{[20
,21
,22
]}

Houlden, Henry ^{[27
,28
]}

Houlston, Richard S. ^{[29
]}

Howles, Sarah A. ^{[30
]}

Kleta, Robert ^{[11
]}

Lekkerkerker, Iris ^{[31
]}

Lin, Siying ^{[2
,4
]}

Liskova, Petra ^{[32
,33
,34
]}

Mitchison, Hannah H. ^{[21
]}

Morsy, Heba ^{[35
]}

Mumford, Andrew D. ^{[13
]}

Newman, William G. ^{[36
,37
]}

Neatu, Ruxandra ^{[38
]}

O'Toole, Edel A. ^{[39
]}

Ong, Albert C. M. ^{[40
,41
]}

Pagnamenta, Alistair T. ^{[42
,43
]}

Rahman, Shamima ^{[21
]}

Rajan, Neil ^{[25
,44
,45
]}

Robinson, Peter N. ^{[46
,47
]}

Ryten, Mina ^{[21
,22
,48
,49
,50
]}

Sadeghi-Alavijeh, Omid ^{[11
]}

Sayer, John A. ^{[51
,52
,53
]}

Shovlin, Claire L. ^{[54
]}

Taylor, Jenny C. ^{[42
,43
]}

Teltsh, Omri ^{[7
]}

机构：

[1] Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol & Precis Med, London, England

[2] UCL, UCL Inst Ophthalmol, London, England

[3] UCL, UCL Genet Inst, London, England

[4] Moorfields Eye Hosp, Biomed Res Ctr, Natl Inst Hlth Res, London, England

[5] City St Georges Univ London, Cardiovasc & Genom Res Inst, Sch Hlth & Med Sci, Cardiol Sect, LONDON, England

[6] St Georges Univ Hosp NHS Fdn Trust, Cardiol Dept, London, England

[7] Royal Coll Surgeons Ireland, Sch Pharm & Biomol Sci, Dublin, Ireland

[8] Newcastle Upon Tyne NHS Fdn Trust, Virol, Newcastle Upon Tyne, England

[9] Catholic Univ Leuven Radiol, Univ Hosp, Louvain, Belgium

[10] Katholieke Univ Leuven, Leuven, Belgium

[11] Imperial Coll London, Dept Renal Med, London, England

[12] UCL, UCL Ear Inst, London, England

[13] Univ Bristol, Sch Cellular & Mol Med, Bristol, England

[14] Queen Mary Univ London, William Harvey Res Inst, Ctr Endocrinol, London, England

[15] Univ Cambridge, Med Res Council, Mitochondrial Biol Unit, Cambridge Biomed Campus, Cambridge, England

[16] Royal Coll Surgeons Ireland, Beaumont Hosp, Dublin, Ireland

[17] Beaumont Hosp, Dept Nephrol, Dublin, Ireland

[18] Univ Exeter, Med Sch, Dept Clin & Biomed Sci, Exeter, England

[19] UCL, Inst Cardiovasc Sci, London, England

[20] UCL, UCL Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England

[21] UCL, Great Ormond St Inst Child Hlth, Genet & Genom Med Dept, London, England

[22] Aligning Sci Parkinsons ASAP Collaborat Res Networ, Chevy Chase, MD USA

[23] Univ Montreal, Dept Pediat, CHU St Justine, Montreal, PQ, Canada

[24] McGill Univ, Montreal, PQ, Canada

[25] Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, England

[26] Great North Childrens Hosp, Newcastle Upon Tyne, England

[27] UCL, Inst Neurol, London, England

[28] Natl Hosp Neurol & Neurosurg, London, England

[29] Inst Canc Res, Div Genet & Epidemiol, London, England

[30] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England

[31] UMC Utrecht, Dept Genet, Utrecht, Netherlands

[32] Charles Univ Prague, Gen Univ Hosp Prague, Fac Med 1, Prague, Czech Republic

[33] Gen Univ Hosp Prague, Prague, Czech Republic

[34] Charles Univ Prague, Gen Univ Hosp, Fac Med 1, Prague, Czech Republic

[35] UCL, Inst Neurol, Dept Neuromuscular Dis, London, England

[36] Univ Manchester, Div Evolut Infect & Genom, Manchester, England

[37] Manchester Univ NHS Fdn Trust, Manchester Ctr Genom Med, Manchester, England

[38] Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, England

[39] QMUL, Blizard Inst, Ctr Cell Biol & Cutaneous Res, London, England

[40] Univ Sheffield, Sch Med & Populat Hlth, Div Clin Med, Kidney Genet Grp, Sheffield, England

[41] Sheffield Teaching Hosp NHS Fdn Trust, Sheffield Kidney Inst, Sheffield, England

[42] Univ Oxford, Ctr Human Genet, Oxford, England

[43] NIHR Oxford Biomed Res Ctr, Oxford, England

[44] ROYAL VICTORIA INFIRM, Newcastle Eye Ctr, Queen Victoria Rd, NEWCASTLE UPON TYNE NE1 4LP, England

[45] Royal Victoria Infirm, NIHR Biomed Res Ctr, Newcastle Upon Tyne, England

[46] Jackson Lab Genom Med, Farmington, CT USA

[47] Charite Univ Med Berlin, Berlin Inst Hlth, Berlin, Germany

[48] Great Ormond St Inst Child Hlth, NIHR GOSH Biomed Res Ctr, London, England

[49] Univ Cambridge, Sch Clin Med, Dept Clin Neurosci, Cambridge, England

[50] Univ Cambridge, Dept Med Genet, NIHR Cambridge Biomed Res Ctr, Cambridge, England

来源：

NATURE | 2025年

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

PATHOGENIC VARIANTS; MUNC13-1; SPECTRUM; INSULIN;

D O I：

10.1038/s41586-025-08623-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta cell regulator3,4UNC13A, 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.

引用

页数：17

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