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 >4.95×10⁻⁵). 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.

中文翻译：

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对致病性证据的评估表明 BLK、KLF11 和 PAX4 不应包含在 MODY 的诊断测试中

成年型青年糖尿病 (MODY) 是单基因糖尿病的常染色体显性遗传形式，据报道由 16 个基因的变异引起。BLK (MODY11)、KLF11 (MODY7) 和PAX4 (MODY9) 中的变异是否会导致 MODY 引起了关注。我们检查了这些基因中已发表的假定致病变异的变异水平遗传证据（与糖尿病的共同分离和人群频率），并使用负荷测试来测试与人群对照相比的 MODY 队列（n = 1227）中的基因水平证据。英国生物银行，n=185,898）。为了进行比较，我们分析了 MODY、HNF1A和HNF4A 的公认原因。BLK、KLF11和PAX4 中已发布的变体与HNF1A和HNF4A（LOD 分数 >9）相比，与糖尿病的共分离较差（组合 LOD 分数≤1.2），并且都太常见而不会引起 MODY（次要等位基因频率 >4.95×10 ^-5）。与英国生物银行相比，MODY 队列中未富集超稀有错义和蛋白质截短变体 (PTV)（PTV P > 0.05，所有三个基因的错义P > 0.1），而HNF1A和HNF4A富集（P <10 ^{- 6}）。使用不同人群队列的敏感性分析支持了我们的结果。变异和基因水平的遗传证据不支持BLK、KLF11或PAX4作为MODY的原因。它们不应包含在 MODY 诊断基因检测中。