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.
Highlights
Characteristics N Age of diagnosis of diabetes, years Female Sex Age at recruitment, years BMI, kg/m2 Parents with diabetes HbA1c, % HbA1c, mmol/mol On Insulin alone On Insulin and other hypoglycaemic agents On other hypoglycaemic agents alone European ancestry
The frequency of ultra-rare synonymous variants in a MODY cohort n=1227 were compared to the frequency in the UK Biobank n=185,898
*excluding two synonymous variants in HNF1A that were on a haplotype with a pathogenic PTV
Summary
Characteristics N Age of diagnosis of diabetes, years Female Sex Age at recruitment, years BMI, kg/m2 Parents with diabetes HbA1c, % HbA1c, mmol/mol On Insulin alone On Insulin and other hypoglycaemic agents On other hypoglycaemic agents alone European ancestry Table showing coding variants where they were associated with MODY-like diabetes. Allele count /total alleles in gnomAD v2.1.1
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