Sriram Aparajita, Wakeling Matthew N, Hattersley Andrew T, Weedon Michael N, Colclough Kevin, Laver Thomas W, Patel Kashyap A
Department of Clinical and Biomedical Science, University of Exeter, Exeter, U.K.
Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K.
Diabetes. 2025 Aug 8. doi: 10.2337/db25-0442.
An accurate genetic diagnosis of maturity-onset diabetes of the young (MODY) is critical for personalized treatment. To avoid misdiagnosis, only genes with strong evidence of causality must be tested. Heterozygous variants in NEUROD1, PDX1, APPL1, and WFS1 have been implicated in MODY, but strong genetic evidence supporting causality is lacking. We therefore assessed their existing genetic evidence and performed gene-level burden tests in a large MODY cohort, alongside two established MODY genes as positive controls (HNF1A- high penetrance, RFX6 -low penetrance). The first reported MODY-associated variants in NEUROD1, PDX1, APPL1, and WFS1 were <1:20,000 frequency. Based on the small number of large published pedigrees per gene (n < 3), MODY-associated variants showed only modest cosegregation in these genes. Crucially, ultra-rare (minor allele frequency <1:10,000) protein-truncating and predicted-damaging missense variants in APPL1 and WFS1 were not enriched in a MODY cohort (n = 2,571) compared with population control individuals (n = 155,501; all P > 0.05). In contrast, variants in NEUROD1 and PDX1 were enriched, albeit at levels comparable to RFX6. Multiple sensitivity analyses corroborated these findings. In summary, rare heterozygous variants in NEUROD1 and PDX1 are low-penetrance causes of MODY, while those in APPL1 and WFS1 lack robust genetic evidence for causality and should not be included in MODY testing panels.
Testing genes with limited evidence of causality risks misdiagnosis of maturity-onset diabetes of the young (MODY). There is limited evidence as to whether rare variants in PDX1, NEUROD1, APPL1, and WFS1 cause MODY. Rare damaging variants in APPL1 and WFS1 are not enriched in a MODY cohort, but those in PDX1 and NEUROD1 are, at a level similar to low-penetrance MODY genes. PDX1 and NEUROD1 should be included in MODY gene panels, while heterozygous APPL1 and WFS1 variants should not be reported as causes of MODY.
对青年发病的成年型糖尿病（MODY）进行准确的基因诊断对于个性化治疗至关重要。为避免误诊，仅应对有确凿因果关系证据的基因进行检测。NEUROD1、PDX1、APPL1和WFS1中的杂合变异已被认为与MODY有关，但缺乏支持因果关系的有力基因证据。因此，我们评估了它们现有的基因证据，并在一个大型MODY队列中进行了基因水平的负担测试，同时将两个已确定的MODY基因作为阳性对照（HNF1A——高外显率，RFX6——低外显率）。首次报道的NEUROD1、PDX1、APPL1和WFS1中与MODY相关的变异频率<1:20,000。基于每个基因已发表的大型家系数量较少（n<3），与MODY相关的变异在这些基因中仅显示出适度的共分离。至关重要的是，与人群对照个体（n = 155,501；所有P>0.05）相比，APPL1和WFS1中极罕见（次要等位基因频率<1:10,000）的蛋白质截短和预测有害的错义变异在MODY队列（n = 2,571）中未富集。相比之下，NEUROD1和PDX1中的变异是富集的，尽管其水平与RFX6相当。多项敏感性分析证实了这些发现。总之，NEUROD1和PDX1中的罕见杂合变异是MODY的低外显率病因，而APPL1和WFS1中的变异缺乏因果关系的有力基因证据，不应纳入MODY检测面板。
检测因果关系证据有限的基因有导致青年发病的成年型糖尿病（MODY）误诊的风险。关于PDX1、NEUROD1、APPL1和WFS1中的罕见变异是否导致MODY，证据有限。APPL1和WFS1中的罕见有害变异在MODY队列中未富集，但PDX1和NEUROD1中的变异是富集的，其水平与低外显率MODY基因相似。PDX1和NEUROD1应纳入MODY基因检测面板，而杂合的APPL1和WFS1变异不应报告为MODY的病因。
