Exome sequencing in children with clinically suspected maturity-onset diabetes of the young.

Objective Commercial gene panels identify pathogenic variants in as low as 27% of patients suspected to have MODY, suggesting the role of yet unidentified pathogenic variants. We sought to identify novel gene variants associated with MODY. Research design and methods We recruited 10 children with a clinical suspicion of MODY but non-diagnostic commercial MODY gene panels. We performed exome sequencing (ES) in them and their parents. Results Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non-Hispanic white, 5 Hispanic, and 1 Asian. Our variant prioritization analysis identified a pathogenic, de novo variant in INS (c.94G > A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with "autoantibody-negative type 1 diabetes (T1D)" at 3 y/o. This rare variant, absent in the general population (gnomAD database), has been reported previously in neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 in a child with a previous diagnosis of "autoantibody-negative T1D" at 12 y/o. The variant was inherited from the mother, who was diagnosed with "thin type 2 diabetes" at 25 y/o. Heterozygous protein-truncating variants in RFX6 gene have been recently reported in individuals with MODY. Conclusions We diagnosed two patients with MODY using ES in children initially classified as "T1D". One has a likely pathogenic novel gene variant not previously associated with MODY. We demonstrate the clinical utility of ES in patients with clinical suspicion of MODY.