التفاصيل البيبلوغرافية
| العنوان: |
Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data. |
| المؤلفون: |
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 |
| المصدر: |
MedRxiv : the preprint server for health sciences [medRxiv] 2023 Dec 21. Date of Electronic Publication: 2023 Dec 21. |
| نوع المنشور: |
Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of β cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery. |
| معلومات مُعتمدة: |
MR/X004597/1 United Kingdom MRC_ Medical Research Council; 25514 United Kingdom CRUK_ Cancer Research UK; 207556/Z/17/Z United Kingdom WT_ Wellcome Trust; MC_EX_MR/M009203/1 United Kingdom MRC_ Medical Research Council; MC_UP_1102/20 United Kingdom MRC_ Medical Research Council; MR/N008324/1 United Kingdom MRC_ Medical Research Council; MR/S031820/1 United Kingdom MRC_ Medical Research Council; R24 OD011883 United States OD NIH HHS; RM1 HG010860 United States HG NHGRI NIH HHS; MC_PC_14089 United Kingdom MRC_ Medical Research Council; MR/M009203/1 United Kingdom MRC_ Medical Research Council; MR/S021329/1 United Kingdom MRC_ Medical Research Council |
| تواريخ الأحداث: |
Date Created: 20240110 Latest Revision: 20240501 |
| رمز التحديث: |
20240501 |
| مُعرف محوري في PubMed: |
PMC10775325 |
| DOI: |
10.1101/2023.12.20.23300294 |
| PMID: |
38196618 |
| قاعدة البيانات: |
MEDLINE |
