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Evaluation of Evidence for Pathogenicity Demonstrates That BLK, KLF11, and PAX4 Should Not Be Included in Diagnostic
Thomas W Laver1, Matthew N Wakeling1, Olivia Knox1
1Institute of Biomedical and Clinical Science, University of Exeter, Exeter, U.K.
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 (cosegregation 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 = 1,227) compared with a control population (UK Biobank [n = 185,898]). For comparison we analyzed well-established causes of MODY, HNF1A, and HNF4A. The published variants in BLK, KLF11, and PAX4 showed poor cosegregation with diabetes (combined logarithm of the odds [LOD] scores ≤1.2), compared with HNF1A and HNF4A (LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95 × 10-5). Ultra-rare missense and protein-truncating variants (PTV) were not enriched in a MODY cohort compared with the UK Biobank population (PTV P > 0.05, missense P > 0.1 for all three genes) while HNF1A and HNF4A were enriched (P < 10-6). Findings of sensitivity analyses with different population cohorts supported our results. Variant and gene-level genetic evidence does not support BLK, KLF11, or PAX4 as a cause of MODY. They should not be included in MODY diagnostic genetic testing.
Insights
Genetic evidence does not support BLK, KLF11, or PAX4 as causes of maturity-onset diabetes of the young (MODY). These genes should be excluded from MODY genetic testing panels.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes caused by variants in at least 16 genes.
- Previous studies suggested BLK (MODY11), KLF11 (MODY7), and PAX4 (MODY9) as potential MODY genes, but robust evidence was lacking.
Purpose of the Study:
- To evaluate the genetic evidence for BLK, KLF11, and PAX4 as causes of MODY.
- To compare the genetic evidence for these genes with established MODY genes (HNF1A, HNF4A).
Main Methods:
- Analysis of variant-level data, including cosegregation with diabetes and population frequency.
- Gene-level burden testing in a MODY cohort (n=1,227) versus a large control population (UK Biobank, n=185,898).
- Comparison of genetic evidence for BLK, KLF11, PAX4 against HNF1A and HNF4A.
Main Results:
- Variants in BLK, KLF11, and PAX4 showed poor cosegregation with diabetes (LOD scores ≤1.2) and were too common in the population to cause MODY.
- Ultra-rare variants in BLK, KLF11, and PAX4 were not enriched in MODY patients compared to controls.
- Established MODY genes HNF1A and HNF4A showed strong genetic evidence (LOD scores >9) and enrichment of rare variants in MODY patients.
Conclusions:
- Genetic evidence does not support BLK, KLF11, or PAX4 as causative genes for MODY.
- These genes should be excluded from genetic testing panels for MODY diagnosis to improve diagnostic accuracy.
