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dc.contributor.authorLaver, T. W.
dc.contributor.authorWakeling, M. N.
dc.contributor.authorKnox, O.
dc.contributor.authorColclough, K.
dc.contributor.authorWright, C. F.
dc.contributor.authorEllard, S.
dc.contributor.authorHattersley, A. T.
dc.contributor.authorWeedon, M. N.
dc.contributor.authorPatel, K. A.
dc.identifier.citationDiabetes. 2022 Feb 2:db210844. doi: 10.2337/db21-0844.
dc.description.abstractMaturity 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.
dc.publisherAmerican Diabetes Association
dc.rights© 2022 by the American Diabetes Association.
dc.titleEvaluation of Evidence for Pathogenicity Demonstrates that BLK, KLF11 and PAX4 Should not be Included in Diagnostic Testing for MODY
dc.typeJournal Article
dc.description.noteThe article is available via Open Access. Click on the 'Additional link' above to access the full-text.
dc.description.admin-noteAccepted version, submitted version

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© 2022 by the American Diabetes Association.
Except where otherwise noted, this item's license is described as © 2022 by the American Diabetes Association.