Extended Data Fig. 8: Additional transcription factor motifs disrupted by variants.

a, b) Sanger sequencing identified 2 in cis de novo variants 12 base pairs apart (g.71,108,648 C > G and g.71,108,660 G > A) in patient 11. g.71,108,648 is affected by 3 different de novo substitutions in 6 individuals and resides within a predicted NFATC binding motif. Two further de novo variants identified in 3 patients are also predicted to impact on NFATC binding (Fig. 3). In contrast, further variants affecting g.71,108,660 have not been identified, this suggests that the g.71,108,648 C > G is causative of the disease in this patient. Nevertheless, it is of note that g.71,108,660 G > A is predicted to affect a HIC family motif a) and human islet scRNA-seq (GSE101207)³⁰ determines HIC2 is expressed in beta-cells b) Interestingly, HIC2 is a transactivator of SIRT1⁴⁷ and the loss of SIRT1 impairs glucose sensing in beta-cells in mice⁴⁸. c-e) Tier 2, secondary candidate motifs for disruption have lower normalised motif scores than Tier 1 matches. c) Two additional motif families are implicated TEAD and SMAD. TEAD shares partial consensus with NFAT (TTCCA) and is alternative candidate to NFAT. TEAD1 but not TEAD2 is expressed in beta-cells e) and TEAD1 plays a critical role in pancreatic progenitors²², however it should be noted that TEAD1 does not bind the critical region in pancreatic progenitors when the region is bound by FOXA2 (Fig. 3b). The SMAD family are signal transducers of TGF-beta signalling and play an important role in beta-cell development, function, and proliferation⁴⁹. For all boxplots, in panels (b, d, e), central line denotes median, box limit the interquartile range, and whiskers extend to furthest point within 1.5 interquartile range.