Evaluation of Evidence for Pathogenicity Demonstrates that BLK, KLF11 and PAX4 Should not be Included in Diagnostic Testing for MODY
dc.contributor.author | Laver, TW | |
dc.contributor.author | Wakeling, MN | |
dc.contributor.author | Knox, O | |
dc.contributor.author | Colclough, K | |
dc.contributor.author | Wright, CF | |
dc.contributor.author | Ellard, S | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Weedon, MN | |
dc.contributor.author | Patel, KA | |
dc.date.accessioned | 2022-03-24T09:46:36Z | |
dc.date.issued | 2022-02-02 | |
dc.date.updated | 2022-03-21T17:50:27Z | |
dc.description.abstract | Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants in BLK (MODY11), KLF11 (MODY7) and PAX4 (MODY9) cause MODY. We examined variant-level genetic evidence (co-segregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n=1227) compared to population control (UK Biobank, n=185,898). For comparison we analysed well-established causes of MODY, HNF1A and HNF4A. The published variants in BLK, KLF11 and PAX4 showed poor co-segregation with diabetes (combined LOD scores ≤1.2), compared to HNF1A and HNF4A (LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95x10-5). Ultra-rare missense and protein-truncating variants (PTVs) were not enriched in a MODY cohort compared to the UK Biobank (PTVs P>0.05, missense P>0.1 for all three genes) while HNF1A and HNF4A were enriched (P<10-6). Sensitivity analyses using different population cohorts supported our results. Variant and gene-level genetic evidence does not support BLK, KLF11 or PAX4 as causes of MODY. They should not be included in MODY diagnostic genetic testing. | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | Diabetes UK | en_GB |
dc.description.sponsorship | Research England | en_GB |
dc.description.sponsorship | Wellcome Trust | en_GB |
dc.format.medium | Print-Electronic | |
dc.identifier.citation | Published online 2 February 2022 | en_GB |
dc.identifier.doi | https://doi.org/10.2337/db21-0844 | |
dc.identifier.grantnumber | MR/T00200X/1 | en_GB |
dc.identifier.grantnumber | 19/0005994 | en_GB |
dc.identifier.grantnumber | 219606/Z/19/Z | en_GB |
dc.identifier.grantnumber | WT098395/Z/12/Z | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/129140 | |
dc.identifier | ORCID: 0000-0001-6399-0089 (Laver, Thomas W) | |
dc.identifier | ScopusID: 6506037245 (Laver, Thomas W) | |
dc.identifier | ORCID: 0000-0001-5620-473X (Hattersley, Andrew T) | |
dc.identifier | ORCID: 0000-0002-6174-6135 (Weedon, Michael N) | |
dc.identifier | ORCID: 0000-0002-9240-8104 (Patel, Kashyap A) | |
dc.identifier | ScopusID: 57188657944 (Patel, Kashyap A) | |
dc.language.iso | en | en_GB |
dc.publisher | American Diabetes Association | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/35108381 | en_GB |
dc.relation.url | https://gnomad.broadinstitute.org/ | en_GB |
dc.rights | © 2022 by the American Diabetes Association. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission | en_GB |
dc.title | Evaluation of Evidence for Pathogenicity Demonstrates that BLK, KLF11 and PAX4 Should not be Included in Diagnostic Testing for MODY | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2022-03-24T09:46:36Z | |
dc.identifier.issn | 0012-1797 | |
exeter.place-of-publication | United States | |
dc.description | This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record | en_GB |
dc.description | Data and Resource Availability: UK Biobank data is accessible via application: https://www.ukbiobank.ac.uk/enable-yourresearch. GnomAD data is publically available: https://gnomad.broadinstitute.org/. The MODY cohort data is not publicly available due the limitations of the current ethics and to protect patient confidentiality but is available from the corresponding authors on reasonable request. No applicable resources were generated or analyzed during the current study. | en_GB |
dc.identifier.eissn | 1939-327X | |
dc.identifier.journal | Diabetes | en_GB |
dc.relation.ispartof | Diabetes | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2022-01-30 | |
rioxxterms.version | AM | en_GB |
rioxxterms.licenseref.startdate | 2022-02-02 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2022-03-22T08:52:31Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2022-03-24T09:46:47Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2022-02-02 |
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Except where otherwise noted, this item's licence is described as © 2022 by the American Diabetes Association. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission