NEUROD1 and PDX1 are low penetrance causes of MODY while rare variants in APPL1 and WFS1 are not associated with MODY

An accurate genetic diagnosis of Maturity-Onset Diabetes of the Young (MODY) is critical for personalised 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 the 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 (n<3), MODY-associated variants showed only modest co-segregation in these genes. Crucially, ultra-rare (MAF<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 to population controls (n=155,501; all p>0.06). 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.