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. Article highlightsO_LIWhy did we undertake this study? Testing genes with limited evidence of causality risks misdiagnosis of MODY. C_LIO_LIWhat is the specific question(s) we wanted to answer? Do rare variants in PDX1, NEUROD1, APPL1, and WFS1 cause MODY? C_LIO_LIWhat did we find? 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. C_LIO_LIWhat are the implications of our findings? PDX1 and NEUROD1 should be included in MODY gene panels, while heterozygous APPL1 and WFS1 variants should not be reported as causes of MODY. C_LI